Compositions and methods for treating beta-amyloid related diseases

Abstract

In alternative embodiments the invention provides compositions and methods for ameliorating diseases and conditions having a beta-amyloid component, including Alzheimer's disease (AD), Vascular Dementia (VD), dementia, pre-dementia, Cognitive Dysfunction Syndrome (CDS) and loss of cognition in humans and in non-human animal. In alternative embodiment the invention provides analogs of AB-007 and its acid form E64c (loxistatin), their preparation, and pharmaceutical compositions thereof and methods of making and using same. In alternative embodiments compositions of the invention are deuterated analogs of AB-007 (or E64d) and E64c (or loxistatin). In alternative embodiments compositions of the invention are metabolically blocked forms as compared to AB-007 and loxistatin. In alternative embodiments compositions of the invention are used to ameliorate (including treat, slow, reverse or prevent) a disease or condition which can be ameliorated by partial or complete inhibition of a cysteine protease, e.g., AD, VD, CDS. The invention also provides alternative dosage forms and formulations for AB-007 and loxistatin, and for compounds of this invention, which can be used e.g., to treat AD, VD and CDS, in humans and in non-human animals.

1 - 29 . (canceled) 
     
     
         30 . A method of treating traumatic brain injury, posttraumatic stress disorder, traumatic war neurosis, and/or posttramatic stress syndrome comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein
 R is —H or alkyl; 
 each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10  is independently selected from the group consisting of —H, -D, —F, —OH, and —CH 3 ; 
 
       or a pharmaceutically acceptable salt or solvate thereof; with the proviso that at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10  is not —H. 
     
     
         31 . The method of claim  1  wherein the compound has the stereochemistry of Formula I′: 
       
         
           
           
               
               
           
         
       
     
     
         32 . The method of claim  1  or claim  2 , wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10  is independently selected from the group consisting of —H and -D. 
     
     
         33 . The method of claims  1  to  3  wherein each of R 1 , R 2 , R 3 , R 4 , and R 5 , is —H and each of R 6 , R 7 , R 8 , R 9 , and R 10  is independently selected from the group consisting of —H and -D. 
     
     
         34 . The method of claims  1  to  4  wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , and R 10  is —H and each of R 6 , R 7 , R 8 , and R 9  is independently selected from the group consisting of —H and -D. 
     
     
         35 . The method of claims  1  to  5  wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10  is independently selected from the group consisting of —H and —F. 
     
     
         36 . The method of claim  6  wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , and R 10  is —H and each of R 6 , R 7 , R 8 , and R 9  is independently selected from the group consisting of —H and —F. 
     
     
         37 . The method of claims  1  to  7  wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10  is independently selected from the group consisting of —H and —OH. 
     
     
         38 . The method claim  10  wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , and R 10  is —H and each of R 6 , R 7 , R 8 , and R 9  is independently selected from the group consisting of —H and —OH. 
     
     
         39 . The method of claims  1  to  7  wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10  is independently selected from the group consisting of —H and —CH 3 . 
     
     
         40 . The method of claim  10  wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , and R 10  is —H and each of R 6 , R 7 , R 8 , and R 9  is independently selected from the group consisting of —H and —CH 3 . 
     
     
         41 . A method of treating traumatic brain injury, posttraumatic stress disorder, traumatic war neurosis, and/or posttraumatic stress syndrome comprising administering to a patient in need thereof a therapeutically effective amount of a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salts, hydrates, stereoisomers or solvates thereof. 
     
     
         42 . A method of treating traumatic brain injury, posttraumatic stress disorder, traumatic war neurosis, and/or posttramatic stress syndrome comprising administering to a patient in need thereof a therapeutically effective amount of a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, stereoisomer or solvate thereof. 
     
     
         43 . The method of claim  1  or claim  2  wherein traumatic brain injury is treated. 
     
     
         44 . The method of claim  12  wherein traumatic brain injury is treated. 
     
     
         45 . The method of claim  13  wherein traumatic brain injury is treated.