N-[(piperazinyl)hetary]arylsulfonamide compounds with affinity for the dopamine d3 receptor

Abstract

The invention relates to N-[(piperazinyl)hetaryl]arylsulfonamide compounds of the general formula (I) in which Q is a bivalent, 6-membered heteroaromatic radical which possesses 1 or 2 N atoms as ring members and which optionally carries one or two substituents R a which is/are selected, independently of each other, from halogen, CN, NO 2 , CO 2 R 4 , COR 5 , C 1 —C 4 -alkyl and C 1 —C 4 -haloalkyl; Ar is phenyl or a 6-membered heteroaromatic radical which possesses 1 or 2 N atoms as ring members and which optionally carries one or two substituents R b , which is/are selected from halogen, NO 2 , CN, CO 2 R 4 , COR 5 , C 1 —C 6 -alkyl, C 2 —C 6 -alkenyl, C 2 —C 6 -alkynyl, C 3 —C 6 -cycloalkyl, C 3 —C 6 -cycloalkyl-C 1 —C 4 -alkyl and C 1 —C 4 -haloalkyl, with it also being possible for two radicals R b which are bonded to adjacent C atoms of Ar to be together C 3 —C 4 -alkylene; R 1 is hydrogen, C 1 —C 4 -alkyl, C 1 —C 4 -haloalkyl, C 3 —C 6 -cycloalkyl, C 3 —C 6 -cycloalkyl-C 1 —C 4 -alkyl, C 1 —C 4 -hydroxyalkyl, C 1 —C 4 -alkoxy-C 1 —C 4 -alkyl, C 3 —C 4 -alkenyl or C 3 —C 4 -alkynyl; with the radicals n, R 1 , R 2 , R 3 , R 4 and R 5 having the meanings given in the patent claims, to the N-oxides and to the physiologically tolerated acid addition salts of these compounds and to pharmaceutical compositions which comprise at least one N-[(piperazinyl)hetaryl]arylsulfonamide compound as claimed in one of claims 1 to 10 and/or at least one physiologically tolerated acid addition salt of I and/or an N-oxide of I, where appropriate together with physiologically acceptable carriers and/or auxiliary substances for treating diseases which respond to influencing by dopamine D 3 receptor antagonists or agonists, in particular for treating diseases of the central nervous system and disturbances of kidney function.

1 . An N-[(piperazinyl)hetaryl]arylsulfonamide compound of the general formula I  
     
       
         
         
             
             
         
       
     
     in which 
 R is oxygen, a group N—R 3  or a group CR 3a R 3b ;  
 Q is a bivalent, 6-membered heteroaromatic radical which possesses 1 or 2 N atoms as ring members and which optionally carries one or two substituents R a  which is/are selected, independently of each other, from halogen, CN, NO 2 , CO 2 R 4 , COR 5 , C 1 —C 4 -alkyl, C 1 —C 4 -alkoxy, C 1 —C 4 -haloalkyl, NH 2 , NHR 6 , NR 6 R 7  and C 1 —C 4 -haloalkoxy;  
 Ar is phenyl or a 6-membered heteroaromatic radical which possesses 1 or 2 N atoms as ring members and which optionally carries one or two substituents R b , which is/are selected from halogen, NO 2 , CN, CO 2 R 4 , COR 5 , NH 2 , NHR 6 , NR 6 R 7 , C 1 —C 6 -alkyl, C 1 —C 6 -haloalkyl, C 1 —C 6 -alkoxy, C 1 -C 6 s22-haloalkoxy, C 2 —C 6 -alkenyl, C 2 —C 6 -alkynyl, C 3 —C 6 -cycloalkyl, C 3 —C 6 -cycloalkoxy, C 3 —C 6 -cycloalkyl-C 1 —C 4 -alkyl and C 1 —C 4 -haloalkyl, with it also being possible for two radicals R b  which are bonded to adjacent C atoms of Ar to be together C 3 —C 4 -alkylene;  
 n is 0, 1 or 2;  
 R 1  is hydrogen, C 1 —C 4 -alkyl, C 1 —C 4 -haloalkyl, C 3 —C 6 -cycloalkyl, C 3 —C 6 -cycloalkyl-C 1 —C 4 -alkyl, C 1 —C 4 -hydroxyalkyl, C 1 —C 4 -alkoxy-C 1 —C 4 -alkyl, C 3 -C 4 -alkenyl or C 3 —C 4 -alkynyl;  
 R 2  is C 1 —C 4 -alkyl or, together with R 1 , is C 2 —C 5 -alkylene or, in the case of n=2, the two radicals R 2  can together be C 1 —C 4 -alkylene;  
 R 3  is hydrogen or C 1 —C 4 -alkyl;  
 R 3a , R 3b  are, independently of each other, hydrogen or C 1 —C 4 -alkyl;  
 R 4  is C 1 —C 4 -alkyl, C 1 —C 4 -haloalkyl, C 2 —C 4 -alkenyl C 3 —C 6 -cycloalkyl, C 3 —C 6 -cycloalkyl-C 1 —C 4 -alkyl, phenyl or benzyl; and  
 R 5  is hydrogen, C 1 —C 4 -alkyl, C 1 —C 4 -haloalkyl, C 2 —C 4 -alkenyl C 3 —C 6 -cycloalkyl,  
 C 3 —C 6 -cycloalkyl-C 1 —C 4 -alkyl, phenyl or benzyl;  
 R 6 , R 7  are each independently selected from C 1 —C 4 -alkyl, C 1 —C 4 -haloalkyl or together with the nitrogen to which they are bound form a saturated 3-, 4-, 5- or 6-membered heterocycle, which additionally may comprise an oxygen atom or an additional nitrogen atom as a ring member and which may carry 1, 2, 3 or 4 C 1 —C 4  alkyl groups;  
 the N-oxides thereof and the physiologically tolerated acid addition salts of these compounds;  
 with the exception of the compounds: 4-methyl-N-[6-(4-methylpiperazin-1-yl)pyridin-3-yl)benzenesulfonamide and 4-chloro-N-[6-(4-methylpiperazin-1-yl)pyridin-3-yl)benzenesulfonamide.  
 
