Piperidine, tetrahydropyridine and piperazine derivatives, their preparation and use

Abstract

A piperidine, tetrahydropyridine or piperazine derivative having formula (I), any of its enantiomers or any mixture thereof, or an acid addition salt thereof, wherein B is C 1-10 -alkylene, C 1-10 -alkenylene or C 1-10 -alkynylene; X is —O—, —S—, or CR 4 R 5 —; and Y is —CR 6 R 7 , —CR 6 R 7 —CR 8 R 9 , or CR 6 ═CR 7 —; or X and Y together form a group —CR 4 ═CR 5 , or —CR 4 —CR 5 —CR 6 R 7− ; Z is —O—, or —S—; W is N, C, or CH, and the dotted line is an optional bond; A is a bicyclic ring selected from (Ia) or (Ib) wherein E 1 , E 2 and E 3 are selected from O, S, N, NR 11 , C, CR 12 and CHR 13 , and the dotted line indicates an optional bond, provided that E 2 and E 1 and/or E 3 may not simultaneously be O, or S. The compounds of the invention are considered useful for the treatment of affective disorders, such as depression, psychosis, anxiety disorders including general anxiety disorder, panic disorder, obsessive compulsive disorder, and eating disorders.

1 . A pipenrdine, tetrahydropyridine or piperazine derivative having the formula:  
       
         
           
           
               
               
           
         
       
       any of its enantiomers or any mixture thereof, or an acid addition salt thereof, 
 wherein 
 B is C 1-10 -alkylene, C 2-10 -alkenylene or C 2-10 -alkynylene;  
 X is —O—, —S—, or —CR 4 R 5 —; and  
 Y is —CR 6 R 7 —, —CR 6 R 7 —CR 8 R 9 —, or —CR 6 —CR 7 —; or  
 X and Y together form a group —CR 4 ═CR 5 —, or —CR 4 ═CR 5 —CR 6 R 7 —;  
 Z is —O—, or —S—;  
 W is N, C, or CH, and the dotted line is an optional bond;  
 
 R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are each independently selected from hydrogen, halogen, trifluoromethyl, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-6 alkyl, C 1-6 -alkoxy, C 1-6 -alkylthio, amino, C 1-6 -alkylamino, C 1-6 -dialkylamino, phenylamino or phenyl-C 1-6 -alkylamino wherein the phenyl group may be substituted, acylamino, hydroxy, —SH, cyano, nitro, —COOR 18 , —SO 2 —R 19  and C 1-6 -alkyl substituted with a substituent selected from halogen, C 1-6 -alkoxy, C 1-6 alkylthio, amino, C 1-6 alkylamino, C 1-6 -dialkylamino, acylamino, hydroxy, —SH, cyano, nitro, —COOR 18  and —SO 2 —R 19 ;  
 R 18  is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, phenyl or phenyl-C 1-6 -alkyl wherein the phenyl groups may be substituted, amino, C 1-6 -alkylamino or C 1-6 -dialkylamino, and  
 R 19  is C 1-6 -alkyl, amino, C 1-6 -alkylamino, C 1-6 -dialkylamino, phenyl or phenyl-C 1-6 -alkyl wherein the phenyl groups may be substituted;  
 A is a bicyclic ring selected from  
                     
 wherein E 1 , E 2  and E 3  are selected from O, S, N, NR 11 , C, CR 12  and CHR 13 , and the dotted line indicates an optional bond, provided that E 2  and E 1  and/or E 3  may not simultaneously be O, or S;  
 R 1 , R 2 , R 3 , R 12 , R 13 , R 14 , R 15 , R 16  and R 17  are each independently selected from hydrogen, halogen, trifluoromethy, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-6 -alkyl, C 1-6 -alkoxy, hydroxy, formyl, acyl, amino, C 1-6 -alkylamino, C 1-6 -dialkylamino, acylamino, C 1-6 -alkoxycarbonylamino, aminocarbonylamino, C 1-6 -alkylaminocarbonylamino, C 1-6 -dialkylaminocarbonylamino, nitro, cyano and —SO 2 -R 19 , wherein R 19  is C 1-6 -alkyl, amino, C 1-6 -alkylamino, C 1-6 -dialkylamino, phenyl, or phenyl-C 1-6 -alkyl wherein the phenyl groups may be substituted;  
 R 11  is selected from hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-6 -alkyl, phenyl or phenyl-C 1-6 -alkyl wherein the phenyl group may be substituted, acyl, formyl and —SO 2 —R 19 , wherein R 19  is C 1-6 -alkyl, amino, C 1-6 alkylamino, C 1-6 -dialkylamino, phenyl or phenyl-C 1-6 -alkyl wherein the phenyl groups may be substituted;  
 provided that at least one of R 4 —R 9  is different from hydrogen when A is a group of formula  
                     
 
     
     
         2 . A compound according to  claim 1  wherein A is selected from the groups of formula (Ic), (Id) and (Ie)  
       
         
           
           
               
               
           
         
         wherein E 1 , E 2 , E 3 , and R 14 , R 15 , R 16  and R 17  are as defined in  claim 1  and E 5  is N, C or CR 12 .  
       
