N- and O-Substituted 4-[2-(Diphenylmethoxy)-Ethyl]-1-[(Phenyl)Methyl]Piperdine Analogs and Methods of Treating CNS Disorders Therewith

Abstract

N- and O-substituted 4[2-diaromaticmethoxy and methylamino)alkyl]piperidines exhibit high CNS activity with respect to the dopamine transporter (DAT) and serotonin transporter (SERT). Preferred compounds exhibit highly differential behavior as between the DAT and SERT and between the DAT and the norepinephrine transporter (NET). The compounds have utility in treating CNS disorders, including but not limited to cocaine addiction, depression, and Parkinson's disease.

1 .- 31 . (canceled) 
   
   
       32 . Compounds exhibiting CNS activity in mammalian species, said compounds having the formulae: 
     
       
         
         
             
             
         
       
       wherein A in formulae (III) is 
     
     
       
         
         
             
             
         
       
     
     and A in formula II is 
     
       
         
         
             
             
         
       
       B is 
     
     
       
         
         
             
             
         
       
       X is selected from the group consisting of N, —NH—, —NR 4 —, —O—, and —S—; 
       R 4  is C 1-4  alkyl, NH 2 , C 1-4  hydroxyalkyl, halogenated C 1-4  alkyl, C 2-4  alkenyl, C 2-4  hydroxyalkenyl, halogenated C 2-4  alkenyl, C 2-4  and alkynyl, and C 2-4  halogenated alkynyl; 
       Y is —NH 2 , —OH, ═O, or —O—C(O)—R 5 ; 
       l is 0, 1, or 2; 
       n is 1 or 2; 
       m is 1 or 2; 
       o is 0, 1, 2, 3, or 4; 
       p is 0, 1, 2, 3, or 4; 
       q is 0, 1, 2, or 3; 
       r is an integer from 0 to 5 
       R, R 1 , and R 2  are selected from the group consisting of H, F, Cl, Br, I, CN, COOEt, OH, NO 2 , NH 2 , OR 5 , wherein R 5  is C 1-8  alkyl, C 5-6  cycloalkyl, or C 2-8  alkenyl or R 2  is a 5 or 6 membered heterocycle, 
     
     
       
         
         
             
             
         
       
     
     and where any carbon of (CH 2 ) m  may be substituted 
     by OR 7  where R 7  is C 1-18  alkyl or C 2-18  alkylene, or 
     
       
         
         
             
             
         
       
     
     where R 8  is C 1-18  alkyl or C 2-18  alkylene, 
     or a pharmaceutically acceptable salt or derivative thereof, 
     and wherein in formula (III), A may also be COOCH 3 , ═O, CH 3 , F, or OH;
 Z is H or C 1-4  alkylene, the C 1-4  alkylene groups when present forming a ring structure with X when X is N, and where B may also be H, CH 3 , or —CH═CH 2 . 
 
   
   
       33 . A compound of  claim 32 , wherein
 l=0,   n=2.   
   
   
       34 . A compound of  claim 32 , wherein
 l=0,   n=2,   m=1.   
   
   
       35 . A compound of  claim 32 , wherein
 X is —NH— or —O—.   
   
   
       36 . A compound of  claim 35 , wherein
 l=0,   n=2,   m=1, and   p=1.   
   
   
       37 . A compound exhibiting CNS activity in mammalian species, having the formula: 
     
       
         
         
             
             
         
       
       wherein A is 
     
     
       
         
         
             
             
         
       
     
     and where X is selected from the group consisting of —NH—, —NR 4 —, and —O—;
 R 4  is C 1-4  alkyl, NH 2 , C 1-4  hydroxyalkyl, halogenated C 1-4  alkyl, C 2-4  alkenyl, C 2-4  hydroxyalkenyl, halogenated C 2-4  alkenyl, C 2-4  and alkynyl, and C 2-4  halogenated alkynyl; 
 Y is —OH, OR 9 , NH 2 , or NHR 9  wherein R 9  is wherein R 10  is C 6-20  alkyl, 
 
     
       
         
         
             
             
         
       
     
     o is 0, 1, 2, 3, or 4;
 R, R 1  and R 2  are selected from the group consisting of H, F, Cl, Br, I, CN, COOEt, OH, NO 2 , NH 2 , OR 5 ; 
 wherein R 5  is C 1-8  alkyl, C 5-6  cycloalkyl, or C 2-8  alkenyl or R 2  is a 5 or 6 membered heterocycle; 
 p is individually 0, 1, or 2, 
 q is 0, 1, 2, or 3 
 
     wherein at least one R 2  is an electron withdrawing group, and pharmaceutically acceptable salts and derivatives thereof. 
   
   
       38 . The compound of  claim 32  having the structure: 
     
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable salts and derivatives thereof. 
   
   
       39 . The compound of  claim 32  having the structure: 
     
       
         
         
             
             
         
       
       wherein A is 
     
     
       
         
         
             
             
         
       
     
     and where X is selected from the group consisting of —NH—, —NR 4 —, and —O—;
 R 4  is C 1-4  alkyl, NH 2 , C 1-4  hydroxyalkyl, halogenated C 1-4  alkyl, C 2-4  alkenyl, C 2-4  hydroxyalkenyl, halogenated C 2-4  alkenyl, C 2-4  and alkynyl, and C 2-4  halogenated alkynyl; 
 Y is —H, —NH 2 , —OH, ═O, or —O—C(O)—R 5 ; 
 wherein R 5  is C 1-8  alkyl, C 5-6  cycloalkyl, or C 2-8  alkenyl or R 5  is a 5 or 6 membered heterocycle; 
 m is 1 or 2; 
 p is 0, 1, 2, 3, or 4; 
 R 1  is selected from the group consisting of H, F, Cl, Br, I, CN, COOEt, OH, NO 2 , NH 2 , OR 5 , 
 
     wherein R 5  is C 1-8  alkyl, C 5-6  cycloalkyl, or C 2-8  alkenyl or R 2  is a 5 or 6 membered heterocycle, 
     and where any carbon of CH 2  m  may be substituted 
     by OR 7  where R 7  is C 1-18  alkyl or C 2-18  alkylene, or 
     
       
         
         
             
             
         
       
     
     where R 8  is C 1-18  alkyl or C 2-18  alkylene, 
     or a pharmaceutically acceptable salt or derivative thereof.