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

Abstract

Method of treatment of neurological disorders or complications due to stroke or head injury through the administration of a pharmaceutical composition including a pharmaceutically acceptable excipient or carrier and a compound of formula I are provided:

1 . A method of treating neurological disorders comprising administering to a subject in need thereof a composition comprising a pharmaceutically acceptable excipient or carrier and a compound of the formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2  are different, independent groups and are selected from the group consisting of OR 3  and N(R 3′ )(R 3″ ); or 
 R 1  and R 2  are different, are connected through a single bond, and are selected from the group consisting of O and NR 3 ; 
 R 3 , R 3′ , and R 3″  are independently selected from the group consisting of H, C 1  to C 6  alkyl, C 1  to C 6  substituted alkyl, C 3  to C 8  cycloalkyl, substituted C 3  to C 8  cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; 
 R 4  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 single bond and are CH 2 ; 
 R 15  is selected from the group consisting of C═O, CHOH, and CH 2 ; 
 n is 1 or 2; or 
 a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . The method according to  claim 1 , wherein said neurological disorder is selected from Alzheimer's disease; epilepsy; Huntington's Disease; Parkinson's Disease; stroke; spinal cord injury; traumatic brain injury; Lewy body dementia; 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; amyotrophic lateral sclerosis (ALS); multiple sclerosis; Duchenne dystrophy; Becker muscular dystrophy; Facioscapulohumeral (Landouzy-Dejerine) muscular dystrophy; and limb-girdle muscular dystrophy (LGMD). 
     
     
         3 . A method according to  claim 2  wherein the disorder is stroke. 
     
     
         4 . A method of treating complications due to stroke or head trauma comprising administering to a subject in need thereof a composition according to  claim 1 .