Rapamycin Derivatives and the Uses Thereof in the Treatment of Neurological Disorders

Abstract

Provided is a method of treating neurodegenerative disorders comprising administering to a subject in need thereof a compound of formula I:

1 . A method of treating neurodegenerative disorders comprising administering to a subject in need thereof a compound of formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2  are the same or different and are selected from the group consisting of CR 16 R 17  and CR 18 R 19 ; 
 R 3  and R 4  are:
 (a) independently selected from the group consisting of H, OH, O(C 1  to C 6  alkyl), O(substituted C 1  to C 6  alkyl), O(acyl), O(aryl), O(substituted aryl), and halogen; or 
 (b) taken together to form a double bond to O; 
 
 R 5 , R 6 , and R 7  are independently selected from the group consisting of H, OH, and OCH 3 ; 
 R 8  and R 9  are connected through a (i) single bond and are CH 2  or (ii) double bond and are CH; 
 R 15  is selected from the group consisting of C═O, CHOH, and CH 2 ; 
 R 16  and R 17  are independently selected from the group consisting of H, C 1  to C 6  alkyl, C 1  to C 6  substituted alkyl, aryl, substituted aryl, acyl, CF 3 , CN, and NO 2 ; 
 R 18  and R 19  are independently selected from the group consisting of H, C 1  to C 6  alkyl, C 1  to C 6  substituted alkyl, aryl, substituted aryl, acyl, CF 3 , CN, and NO 2 ; or 
 R 17  and R 18  are taken together to form a carbon-based or heterocyclic 5- to 7-membered ring; 
 n is 1 or 2; or 
 a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . A method of treating neurodegenerative disorders comprising administering to a subject in need thereof a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2  are the same or different and are selected from the group consisting of CR 16 R 17  and CR 18 R 19 ; 
 R 3  and R 4  are:
 (a) independently selected from the group consisting of H, OH, O(C 1  to C 6  alkyl), O(substituted C 1  to C 6  alkyl), O(acyl), O(aryl), O(substituted aryl), and halogen; or 
 (b) taken together to form a double bond to O; 
 
 R 5 , R 6 , and R 7  are independently selected from the group consisting of H, OH, and OCH 3 ; 
 R 8  and R 9  are connected through a (i) single bond and are CH 2  or (ii) double bond and are CH; 
 R 15  is selected from the group consisting of C═O, CHOH, and CH 2 ; 
 R 16  and R 17  are independently selected from the group consisting of H, C 1  to C 6  alkyl, C 1  to C 6  substituted alkyl, aryl, substituted aryl, acyl, CF 3 , CN, and NO 2 ; 
 R 18  and R 19  are independently selected from the group consisting of H, C 1  to C 6  alkyl, C 1  to C 6  substituted alkyl, aryl, substituted aryl, acyl, CF 3 , CN, and NO 2 ; or 
 R 17  and R 18  are taken together to form a carbon-based or heterocyclic 5- to 7-membered ring; 
 n is 1 or 2; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The method according to  claim 1  or  2 , wherein said neurodegenerative disorder is selected from Alzheimer's disease, amyotrophic lateral sclerosis, epilepsy, Huntington's Disease, Parkinson's Disease, stroke, spinal cord injury, traumatic brain injury, head trauma, Lewy body dementia, multiple sclerosis, Pick's disease, Niewmann-Pick disease, amyloid angiopathy, cerebral amyloid angiopathy, systemic amyloidosis, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, inclusion body myositis, mild cognitive impairment, Down's syndrome, complications due to stroke and complications due to head trauma 
     
     
         4 . A method of treatment according to  claim 3  wherein the neurodegenerative disorder is complications due to stroke or head trauma.