     
     
         3 . A compound according to  claims 1  to  2  wherein the bicyclic ring A is selected from the group (If) to (Iq)  
       
         
           
           
               
               
           
         
         which is attached to the remainder of the compound of formula (I) via a carbon atom or a nitrogen atom in any of the two rings and  
         wherein the dotted line is an optional bond, E 6  is O or S, and wherein any of the carbon atoms in the ring may be substituted with any of the substituents defined for R 12 -R 17  above, and wherein the nitrogen atoms in the ring may be substituted with any of the substituents defined above for R 11 .  
       
     
     
         4 . A compound according to  claim 3  wherein A is a group of formula (Ih), (Ij) or (Iq).  
     
     
         5 . A compound according to  claim 4  wherein A is a group of formula (Ih) wherein E 6  is O.  
     
     
         6 . A compound according to  claims 4  to  5  wherein A is attached to the remainder of the derivative of formula (I) via position 3 in the five-membered ring.  
     
     
         7 . A compound according to  claim 3  wherein A is a group of formula (If).  
     
     
         8 . A compound according to any of claims  1 - 7  wherein 
 B is C 1-6 -alkylene, C 2-6 -alkenylene, or C 2-6 -alkynylene;  
 X is —O—, or —S—; and  
 Y is —CR 6 R 7 —, —CR 6 R 7 —CR 8 R 9 —, or —CR 6 ═CR 7 —; and  
 Z is —O—, or —S—;  
 W is N, C, or CH; 
 R 6 , R 7 , R 8  and R 9  are each independently selected from hydrogen, halogen, trifluoromethyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkylthio, amino, C 1-6 -alkylamino, C 1-6 -dialkylamino, phenylamino or phenyl-C 1-6 -alkylamino wherein the phenyl group may be substituted, hydroxy, cyano, nitro, —COOR 18 , —SO 2 —R 19  and C 1-6 -alkyl substituted with halogen, C 1-6 -alkoxy, C 1-6 -alkylthio, amino, C 1-6 -alkylamino, C 1-6 -dialkylamino, acylamino, hydroxy, cyano, nitro, —COOR 18  or —SO 2 —R 19 ;  
 R 18  is hydrogen, C 1-6 -alkyl, amino, C 1-6 -alkylamino or C 1-6 -dialkylamino;  
 R 19  is C 1-6 -alkyl, amino, C 1-6 -alkylamino or C 1-6 -dialkylamino;  
 R 1 , R 2 , R 3 , R 12 , R 13 , R 14 , R 15 , R 16  and R 17  are each independently selected from hydrogen, halogen, trifluoromethyl, C 1-6 -alkyl, C 1-6 -alkoxy, hydroxy, amino, C 1-6 -alkylamino, C 1-6 -dialkylamino, nitro and cyano; and  
 R 11  is selected from hydrogen, C 1-6 -alkyl, phenyl or phenyl-C 1-6 -alkyl wherein the phenyl group may be substituted, acyl, formyl and —SO 2 —R 19 , wherein R 19  is C 1-6 -alkyl, amino, C 1-6 -alkylamino or C 1-6 -dialkylamino.  
 
 
     
