Cycloalkylamines as monoamine reuptake inhibitors

Abstract

The invention relates to novel cyclohexylamine derivatives and their use in the treatment and/or prevention of central nervous system (CNS) disorders, such as depression, anxiety, schizophrenia and sleep disorder as well as methods for their synthesis. The invention also relates to pharmaceutical compositions containing the compounds of the invention, as well as methods of inhibiting reuptake of endogenous monoamines, such as dopamine, serotonin and norepinephrine from the synaptic cleft and methods of modulating one or more monoamine transporter.

1 . A compound having a structure according to Formula (I):  
     
       
         
         
             
             
         
       
     
     wherein 
 n is an integer from 0 to 2;  
 s is an integer from 1 to 3;  
 m is an integer from 0 to 12, with the proviso that when n is 0, then m is not greater than 8; and when n is 1, then m is not greater than 10;  
 Ar is a member selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and a fused ring system;  
 each X is a member independently selected from the group consisting of H, halogen, CN, CF 3 , OR 5 , SR 5 , acyl, C(O)OR 5 , C(O)NR 6 R 7 , S(O) 2 R 5 , S(O) 2 NR 6 R 7 , NR 6 R 7 , NR 6 S(O) 2 R 5 , NR 6 C(O)R 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, 
 wherein 
 each R 5 , R 6  and R 7  is a member independently selected from the group consisting of H, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl,  
 wherein two of R 5 , R 6  and R 7 , together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring;  
 
 
 each R 1  and R 2  is a member independently selected from the group consisting of H, halogen, CN, CF 3 , OR 8 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, 
 wherein 
 R 8  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 9 , acyl, C(O)OR 9 , S(O) 2 R 9 , N═N, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, with the proviso that when one member of R 3  and R 4  is N═N, then the other member is not present, 
 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 and substituted or unsubstituted heterocycloalkyl;  
 
 
 wherein 
 at least two of R 1 , R 2 , R 3 , R 4  and X, together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring;  
 at least one of R 1 , R 2 , R 3  and R 4  is optionally joined with Ar to form a 5- to 7-membered ring;  
 and any pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemic mixture, enantiomerically enriched mixture, and enantiomerically pure form thereof.  
 
 
   
   
       2 . The compound according to  claim 1 , wherein said compound is chiral.  
   
   
       3 . The compound according to  claim 1  having a Formula, which is a member selected from the group consisting of Formula (II) and Formula (III):  
     
       
         
         
             
             
         
       
     
   
   
       4 . The compound according to  claim 3 , said compound having a Formula, which is a member selected from the group consisting of:  
     
       
         
         
             
             
         
       
       wherein X 1  and X 2  are members independently selected from the group consisting of H, OR 5 , SR 5 , halogen, CN, CF 3 , S(O) 2 R 5 , NR 6 R 7 , NR 6 S(O) 2 R 5 , NR 6 C(O)R 5 , acyl, substituted or unsubstituted C 1 -C 4  alkyl and substituted or unsubstituted C 1 -C 4  heteroalkyl, 
 wherein at least two of R 1 , R 3 , R 4 , X 1  and X 2 , together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring.  
 
     
   
   
       5 . The compound according to  claim 4 , wherein X 1  and X 2  are members independently selected from the group consisting of H, methyl, ethyl, n-propyl, OH, OMe, Ot, F, Cl, CN, CH 2 OH, CH 2 OMe, and CF 3 .  
   
   
       6 . The compound according to  claim 4 , wherein R 1  is H or substituted or unsubstituted C 1 -C 4  alkyl.  
   
   
       7 . The compound according to  claim 4 , wherein R 3  and R 4  are members independently selected from the group consisting of substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl.  
   
   
       8 . The compound according to  claim 3 , wherein Ar is a member selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted naphthyl.  
   
   
       9 . The compound according to  claim 8 , wherein Ar has a structure, which is a member selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
     wherein 
 Y, Z, Y 1  and Z 1  are members independently selected from the group consisting of H, halogen, CF 3 , CN, OR 11 , SR 11 , NR 12 R 13 , NR 12 S(O) 2 R 11 , NR 12 C(O)R 11 , S(O) 2 R 11 , acyl, C(O)OR 11 , C(O)NR 12 R 13 , S(O) 2 NR 12 R 13 , NR 12 S(O) 2 R 11 , NR 12 C(O)R 11 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, 
 wherein 
 two of Y, Z, Y1 and Z1, together with the atoms to which they are attached, are optionally joined to form a 5- to 7-membered ring; and  
 each R 11 , R 12  and R 13  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 11 , R 12  and R 13 , together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring.  
 
