Piperidine derivatives

Abstract

The present invention relates to a compound of formula I wherein R 1 , R 2 , and Ar are as defined herein or to a pharmaceutically acceptable acid addition salt, to a racemic mixture, or to its corresponding enantiomer and/or optical isomer thereof. These compounds and their pharmaceutical compositions are useful in the treatment of neurological and neuropsychiatric disorders.

1 . A compound of formula I 
     
       
         
         
             
             
         
       
       wherein 
       R 1  is hydrogen, lower alkyl, CD 3 , —(CH 2 ) n —CHO, —(CH 2 ) n —O-lower alkyl, —(CH 2 ) n —OH, —(CH 2 ) n -cycloalkyl or heterocycloalkyl; 
       R 2  is hydrogen, halogen, hydroxy, lower alkyl, di-lower alkyl, —OCH 2 —O-lower alkyl, or lower alkoxy; or the piperidin ring together with R 2  forms 4-aza-spiro[2.5]oct-6-yl; 
       Ar is aryl or heteroaryl, each of which is optionally substituted by one, two or three substituents selected from halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, cycloalkyl, lower alkoxy, S-lower alkyl, heteroaryl, heterocycloalkyl, and phenyl optionally substituted by R′, 
       R′ is halogen, lower alkyl, lower alkoxy, lower alkoxy substituted by halogen, or heteroaryl; 
       R is lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted by one or two R′; and 
       n is 0, 1 2 or 3; 
     
     or a pharmaceutically acceptable acid addition salt, racemic mixture, enantiomer, or optical isomer thereof. 
   
   
       2 . A compound of  claim 1 , wherein R 1  is lower alkyl. 
   
   
       3 . A compound of  claim 2 , wherein Ar and R are both phenyl. 
   
   
       4 . A compound of  claim 3 , wherein the phenyl group for Ar is substituted by at least two CF 3  groups. 
   
   
       5 . A compound of  claim 4 , selected from the group consisting of
 rac-2-fluoro-N-(1-methyl-3-phenyl-piperidin-3-yl)-4,6-bis-trifluoromethyl-benzamide;   rac-2-methoxy-N-(1-methyl-3-phenyl-piperidin-3-yl)-4,6-bis-trifluoromethyl-benzamide;   rac-2-ethyl-N-(1-methyl-3-phenyl-piperidin-3-yl)-4,6-bis-trifluoromethyl-benzamide;   rac-N-[3-(4-fluoro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-4,6-bis-trifluoromethyl-benzamide; and   2-methoxy-N—((R)-1-methyl-3-phenyl-piperidin-3-yl)-4,6-bis-trifluoromethyl-benzamide.   
   
   
       6 . A compound of  claim 3 , wherein the phenyl group for Ar is substituted by at least one CF 3  group. 
   
   
       7 . A compound of  claim 6 , selected from the group consisting of
 rac-2-ethyl-N-(1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide;   rac-2-bromo-6-methoxy-N-(1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide;   rac-N-(1,2-dimethyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;   rac-2-cyclopropyl-N-(1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide;   rac-2-methoxy-N-(1-methyl-3-phenyl-piperidin-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;   rac-N-(1-methyl-3-phenyl-piperidin-3-yl)-2-methylsulfanyl-4-trifluoromethyl-benzamide;   rac-N-[3-(4-fluoro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;   rac-N-[3-(4-chloro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;   2-methoxy-N—((S)-1-methyl-3-phenyl-piperidin-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;   2-methoxy-N—((R)-1-methyl-3-phenyl-piperidin-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide; and   rac-2-difluoromethoxy-N-(1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide.   
   
   
       8 . A compound of  claim 6 , selected from the group consisting of
 rac-N-[3-(3-chloro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;   rac-2-methoxy-N-[3-(4-methoxy-phenyl)-1-methyl-piperidin-3-yl]-6-methylsulfanyl-4-trifluoromethyl-benzamide;   rac-N-(5-fluoro-1-methyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;   rac-N-(1-isopropyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;   2-cyclopropyl-N—((S)-1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide;   2-cyclopropyl-N—((R)-1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide;   rac-2-cyclobutyl-N-(1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide;   rac-N-[3-(2,4-difluoro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;   rac-N-[3-(2-fluoro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;   rac-N-[3-(2,5-difluoro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide; and   rac-2-isopropyl-N-(1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide.   
   