   
   
       2 . The compound as claimed in  claim 1 , wherein R is N—R 3  with R 3  being H or C 1 —C 4 -alkyl.  
   
   
       3 . The compound as claimed in  claim 2 , wherein 
 Q is a bivalent, 6-membered heteroaromatic radical which possesses 1 or 2 N atoms as ring members and which optionally carries one or two substituents    R a  which is/are selected, independently of each other, from halogen, CN, NO 2 , CO 2 R 4 , COR 5 , C 1 —C 4 -alkyl and C 1 —C 4 -haloalkyl and    Ar is phenyl or a 6-membered heteroaromatic radical which possesses 1 or 2N atoms as ring members and which optionally carries one or two substituents R b , which is/are selected from halogen, NO 2 , CN, CO 2 R 4 , COR 5 , C 1 —C 6 -alkyl, C 2 —C 6 -alkenyl, C 2 —C 6 -alkynyl, C 3 —C 6 -cycloalkyl, C 3 —C 6 -cycloalkyl-C\pard plain 1 -C 4 -alkyl and C 1 —C 4 -haloalkyl, with it also being possible for two radicals R b  which are bonded to adjacent C atoms of Ar to be together C 3 —C 4 -alkylene.    
   
   
       4 . The compound as claimed in  claim 1 , in which the piperazine ring is bonded to the heteroaromatic radical Q in the para position in relation to the group R—SO 2 —Ar.  
   
   
       5 . The compound as claimed in  claim 1 , in which Q is a radical of the formula  
     
       
         
         
             
             
         
       
       in which A 1 , A 2  and A 3  are, independently of each other, N or CH, one or two of the variables A 1 , A 2  and A 3  can also be C—R a , k=0 or 1 and R a  is selected from halogen, C 1 -C 4 -alkyl, C 1 —C 4 -haloalkyl, C 1 —C 4 -alkoxy, NH 2 , NHR 6 , NR 6 R 7 s22 and C 1 —C 4 -haloalkoxy, with A 1 , A 2  and A 3  not simultaneously being N or simultaneously being selected from CH and C—R a .  
     
   
   
       6 . The compound as claimed in  claim 5 , in which A 3  is nitrogen, A 2  is CH and A 1  is N or CH and wherein the piperazine radical is located in the 2 position.  
   
   
       7 . The compound as claimed in  claim 6 , in which Q is pyridin-2,5-diyl which carries the piperazine radical in the 2 position.  
   
   
       8 . The compound as claimed in  claim 6 , in which Q is a radical of the formula  
     
       
         
         
             
             
         
       
       in which A 1  and A 2  are, independently of each other, N or CH and R a  is selected from, C 1 —C 4 -alkoxy, NH 2 , NHR 6 , NR 6 R 7  and C 1 —C 4 -haloalkoxy.  
     
   
   
       9 . The compound as claimed in  claim 8 , in which A 1  is N or CH and A 2  is CH and wherein the piperazine radical is located in the 2 position.  
   
   
       10 . The compound as claimed in  claim 1 , in which the radical Ar carries a substituent R b  in the para position and, where appropriate, a further substituent R b  in the meta position or in the ortho position, in each case based on the binding site of the sulfonamide group.  
   