   
   
       10 . The compound of  claim 9 , wherein Y, Z, Y 1  and Z 1  are members independently selected from the group consisting of H, CF 3 , OR 11 , SR 11 , OCF 3 , halogen and CN.  
   
   
       11 . The compound of  claim 9 , wherein Ar has the structure:  
     
       
         
         
             
             
         
       
     
   
   
       12 . A composition comprising a first stereoisomer and at least one additional stereoisomer of a compound according to  claim 1 , wherein said first stereoisomer is present in a diastereomeric excess of at least 80% relative to said at least one additional stereoisomer.  
   
   
       13 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier.  
   
   
       14 . A method of inhibiting binding of a monoamine transporter ligand to a monoamine transporter, said method comprising contacting said monoamine transporter and a compound of  claim 1 .  
   
   
       15 . A method of inhibiting the activity of at least one monoamine transporter, said method comprising contacting said monoamine transporter and a compound of  claim 1 .  
   
   
       16 . The method of  claim 14  or  15 , wherein said monoamine transporter is a member selected from the group consisting of serotonin transporter (SERT), dopamine transporter (DAT), norepinephrine transporter (NET) and combinations thereof.  
   
   
       17 . The method of  claim 15 , wherein said compound inhibits the activity of at least two different monoamine transporters.  
   
   
       18 . A method of inhibiting uptake of at least one monoamine by a cell, said method comprising contacting said cell and a compound of  claim 1 .  
   
   
       19 . The method of  claim 18 , wherein said monoamine is a member selected from the group consisting of serotonin, dopamine, norepinephrine and combinations thereof.  
   
   
       20 . The method of  claim 18 , wherein said compound inhibits uptake of at least two different monoamines.  
   
   
       21 . The method of  claim 18 , wherein said cell is a neuronal cell.  
   
   
       22 . A method of treating depression by inhibiting the activity of at least one monoamine transporter, said method comprising administering to a mammalian subject a compound of  claim 1 .  
   
   
       23 . The method of  claim 22 , wherein said mammalian subject is a human.  
   
   
       24 . The method of  claim 22 , wherein said compound inhibits said activity of at least two different monoamine transporters.  
   
   
       25 . A method of treating a central nervous system disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 .  
   
   
       26 . The method of  claim 25 , wherein said subject is a human.  
   
   
       27 . The method of  claim 25 , wherein said central nervous system disorder is a member selected from the group consisting of depression, cognitive deficit, fibromyalgia, pain, sleep disorder, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), restless leg syndrome, schizophrenia, anxiety, obsessive compulsive disorder, posttraumatic stress disorder, premenstrual dysphoria, and neurodegenerative disease.  
   
   
       28 . The method according to  claim 27 , wherein said depression is a member selected from the group consisting of major depressive disorder (MDD), unipolar depression, bipolar disorder, seasonal affective disorder (SAD) and dysthymia.  
   
   
       29 . The method according to  claim 27 , wherein said neurodegenerative disease is Parkinson's disease.  
   
   
       30 . The method according to  claim 27 , wherein said sleep disorder is sleep apnea.  
   
   
       31 . The method according to  claim 27 , wherein said pain is neuropathic pain.  
   
   
       32 . A compound having a structure, which is a member selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
     wherein 
 n is an integer from 0 to 2;  
 p is an integer from 0 to 2;  
 m is an integer from 0 to 12, with the proviso that when n is 0, then m is not greater than 8; and when n is 1, then m is not greater than 10;  
 Ar is a member selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and a fused ring system;  
 each X is a member independently selected from the group consisting of H, halogen, CN, CF 3 , OR 5 , SR 5 , acyl, C(O)OR 5 , C(O)NR 6 R 7 , S(O) 2 R 5 , S(O) 2 NR 6 R 7 , NR 6 R 7 , NR 6 S(O) 2 R 5 , NR 6 C(O)R 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, 
 wherein 
 each R 5 , R 6  and R 7  is a member independently selected from the group consisting of H, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl,  
 wherein two of R 5 , R 6  and R 7 , together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring;  
 
 
 each R 1  and R 2  is a member independently selected from the group consisting of H, halogen, CN, CF 3 , OR 8 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, 
 wherein 
 R 8  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  
 
 
 wherein 
 at least two of R 1 , R 2  and X, together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring;  
 at least one of R 1  and R 2  is optionally joined with Ar to form a 5- to 7-membered ring;  
 
 and any salt form, solvate, enantiomer, diastereomer, racemic mixture, enantiomerically enriched mixture, and enantiomerically pure form thereof.  
 
   
   
       33 . The compound of  claim 32 , wherein p is 0.