   
       9 . A compound of  claim 6 , selected from the group consisting of
 rac-2-methoxy-6-methylsulfanyl-N-(1-methyl-1,4,5,6-tetrahydro-2H-[3,4′]bipyridinyl-3-yl)-4-trifluoromethyl-benzamide;   rac-2-ethyl-N-(1-methyl-1,4,5,6-tetrahydro-2H-[3,4′]bipyridinyl-3-yl)-4-trifluoromethyl-benzamide;   rac-2-methoxy-6-methylsulfanyl-N-(1-methyl-1,4,5,6-tetrahydro-2H-[3,3′]bipyridinyl-3-yl)-4-trifluoromethyl-benzamide;   rac-2-Ethyl-N-(1-methyl-1,4,5,6-tetrahydro-2H-[3,3′]bipyridinyl-3-yl)-4-trifluoromethyl-benzamide hydrochloride;   2-methoxy-N-((3RS,5SR)-5-methoxy-1-methyl-3-phenyl-piperidin-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;   2-cyclopropyl-N-((3RS,5SR)-5-methoxy-1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide;   2-ethyl-N-((3RS,5SR)-5-methoxy-1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide;   rac-2,6-dimethoxy-N-(1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide;   2-cyclopropyl-N-((3RS,5SR)-1,5-dimethyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide;   rac-2-cyclopropyl-4-trifluoromethyl-N-(1,5,5-trimethyl-3-phenyl-piperidin-3-yl)-benzamide; and   rac-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-N-(1,6,6-trimethyl-3-phenyl-piperidin-3-yl)-benzamide.   
   
   
       10 . A compound of  claim 6 , selected from the group consisting of
 N-((3RS,5SR)-1,5-dimethyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;   2-methoxy-N-((3RS,5SR)-5-methoxymethoxy-1-methyl-3-phenyl-piperidin-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;   rac-N-[3-(3-bromo-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;   rac-N-[3-(2-chloro-4-fluoro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;   rac-2-methoxy-6-methylsulfanyl-N-[1-methyl-3-(3-trifluoromethyl-phenyl)-piperidin-3-yl]-4-trifluoromethyl-benzamide;   rac-2-methoxy-N-[3-(3-methoxy-phenyl)-1-methyl-piperidin-3-yl]-6-methylsulfanyl-4-trifluoromethyl-benzamide;   rac-N-[3-(3-fluoro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;   rac-N-[3-(3-chloro-4-fluoro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;   rac-N-[3-(3,4-difluoro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide; and   rac-2-methoxy-6-methylsulfanyl-N-(1-methyl-3-m-tolyl-piperidin-3-yl)-4-trifluoromethyl-benzamide.   
   
   
       11 . A compound of  claim 6 , selected from the group consisting of
 rac-N-[3-(4-fluoro-3-methyl-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;   rac-N-[3-(3,5-difluoro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;   rac-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-N-(1,5,5-trimethyl-3-phenyl-piperidin-3-yl)-benzamide;   rac-2-ethyl-3-methyl-N-(1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide;   rac-N-(1-tert-butyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;   rac-2-methoxy-N-(4-methyl-6-phenyl-4-aza-spiro[2.5]oct-6-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;   N-((3R,5S) or (3S,5R)-5-hydroxy-1-methyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;   2-methoxy-N-((3R,5S) or (3S,5R)-5-methoxy-1-methyl-3-phenyl-piperidin-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;   2-methoxy-N-((3S,5R) or (3R,5S)-5-methoxy-1-methyl-3-phenyl-piperidin-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide; and   N—[(R or S)-3-(2-fluoro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide.   
   
   
       12 . A compound of  claim 6 , selected from the group consisting of
 N—[(R or S)-3-(2,5-difluoro-phenyl)-1-methyl-piperidin-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;   2-ethyl-N-((R or S)-1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide;   2-methoxy-6-methylsulfanyl-4-trifluoromethyl-N—((S or R)-1,5,5-trimethyl-3-phenyl-piperidin-3-yl)-benzamide;   N-((3S,6S) or (3R,6R)-1,6-dimethyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;   N-((3R,6R) or (3S,6S)-1,6-dimethyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;   N-((3R,6S) or (3S,6R)-1,6-dimethyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;   N-((3S,5R) or (3R,5S)-1,5-dimethyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;   N-((3R,5S) or (3S,5R)-1,5-dimethyl-3-phenyl-piperidin-3-yl)-2-ethyl-4-trifluoromethyl-benzamide;   2-ethyl-N-((3R,5S) or (3S,5R)-5-methoxy-1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide;   2-cyclopropyl-N-((3R,5S) or (3S,5R)-5-methoxy-1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide; and   2,6-Dimethoxy-N—(R or (S)-1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide.   
   