   
       11 . The compound as claimed in  claim 1 , in which Ar is phenyl or pyridyl, which radicals possess, where appropriate, one or 2 R b  substituents.  
   
   
       12 . The compound as claimed in  claim 1 , in which R 1  is different from hydrogen and methyl.  
   
   
       13 . The compound as claimed in  claim 1  of the general formula Ia  
     
       
         
         
             
             
         
       
     
     in which n, R 1 , R 2 , R 3 , R a  and R b  have the meanings given in  claim 1  and in which either 
 A 1 , A 2  and A 3  are, independently of each other, N or CH and one or two of the variables A 1 , A 2  and A 3  can also be C—R a , with Al, A 2  and A 3  not simultaneously being N or simultaneously being selected from CH and C—R a ,  
 X and Y are selected from CH, C—R b′  and N, in which R b′  is halogen, methyl, CN, difluoromethyl or trifluoromethyl, with X and Y not simultaneously being N or simultaneously being C—R b′ , and  
 k is O or 1.  
 
   
   
       14 . The compound of the formula Ia as claimed in  claim 13 , in which k=0, with A 1 , A 2  and A 3  being, independently of each other, N or CH and A 1 , A 2  and A 3  not simultaneously being N or simultaneously being CH.  
   
   
       15 . The compound of the formula Ia as claimed in  claim 14 , in which A 1  is CH or N, A 2  is CH and A 3  is N.  
   
   
       16 . The compound of the formula Ia as claimed in  claim 13 , in which k is 1, A 1  is CH or N, A 2  is CH and A 3  is N, and R a  is selected from, C 1 —C 4 -alkoxy, NH 2 , NHR 6 , NR 6 R 7  and C 1 —C 4 -haloalkoxy and R a  is bound to the carbon atom adjacent to A 3 .  
   
   
       17 . The compound of the formula Ia as claimed in  claim 13 , in which n is 0 or 1 and, in the case of n=1, R 2  is bonded to the C atom of the piperazine ring which is adjacent to the group R 1 —N and is a methyl group having the S configuration.  
   
   
       18 . The compound of the formula Ia as claimed  claim 13 , in which the radical Ar carries a substituent R b  in the para position and, where appropriate, a further substituent R b  in the meta position or in the ortho position, in each case based on the binding site of the sulfonamide group.  
   
   
       19 . The compound of the formula Ia as claimed in  claim 13 , in which Ar is phenyl or pyridyl, which radicals possess, where appropriate, one or 2 R b  substituents.  
   
   
       20 . The compound of the -formula Ia as claimed in  claim 13 , in which R 1  is different from hydrogen and methyl.  
   
   
       21 . The compound of the formula Ia as claimed in  claim 13 , of the general formula Ia.1  
     
       
         
         
             
             
         
       
     
     in which n, X, Y, R 1 , R 2 , R 3 , R a  and R b  have the meanings given in  claim 13  and q is 0, 1 or 2.  
   
   
       22 . The compound of the formula Ia as claimed in  claim 13  of the general formula Ia.2  
     
       
         
         
             
             
         
       
     
     in which n, X, Y, R 1 , R 2 , R 3 , R a  and R b  have the meanings given in  claim 13  and q is 0 or 1.  
   
   
       23 . A pharmaceutical composition which comprises at least one N-[(piperazinyl)hetaryl]arylsulfonamide compound as claimed in  claim 1  and/or at least one physiologically tolerated acid addition salt of I and/or an N-oxide of 1, where appropriate together with physiologically acceptable carriers and/or auxiliary substances.  
   
   
       24 . The use of at least one N-[(piperazinyl)hetaryl]arylsulfonamide compound of the formula I  
     
       
         
         
             
             
         
       
     
     in which Q, Ar, n, R 1 , R 2  and R 3  have the previously mentioned meanings, of the N-oxides thereof and of the physiologically tolerated acid addition salts thereof for producing a pharmaceutical composition for treating diseases which respond to influencing by dopamine D 3  receptor antagonists or dopamine D 3  agonists.  
   
   
       25 . The use as claimed in  claim 24  for treating diseases of the central nervous system.  
   
   
       26 . The use as claimed in  claim 24  for treating kidney function disturbances.  
   
   
       27 . A method for treating a medical disorder susceptible to treatment with a dopamine D 3  receptor antagonist or a dopamine D 3  agonist, said method comprising administering an effective amount of at least one compound of the  claim 1   
     
       
         
         
             
             
         
       
     
     to a subject in need thereof.  
   
   
       28 . The method as claimed in  claim 27 , wherein the medical disorder is a disease of the central nervous system.  
   
   
       29 . The method as claimed in  claim 27  wherein the medical disorder is a disturbance of kidney function.