BLOOD-BRAIN BARRIER-PENETRANT DOPAMINE-ß-HYDROXYLASE INHIBITORS

Abstract

This invention relates to: (a) compounds of formula I (with R 1 to R 5 , n and A as defined herein) and pharmaceutically acceptable salts or solvates thereof that are useful as dopamine-β-hydroxylase inhibitors; (b) pharmaceutical compositions comprising such compounds, salts or solvates; (c) the use of such compounds, salts or solvates in therapy; (d) therapeutic methods of treatment using such compounds, salts or solvates; and (e) processes and intermediates useful for the synthesis of such compounds.

1 . A pharmaceutical composition comprising (i) a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
       
       and (ii) a pharmaceutically acceptable excipient, wherein:
 R 1  is hydrogen, C 1 -C 6  alkyl, partially or fully deuterated C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 2 -C 6  cyanoalkyl, C 1 -C 6  mercaptoalkyl or amino; 
 R 2  is hydrogen or C 1 -C 3  alkyl; 
 R 3  is hydrogen or oxo; 
 or R 2  and R 3  combine to form a structure of formula Ia: 
 
       
         
           
           
               
               
           
         
       
       wherein:
 X is CH 2 , CR 6  or N; 
    is a double bond when X is CR 6  or N and is a single bond when X is CH 2 ; 
 R 4  is hydrogen or C 1 -C 3  alkyl; 
 R 5  is hydrogen or C 1 -C 2  alkyl; 
 or R 4  and R 5  combine, together with the carbon atom to which they are attached, to form a cyclopropyl ring wherein the CH 2  moiety is optionally substituted with two deuterium atoms; 
 R 6  is hydrogen; 
 A is C 5 -C 7  cycloalkyl, furanyl, thiophenyl, methylthiophenyl or 
 
       
         
           
           
               
               
           
         
       
       wherein:
 X 1  is hydrogen, halo or methyl; 
 X 1 ′ is hydrogen or halo; 
 X 2  is hydrogen, halo or methyl; 
 X 2 ′ is hydrogen or halo; 
 X 3  is hydrogen or fluoro; 
 n is 0 or 1, and when n is 0 a single or double bond joins the carbon atoms to which R 3  and R 4  are attached. 
 
     
     
         2 . A compound of formula I, or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is hydrogen, C 1 -C 6  alkyl, partially or fully deuterated C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 2 -C 6  cyanoalkyl, C 1 -C 6  mercaptoalkyl or amino; 
 R 2  is hydrogen or C 1 -C 3  alkyl; 
 R 3  is hydrogen or oxo; 
 or R 2  and R 3  combine to form a structure of formula Ia: 
 
       
         
           
           
               
               
           
         
       
       wherein:
 X is CH 2 , CR 6  or N; 
    is a double bond when X is CR 6  or N and is a single bond when X is CH 2 ; 
 R 4  is hydrogen or C 1 -C 3  alkyl; 
 R 5  is hydrogen or C 1 -C 2  alkyl; 
 or R 4  and R 5  combine, together with the carbon atom to which they are attached, to form a cyclopropyl ring wherein the CH 2  moiety is optionally substituted with two deuterium atoms; 
 R 6  is hydrogen; 
 A is C 5 -C 7  cycloalkyl, furanyl, thiophenyl, methylthiophenyl or 
 
       
         
           
           
               
               
           
         
       
       wherein:
 X 1  is hydrogen, halo or methyl; 
 X 1 ′ is hydrogen or halo; 
 X 2  is hydrogen, halo or methyl; 
 X 2 ′ is hydrogen or halo; 
 X 3  is hydrogen or fluoro; 
 n is 0 or 1, and when n is 0 a single or double bond joins the carbon atoms to which R 3  and R 4  are attached 
 with the proviso that the following compounds are excluded: 
 
       
         
           
           
               
               
           
         
       
     
     
         3 . A pharmaceutical composition according to  claim 1 , wherein:
 R 2  is hydrogen or C 1 -C 3  alkyl; and   R 3  is hydrogen or oxo.   
     
     
         4 . A pharmaceutical composition according to  claim 1 , wherein:
 R 2  and R 3  combine to form a structure of formula Ia:   
       
         
           
           
               
               
           
         
       
       wherein:
 X is CH 2 , CR 6  or N; 
    is a double bond when X is CR 6  or N and is a single bond when X is CH 2 . 
 
     
     
         5 . A pharmaceutical composition according to  claim 4 , wherein   is a double bond and X is CR 6 . 
     
     
         6 . A pharmaceutical composition according to  claim 1 , wherein n is 0 and a single bond joins the carbon atoms to which R 3  and R 4  are attached. 
     
     
         7 . A pharmaceutical composition according to  claim 1 , wherein R 4  and R 5  combine, together with the carbon atom to which they are attached, to form a cyclopropyl ring wherein the CH 2  moiety is optionally substituted with two deuterium atoms. 
     
     
         8 . A pharmaceutical composition according to  claim 1 , wherein more than 50% of substituents R 5  and A have the stereochemical configuration of formula Id 
       
         
           
           
               
               
           
         
       
     
     
         9 . A pharmaceutical composition according to  claim 1 , wherein more than 50% of substituents R 5  and A have the stereochemical configuration of formula Ie 
       
         
           
           
               
               
           
         
       
     
     
         10 . A pharmaceutical composition according to  claim 1 , wherein A is 
       
         
           
           
               
               
           
         
       
       wherein X 1 , X 1 ′, X 2 , X 2 ′ and X 3  are as defined in  claim 1 . 
     
     
         11 . A pharmaceutical composition according to  claim 1 , wherein R 1  is hydrogen, methyl, d3-methyl, propyl, cyclopropyl, cyanomethyl, mercaptoethyl or amino. 
     
     
         12 . A pharmaceutical composition according to  claim 3 , wherein R 2  is hydrogen or methyl. 
     
     
         13 . A pharmaceutical composition according to  claim 3 , wherein R 3  is hydrogen. 
     
     
         14 . A pharmaceutical composition according to  claim 1 , wherein R 4  is hydrogen or methyl. 
     
     
         15 . A pharmaceutical composition according to  claim 1 , wherein R 5  is hydrogen or methyl. 
     
     
         16 . A pharmaceutical composition according to  claim 1 , wherein A is 
       
         
           
           
               
               
           
         
       
       wherein:
 X 1  is hydrogen, fluoro, chloro or methyl; 
 X 1 ′ is hydrogen, fluoro or chloro; 
 X 2  is hydrogen, fluoro, chloro, bromo or methyl; 
 X 2 ′ is hydrogen, fluoro, chloro or bromo; 
 X 3  is hydrogen or fluoro. 
 
     
     
         17 - 18 . (canceled) 
     
     
         19 . A method for treating or preventing conditions ameliorated by inhibition of dopamine-beta-hydroxylase within the central nervous system comprising administering a therapeutically effective amount of a compound of formula I, as defined in  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof. 
     
     
         20 . A pharmaceutical composition comprising (i) a therapeutically effective amount of a compound of formula I, as defined in  claim 2 , or a pharmaceutically acceptable salt or solvate thereof; and (ii) a pharmaceutically acceptable excipient.