   
       13 . A compound of  claim 1 , wherein R 1  is cycloalkyl or heterocycloalkyl and Ar and R are both phenyl. 
   
   
       14 . A compound of  claim 13 , selected from the group consisting of
 rac-N-(1-cyclopentyl-3-phenyl-piperidin-3-yl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide;   rac-N-(1-cyclopropylmethyl-3-phenyl-piperidin-3-yl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide; and   rac-2-methoxy-N-[3-phenyl-1-(tetrahydro-pyran-4-yl)-piperidin-3-yl]-4,6-bis-trifluoromethyl-benzamide.   
   
   
       15 . A compound of  claim 1 , wherein R 1  is lower alkyl, Ar is phenyl and R is heteroaryl. 
   
   
       16 . A compound of  claim 15 , selected from the group consisting of
 rac-N-(5-fluoro-1′-methyl-1′,4′,5′,6′-tetrahydro-2′ H-[2,3′]bipyridinyl-3′-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;   rac-2-methoxy-6-methylsulfanyl-N-(1-methyl-1,4,5,6-tetrahydro-2H-[3,4′]bipyridinyl-3-yl)-4-trifluoromethyl-benzamide;   rac-2-ethyl-N-(1-methyl-1,4,5,6-tetrahydro-2H-[3,4′]bipyridinyl-3-yl)-4-trifluoromethyl-benzamide hydrochloride;   rac-2-methoxy-6-methylsulfanyl-N-(1-methyl-1,4,5,6-tetrahydro-2H-[3,3′]bipyridinyl-3-yl)-4-trifluoromethyl-benzamide; and   rac-2-ethyl-N-(1-methyl-1,4,5,6-tetrahydro-2H-[3,3′]bipyridinyl-3-yl)-4-trifluoromethyl-benzamide.   
   
   
       17 . A compound of  claim 1 , wherein R 1  is hydrogen and Ar and R are phenyl. 
   
   
       18 . A compound of  claim 17 , wherein the compound is
 rac-2-cyclopropyl-N-(3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide.   
   
   
       19 . A compound of  claim 1 , wherein R 2  is hydroxy. 
   
   
       20 . A compound of  claim 19 , selected from the group consisting of
 rac-N-(5-hydroxy-1-methyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide and   N-((3R,5S) or (3S,5R)-5-hydroxy-1-methyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide.   
   
   
       21 . A compound of  claim 3 , wherein R 2  is halogen. 
   
   
       22 . A compound of  claim 21 , wherein the compound is
 rac-N-(5-fluoro-1-methyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide.   
   
   
       23 . A compound of  claim 1 , wherein R 1  is CD 3 . 
   
   
       24 . A compound of  claim 23 , wherein the compound is
 [2H-methyl]-2-methoxy-N—(R) or (S)-1-methyl-3-phenyl-piperidin-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide hydrochloride.   
   
   
       25 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I 
     
       
         
         
             
             
         
       
       wherein 
       R 1  is hydrogen, lower alkyl, CD 3 , —(CH 2 ) n —CHO, —(CH 2 ) n —O-lower alkyl, —(CH 2 ) n —OH, —(CH 2 ) n -cycloalkyl or heterocycloalkyl; 
       R 2  is hydrogen, halogen, hydroxy, lower alkyl, di-lower alkyl, —OCH 2 —O-lower alkyl, or lower alkoxy; or the piperidin ring together with R 2  forms 4-aza-spiro[2.5]oct-6-yl; 
       Ar is aryl or heteroaryl, each of which is optionally substituted by one, two or three substituents selected from halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, cycloalkyl, lower alkoxy, S-lower alkyl, heteroaryl, heterocycloalkyl, and phenyl optionally substituted by R′, 
       R′ is halogen, lower alkyl, lower alkoxy, lower alkoxy substituted by halogen, or heteroaryl; 
       R is lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted by one or two R′; and 
       n is 0, 1 2 or 3; 
     
     or a pharmaceutically acceptable acid addition salt, racemic mixture, enantiomer, or optical isomer thereof and a pharmaceutically acceptable carrier.