Phenyl substituted cycloalkylamines as monoamine reputake inhibitors

Abstract

Phenyl-substituted cyclohexylamine derivatives and methods for their synthesis and characterization are disclosed. Use of these compounds to treat/prevent neurological disorders as well as methods for their synthesis are set forth herein. Exemplary compounds of the invention inhibit reuptake of endogenous monoamines, such as dopamine, serotonin and norepinephrine (e.g., from the synaptic cleft) and modulate one or more monoamine transporter. Pharmaceutical formulations incorporating compounds of the invention are also provided.

What is claimed is: 
     
         1 . A compound having a structure which is a member selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein
 n is an integer selected from the group consisting of 0 to 2; 
 s is an integer selected from the group consisting of 0 to 2; 
 A is a member selected from the group consisting of H, substituted or unsubstituted alkyl, halogen and substituted or unsubstituted haloalkyl; 
 X is a member selected from the group consisting of H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted haloalkyl and OR 5    
 wherein 'R 5  is a member selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl substituted or unsubstituted heteroaryl, acyl and S(O) 2 R 5a ,
 wherein
 R 5a  is a member selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl; 
 
 
 Y and Z are members independently selected from the group consisting of halogen, CF 3 , CN, OR 9 , SR 9 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, NR 10 R 11  and NO 2 . 
 wherein Y and Z, together with the atoms to which they are attached, are optionally joined to form a 5- to 7-membered ring, optionally including from 1 to 3 heteroatoms, 
 wherein
 R 9  is a member selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocylcoalkyl; and 
 R 10  and R 11  are members independently selected from the group consisting of H, OR 12 , acyl, S(O) 2 R 13 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, 
 wherein
 R 12  is a member selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl; and 
 R 13  is a member selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, 
 
 wherein R 10  and R 11 , together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring, optionally including from 1 to 3 heteroatoms; 
 
 R 1  and R 2  are members independently selected from the group consisting of H, halogen, CN, CF 3 , OR 6 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, 
 wherein
 R 6  is a member selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl; and 
 
 R 3  and R 4  are members independently selected from the group consisting of H, OR 7 , acyl, S(O) 2 R 8  substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, 
 wherein
 R 7  is a member selected front the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl; 
 R 8  is a member selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl; and 
 
 wherein at least two of R 1 , R 2 , R 3  and R 4 , together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring, optionally including from 1 to 3 heteroatoms. 
 
       
     
     
         2 . The compound of  claim 1 , wherein R 3  and R 4  are members independently selected front the group consisting of substituted or unsubstituted C 1 -C 4  alkyl and substituted or unsubstituted C 1 -C 4  heteroalkyl. 
     
     
         3 . The compound of  claim 1 , wherein R 3  and R 4  are members independently selected from the group consisting of substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl and substituted or unsubstituted cycloalkyl. 
     
     
         4 . The compound of  claim 1 , having a structure which is a member selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein A is H. 
       
     
     
         5 . The compound of  claim 4 , having a structure which is a member selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 4 , wherein Y and X are members independently selected from the group consisting of H, halogen, CN and CF 3 . 
     
     
         7 . The compound of  claim 6 , wherein Y and X are chloro. 
     
     
         8 . The compound of  claim 7 , wherein s is 1. 
     
     
         9 . The compound of  claim 8 , wherein n is 1. 
     
     
         10 . The compound of  claim 9 , having a structure which is a member selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein R 4  is a member selected from the group consisting of H and CH 3 . 
       
     
     
         11 . The compound of  claim 4 , having a structure which is a member selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein
 A 1 , A 2 , A 3  and A 4  are each independently selected from the group consisting of O, S, N(R b ) b , and C(R b ) b (R c ); 
 a is an integer selected from the group consisting of 0 to 2; 
 b is an integer selected from the group consisting of 0 to 1; 
 R b  and R c  are members independently selected from the group consisting of H, halogen, CF 3 , CN, OR 14 , SR 14 , NR 15 R 16 , NR 15 S(O) 2 R 14 , NR 15 C(O)R 14 , S(O) 2 R 14 , acyl, C(O)OR 14 , C(O)NR 15 R 16 , S(O) 2 NR 15 R 16 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl; 
 each R 14 , R 15  and R 16  is a member independently selected from the group consisting of H, acyl, substituted, or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, wherein two of R 14 , R 15  and R 16 , together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring, which optionally includes from 1 to 3 heteroatoms. 
 
       
     
     
         12 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, vehicle or diluent. 
     
     
         13 . A method for treating or preventing a neurological disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         14 . The method of  claim 13 , wherein said neurological disorder is a member selected from the group consisting of substance abuse, fibromyalgia, pain, sleep disorder, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), restless leg syndrome, depression, schizophrenia, anxiety, obsessive compulsive disorder, panic disorder, posttraumatic stress disorder, premenstrual dysphoria, and neurodegenerative disease. 
     
     
         15 . The method of  claim 14 , wherein said sleep disorder is sleep apnea. 
     
     
         16 . The method of  claim 14 , wherein said pain is neuropathic pain. 
     
     
         17 . A method for treating or preventing an eating disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         18 . A method for treating or preventing obesity, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         19 . A method of inhibiting reuptake of at least one monoamine from a cell, said method comprising administering to a mammalian subject a compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         20 . The method of  19 , wherein said monoamine is a member selected from group consisting of serotonin, dopamine and norepinephrine. 
     
     
         21 . A method of modulating one or more monoamine transporter, said method comprising administering to a mammalian subject a compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         22 . The method of  claim 21 , wherein said monoamine transporter is a member selected from the group consisting of serotonin transporter (SERT), dopamine transporter (DAT) aminorepinephrine (NET) transporter. 
     
     
         23 . The method of  claim 14 , wherein, said substance abuse is abuse of a member selected from cocaine, nicotine or a combination thereof. 
     
     
         24 . The method of  claim 14 , wherein said neurodegenerative disease is Parkinson's disease. 
     
     
         25 . A compound having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         26 . A pharmaceutical formulation comprising a compound according to  claim 25  in combination with a pharmaceutically acceptable excipient. 
     
     
         27 . A compound having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         28 . A pharmaceutical formulation comprising a compound according to  claim 27  in combination with a pharmaceutically acceptable excipient. 
     
     
         29 . A compound having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         30 . A pharmaceutical formulation comprising a compound according to  claim 29  in combination with a pharmaceutically acceptable excipient.