     
         9 . A compound according to  claim 1  which is selected from 
 1-[1,4-Benzodioxan-5-yl]-4-[1-(inden-1-yl)-4-butyl]piperazine,  
 1-[1,4-Benzodioxan-5-yl]-4-[1-(indan-1-yl)-1-buten-4-yl]piperazine,  
 1-[1,4-Benzodioxan-5-yl]-4-[1-(indan-1-yl)-4-butyl]piperazine,  
 1-[1,4-Benzodioxan-5-yl]-4-[2-(5-fluorobenzofuran-3-yl)ethyl]piperazine,  
 1-[1,4-Benzodioxan-5-yl]-4-[3-(6-fluorobenzo[1,2]isoxazol-3-yl)-1-propyl]piperazine,  
 1-[Benzofuran-7-yl]-4-[2-(5-fluorobenzofuran-3-yl)ethyl]piperazine,  
 1-[1,4-Benzodioxan-5-yl]-4-[2-(6chloroindazol-3-yl)ethyl]piperazine,  
 1-[1,4-Benzodioxan-5-yl]-4-[2-(4-methylbenzofuran-3-yl)ethyl]piperazine,  
 1-[1,4-Benzodioxan-5-yl]-4-[2-(5-chlorobenzofuran-3-yl)ethyl]piperazine,  
 1-[1,4-Benzodioxan-5-yl]-4-[2-(6-methylbenzofuran-3-yl)ethyl]piperazine,  
 1-[1,4-Benzodioxan-5-yl]-4-[2-(benzofuran-3-yl)ethyl]piperazine,  
 1-[2-(5-Chlorobenzofuran-3-yl)ethyl]-4-[2,3-dihydrobenzofuran-7-yl]-1,2,3,6-tetrahydropyridine,  
 4-[Benzofaran-7-yl]-1-[2-(5-fluorobenzofuran-3-yl)ethyl]-1,2,3,6-tetrahydropyridine,  
 1-[1,4-Benzodioxan-5-yl]-4-[2-(7chlorobenzofuran-3-yl)ethyl]piperazine,  
 1-[1,4-Benzodioxan-5-yl]-4-[3-(7-chlorobenzofuran-3-yl)-1-proyl]piperazine,  
 1-[8-Cyano-1,4-benzodioxan-5-yl]-4-[3-(7-chlorobenzofuran-3-yl)propyl]piperazine,  
 1-[1,4-Benzodioxan-5-yl]-4-[3-(7chloro-4-methylbenzofuran-3-yl)-1-propyl]piperazine,  
 1-[1,4-Benzodioxan-5-yl]-4-[3-(4-methylbenzofuran-3-yl)-1-propyl]piperazine  
 1-[1,4-Benzodioxan-5-yl]-4-[2-(6-bromobenzofuran-3-yl)ethyl]piperazine,  
 1-[1,4-Benzodioxan-5-yl]-4-[3-(4-chlorobenzofuran-3-yl)-1-propyl]piperazine  
 1-[1,4-Benzodioxan-5-yl]-4-[4-(4-methylbenzofuran-3-yl)-1-butyl]piperazine  
 1-[1,4-Benzodioxan-5-yl]-4-[4-(4-chlorobenzofuran-3-yl)-1-butyl]piperazine  
 1-[1,4-Benzodioxan-5-yl]-4-[4-(7-chlorobenzofuran-3-yl)-1-butyl]piperazine  
 4-[1,4-Benzodioxan-5-yl]-1-[2-(5-fluorobenzofuran-3-yl)ethyl]-1,2,3,6-tetrahydropyridine,  
 4-[1,4-Benzodioxan-5-yl]-1-[2-(5-fluorobenzofuran-3-yl)ethyl]piperidine,  
 4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-hydroxymethyl-1,4-benzodioxan-5-yl]piperazine,  
 4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-cyano-1,4-benzodioxan-5-yl]piperazine,  
 4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-trifluoromethyl-1,4-benzodioxan-5-yl]piperazine,  
 4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(ethyl-oxo-carbonyl)-1,4-benzodioxan-5-yl]piperazine,  
 1-[2-Carbamoyl-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]piperazine,  
 4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(N,N-dimethylcarbamoyl)-1,4-benzodioxan-5-yl]piperazine,  
 1-[2-Amino-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]piperazine,  
 1-[2-Acetamido-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]piperazine,  
 4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(N,N-dimethylamino)-1,4-benzodioxan-5-yl]piperazine,  
 4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-hydroxymethyl-1,4-benzodioxan-5-yl]tetrahydropyridine,  
 4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-cyano-1,4-benzodioxan-5-yl]tetrahydropyridine,  
 4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-trifluoromethyl-1,4benzodioxan-5-yl]tetrahydropyridine,  
 4-[6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(ethyl-oxo-carbonyl)-1,4-benzodioxan-5-yl]tetrahydropyridine,  
 1-[2-Carbamoyl-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]tetrahydropyridine,  
 4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(N,N-dimethylcarbamoyl)-1,4-benzodioxan-5-yl]tetrahydropyridine,  
 1-[2-Amino-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]tetrahydropyridine,  
 1-[2-Acetamido-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]tetrahydropyridine,  
 4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(N,N-dimethylamino)-1,4-benzodioxan-5-yl]tetrahydropyridine,  
 4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-hydroxymethyl-1,4-benzodioxan-5-yl]piperidine,  
 4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-cyano-1,4-benzodioxan-5-yl]piperidine  
 4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-trifluoromethyl-1,4-benzodioxan-5-yl]piperidine,  
 4-[2-(6-Chloro-1H-indol-3-yl]-1-[2-(ethyl-oxo-carbonyl)-1,4-benzodioxan-5-yl]piperidine,  
 1-[2-Carbamoyl-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]piperidine,  
 4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(N,N-dimethylcarbamoyl)-1,4-benzodioxan-5-yl]piperidine,  
 1-[2-Amino-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]piperidine,  
 1-[2-Acetamido-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]piperidine,  
 4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(N,N-dimethylamino)-1,4-benzodioxan-5-yl]piperidine,  
 1-[2,2-Bis(hydroxymethyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]piperazine,  
 4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2,2-dicyano-1,4-benzodioxan-5-yl]piperazine,  
 1-[2,2-Bis(trifluoromethyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]piperazine,  
 1-[2,2-Bis(ethyl-oxo-carbonyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]piperazine,  
 1-[2,2-Bis(hydroxymethyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]tetrahydropyridine,  
 4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2,2-dicyano-1,4-benzodioxan-5-yl]tetrahydropyridine,  
 1-[2,2-Bis(trifluoromethyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]tetrahydropyridine,  
 1-[2,2-Bis(ethyl-oxo-carbonyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]tetrahydropyridine,  
 b  1 -[2,2-Bis(hydroxymethyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]piperidine,  
 4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2,2-dicyano-1,4-benzodioxan-5-yl]piperidine,  
 1-[2,2-Bis(trifluoromethyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]piperidine,  
 1-[2,2-Bis(ethyl-oxo-carbonyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]piperidine, or a pharmaceutically acceptable acid addition salt thereof.  
 
