Piperidinyl indole and tetrohydropyridinyl indole derivatives and methods of their use

Abstract

3-Piperidin-4-yl-1H-indole and 3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole derivatives are disclosed. Methods of using the derivatives and compositions containing the derivatives in the prevention and/or treatment of serotonin disorders, such as depression and anxiety, are also disclosed. Additionally, processes for the preparation of 3-piperidin-4-yl-1H-indole and 3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole derivatives are disclosed.

1 . The compound of formula I:  
     
       
         
         
             
             
         
       
     
     or a N-oxide, stereoisomer or pharmaceutically acceptable salt thereof, 
 wherein:  
 A is a heterocycle having the formula:  
                     
 X is O or S;  
 R 1  is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, fluoro, alkoxy, heteroaryloxy, cycloalkoxy, hydroxy, nitrile, carboxy, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, fluorinated alkyl, aryl, aryloxy, alkylaryl, heteroaryl, alkylheteroaryl, NH 2 , NHR 11 , NR 11 R 11 , —O-alkyl-NR 11 R 11 , or -aryl-O-alkyl-NR 11 R 11 ;  
 R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are, independently, hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, halo, cyano, alkoxy, heteroaryloxy, cycloalkoxy, hydroxy, nitro, nitrile, NH 2 , NHR 11 , NR 11 R 11 , CHO, alkylcarbonyl, arylcarbonyl, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy aminocarbonyl, alkylaminocarbonyl, fluorinated alkyl, aryl, aryloxy, alkylaryl, heteroaryl, alkylheteroaryl, —O-alkyl-NR 11 R 11 , or -aryl-O-alkyl-NR 11 R 11 ;  
 R 10  is hydrogen, alkyl, cycloalkyl, alkenyl of 3 to 6 carbon atoms (with the proviso that the carbon bearing the double bond should not be directly connected to N), alkynyl of 3 to 6 carbon atoms (with the proviso that the carbon bearing the triple bond should not be directly connected to N), alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, fluorinated alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, SO 2 -aryl, SO 2 -heteroaryl or SO 2 -alkyl;  
 R 2  and R 3 , R 3  and R 4 , or R 4  and R 5  can be attached together to form a cycloalkyl or optionally substituted aromatic or hetero aromatic ring containing one or two hetero atoms such as N, O, S, S═O or SO 2 ;  
 R 11  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl (with the proviso that the carbon bearing the double bond is not bonded directly to the heteroatoms such as O, S or N—R 11 ), optionally substituted alkynyl (with the proviso that the carbon bearing the triple bond is not bonded directly to the heteroatoms such as O, S or N—R 11 ), optionally substituted aryl, optionally substituted alkylaryl, heteroaryl optionally substituted with R 2 , optionally substituted alkylheteroaryl, SO 2 -aryl, SO 2 -heteroaryl or SO 2 -alkyl;  
 with the proviso that if two R 11  groups are attached to nitrogen, then they can together form a 4 to 7 membered cyclic system having 0 to 2 hetero atoms selected from O, S═(O) r , r is an integer from 0 to 2, and NR 11 ; and  
 n is an integer from 1 to 6.  
 
   
   
       2 . A compound according to  claim 1 , wherein said R 1  is hydrogen or alkyl.  
   
   
       3 . A compound according to  claim 1 , wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9  are independently hydrogen, halo, alkyl, alkoxy, alkenyl, NR 11 R 11 , or cyano.  
   
   
       4 . A compound according to  claim 1 , wherein said R 10  is hydrogen, alkyl, aryl or heteroaryl.  
   
   
       5 . A compound according to  claim 1 , wherein said R 11  is hydrogen, alkyl, aryl or heteroaryl.  
   
   
       6 . A compound according to  claim 1 , wherein said compound is: 
 3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole;    3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1-(2-propenyl)-1H-indole;    3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1-methyl-1H-indole;    3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole;    3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1-(2-propenyl)-1H-indole;    3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1-methyl-1H-indole; or    3-{1-(2-naphtho[1,2-b]furan-3-yl-ethyl)-piperidin-4-yl]-1H-indole.    
   
   
       7 . A composition, comprising the compound of  claim 1  and one or more pharmaceutically acceptable carriers.  
   
   
       8 . A method of preventing and/or treating a patient suspected of suffering from a serotonin-related disorder, comprising the step of administering to the patient a therapeutically effective amount a compound of  claim 1 .  
   
   
       9 . A method according to  claim 8 , wherein said serotonin-related disorder is depression, anxiety, cognitive deficits, schizophrenia, prostate cancer, or nicotine withdrawal.  
   
   
       10 . A method according to  claim 8 , wherein said serotonin-related disorder is depression.  
   
   
       11 . A method according to  claim 8 , wherein said serotonin-related disorder is anxiety.  
   
   
       12 . A method of antagonizing 5-HT 1A  receptors in a patient in need thereof, comprising the step of administering to the patient a therapeutically effective amount of a compound of  claim 1 .  
   
   
       13 . A method of inhibiting the reuptake of serotonin in a patient in need thereof, comprising the step of administering to the patient a therapeutically effective amount of a compound of  claim 1 .  
   
   
       14 . A method of antagonizing 5-HT 1A  receptors and inhibiting the reuptake of serotonin in a patient in need thereof, comprising the step of: 
 administering to the patient a therapeutically effective amount of a compound of  claim 1.