Tetrahydroprotoberbine compounds and uses thereof in the treatment of neurological, psychiatric and neurodegenerative diseases

Abstract

Tetrahydroprotoberbine (THPB) compounds and their use in the treatment of neurological, psychiatric and neurodegenerative diseases is provided. The compounds include d-govadine, l-govadine and racemic govadine, as well as d-THPBs of general formula (I). Enantioselective processes for preparing compounds of formula (I), and d- and l-govadine are also provided.

1 . A method of treating a cognitive disorder comprising administering to a subject in need thereof an effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:
 R1 and R2 are independently H, alkyl, benzyl or —COR9; or R1 and R2 together form (CH 2 ) m ; 
 R4 is H, alkyl, benzyl or —COR9; 
 R3 is H or OR10, wherein R10 is H, alkyl, benzyl or —COR9, or R10 taken together with R4 forms (CH 2 ) m ; 
 R5 is H or OR11, wherein R11 is H, alkyl, benzyl or —COR9 or R11 taken together with R4 forms (CH 2 ) m ; 
 R6 is H or halogen; 
 R9 is H or alkyl; 
 m is 1 or 2, and 
 
         wherein when R10 taken together with R4 forms (CH 2 ) m , then R5 is H or OR11, wherein R11 is H, alkyl, benzyl or —COR9, and 
         wherein when R11 taken together with R4 forms (CH 2 ) m , then R3 is H or OR11, wherein R11 is H, alkyl, benzyl or —COR9, and 
         wherein at least one of R3 and R5 is other than H. 
       
     
     
         2 . The method according to  claim 1 , wherein the cognitive disorder is autism, dyslexia, attention deficit hyperactivity disorder (ADHD), anxiety, schizophrenia, obsessive compulsive disorders, psychosis, bipolar disorders, Tourette's syndrome, mild cognitive impairment (MCI) and disorders of learning in children, adolescents and adults, Age Associated Memory Impairment, Age Associated Cognitive Decline, Down's Syndrome, dementia related to Parkinson's disease, cognitive impairment associated with schizophrenia, attention deficit hyperactivity disorder 9ADHD), a sleep disorder, dementia or mild cognitive impairment. 
     
     
         3 . The method according to  claim 1 , wherein the compound is administered in conjunction with one or more other therapeutic agents. 
     
     
         4 . The method according to  claim 1 , wherein R3 is H and R5 is OR11. 
     
     
         5 . The method according to  claim 1 , wherein R5 is H and R3 is OR10. 
     
     
         6 . The method according to  claim 1 , wherein
 R1 and R2 are independently H or alkyl, or R1 and R2 together form (CH 2 ) m ;   R5 is H or O-alkyl;   R6 is H or halogen;   R7 is H;   R8 is H or alkyl; and   either R3 is H or O-alkyl, and R4 is H, or   R3 is OR10 and R10 and R4 together form (CH 2 ) m .   
     
     
         7 . The method according to  claim 1 , wherein
 R1 and R2 are independently H or alkyl, or R1 and R2 together form (CH 2 ) m ;   R3 is H or O-alkyl;   R6 is H or halogen;   R7 is H;   R8 is H or alkyl; and   either R4 is H, and R5 is H or O-alkyl, or   R5 is OR11 and R11 and R4 together form (CH 2 ) m .   
     
     
         8 . The method according to  claim 1 , wherein
 R1 and R2 are independently H or alkyl;   R3 and R5 are independently H or O-alkyl;   R4 and R7 are H;   R6 is H or halogen; and   R8 is H or alkyl.   
     
     
         9 . The method according to  claim 1 , wherein
 R1 and R2 are independently H or alkyl;   R3 and R5 are independently H or O-alkyl;   R4, R6 and R7 are H; and   R8 is H or alkyl.   
     
     
         10 . The method according to  claim 1 , wherein each alkyl is a C 1 -C 4  alkyl. 
     
     
         11 . The method according to  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         12 . The method according to  claim 1 , wherein the compound is administered in conjunction with one or more other therapeutic agents. 
     
     
         13 . The method according to  claim 1 , wherein administration involves an effective amount of enantiomerically pure d-govadine derived from a process comprising the steps:
 (a) performing a coupling reaction between compounds (XVI) and (XVII) to provide amide (XVIII);   (b) performing a Bischler-Napieralski reaction on the amide (XVIII) to provide dihydroisoquinoline intermediate (XIX);   (c) reducing the dihydroisoquinoline intermediate (XIX) with a chiral catalyst to provide compound (XIV) or (XV);   (d) performing a Mannich-type cyclization on compound (XIV) or (XV) to obtain d- or l-govadine,   
       wherein the synthesis route is as follows: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and wherein X is Cl or OH, and R12 is a protecting group, 
         or wherein X is OH, and the coupling reaction is a thermal coupling reaction in the presence or absence of solvent; wherein the Bischler-Napieralski reaction uses POCl 3 ; wherein the chiral catalyst is Noyori's catalyst; wherein the Mannich-type cyclization is a Pictet-Spengler cyclization and wherein the synthesis route is as follows: 
       
       
         
           
           
               
               
           
         
       
     
     
         14 . The method according to  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         15 . A method of treating a neurological, psychiatric of neurodegenerative disease comprising administering to a subject in need thereof an effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate or prodrug thereof, 
         wherein:
 R1 and R2 are independently H, alkyl, benzyl or —COR9; or R1 and R2 together form (CH 2 ) m ; 
 R4 is H, alkyl, benzyl, or —COR9; 
 R3 is H or OR10, wherein R10 is H, alkyl, benzyl or —COR9, or R10 taken together with R4 forms (CH 2 ) m ; 
 R5 is H or OR11, wherein R11 is H, alkyl, benzyl or —COR9, or R11 taken together with R4 forms (CH 2 ) m ; 
 R6 is H or halogen; 
 R9 is H or alkyl; 
 m is 1 or 2, and 
 
         wherein when R10 taken together with R4 forms (CH 2 ) m , then R5 is H or OR11, wherein R11 is H, alkyl, benzyl or —COR9, and 
         wherein when R11 taken together with R4 forms (CH 2 ) m , then R3 is H or OR11, wherein R11 is H, alkyl, benzyl or —COR9, and 
         wherein at least one of R3 and R5 is other than H. 
       
     
     
         16 . A compound having the structure: 
       
         
           
           
               
               
           
         
         or a prodrug, derivative, salt, ester or solvate thereof.