     
     
         10 . A compound according to  claim 1  which is selected from 
 1-[1,4-Benzodioxan-5-yl]-4-[1-(inden-1-yl)-4-butyl]piperazine,  
 1-[1,4-Benzodioxan-5-yl]-4-[1-(indan-1-yl)-1-buten-4-yl]piperazine,  
 1-[1,4-Benzodioxan-5-yl]-4-[1-(indan-1-yl)-4-butyl]piperazine,  
 1-[1,4-Benzodioxan-5-yl]-4-[2-(5-fluorobenzofuran-3-yl)ethyl]piperazine,  
 1-[1,4-Benzodioxan-5-yl]-4-[3-(6-fluorobenzo[1,2]isoxazol-3-yl)-1-propyl]piperazine,  
 1-[Benzofuran-7-yl]-4-[2-(5-fluorobenzofuran-3-yl)ethyl]piperazine,  
 1-[1,4-Benzodioxan-5-yl]-4-[2-(6-chloroindazol-3-yl)ethyl]piperazine,  
 1-[1,4-Benzodioxan-5-yl]-4-[2-(4-methylbenzofuran-3-yl)ethyl]piperazine,  
 1-[1,4-Benzodioxan-5-yl]-4-[2-(5-chlorobenzofuran-3-yl)ethyl]piperazine,  
 1-[1,4-Benzodioxan-5-yl]-4-[2-(6-methylbenzofuran-3-yl)ethyl]piperazine,  
 1-[1,4-Benzodioxan-5-yl]-4-[2-(benzofuran-3-yl)ethyl]piperazine,  
 1-[1,4-Benzodioxan-5-yl]-4-[2-(7-chlorobenzofuran-3-yl)ethyl]piperazine,  
 1-[1,4-Benzodioxan-5-yl]-4-[3-(7-chloro-4-methylbenzofuran-3-yl)-1-propyl]piperazine,  
 1-[1,4-Benzodioxan-5-yl]-4-[3-(4-methylbenzofuran-3-yl)-1-propyl]piperazine,  
 1-[2-(5-Chlorobenzofuran-3-yl)ethyl]-4-[2,3-dihydrobenzofuran-7-yl]-1,2,3,6-tetrahydropyridine, and 4-[Benzofuran-7-yl-]1-[2-(5-fluorobenzofuran-3-yl)ethyl]-1,2,3,6-tetrahydropyridine,  
 or a pharmaceutically acceptable acid addition salt thereof.  
 
     
     
         11 . A pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or diluent.  
     
     
         12 . The use of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of a disorder or disease responsive to the inhibition of serotonin reuptake and antagonism of 5-HT 1A  receptors.  
     
     
         13 . The use of a compound or formula I or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of affective disorders, such as depression, psychosis, anxiety disorders including general anxiety disorder, panic disorder, obsessive compulsive disorder, and eating disorders.  
     
     
         14 . A method of treating affective disorders, such as depression, psychosis, anxiety disorders including general anxiety disorder, panic disorder, obsessive compulsive disorder, and eating disorders comprising administering a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.