Triazole compounds suitable for treating disorders that respond to modulation of the dopamine d3 receptor

Abstract

The invention relates to compounds of formula (I), wherein n is 1 or 2, Ar is a C-bound 1,2,4-triazol radical which carries a radical R 1 on the remaining carbon atom and a radical R 1a on one of the nitrogen atoms; R 1 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxymethyl, fluorinated C 1 -C 6 alkyl, fluorinated C 3 -C 6 cycloalkyl, fluorinated C 1 -C 4 alkoxymethyl, or optionally substituted phenyl or 5- or 6-membered heteroaryl; R 1a is hydrogen or C 1 -C 4 alkyl; and R 2 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, fluorinated C 1 -C 6 alkyl or fluorinated C 3 -C 6 cycloalkyl; and to the physiologically tolerated acid addition salts of there compounds. The invention also relates to a pharmaceutically composition that comprises at least one triazole compound of the formula (I) and/or at least one physiologically tolerated acid addition salt thereof, and further to a method for treating disorders that respond beneficially to dopamine D 3 receptor antagonists or dopamine D 3 agonists, said method comprising administering an effective amount of at least one triazole compound or physiologically tolerated acid addition salt of the formula (I) to a subject in need thereof.

1 . Triazole compounds of the formula I 
       
         
           
           
               
               
           
         
         wherein 
         n is 1 or 2; 
         Ar is a C-bound 1,2,4-triazol radical which carries a radical R 1  on the remaining carbon atom and a radical R 1a  on one of the nitrogen atoms; 
         R 1  is hydrogen, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 1 -C 4  alkoxymethyl, fluorinated C 1 -C 6  alkyl, fluorinated C 3 -C 6  cycloalkyl, fluorinated C 1 -C 4  alkoxymethyl,
 phenyl or 5- or 6-membered heteroaryl, wherein phenyl and heteroaryl may be unsubstituted or substituted by 1, 2, 3 or 4 radicals R a  selected independently of each other from halogen, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 1 -C 4  alkoxy-C 1 -C 4 -alkyl, fluorinated C 1 -C 4  alkyl, CN, NO 2 , OR 3 , NR 3 R 4 , C(O)NR 3 R 4 , O—C(O)NR 3 R 4 , SO 2 NR 3 R 4 , COOR 5 , SR 6 , SOR 6 , SO 2 R 6 , O—C(O)R 7 , COR 7  or C 3 -C 5  cycloalkylmethyl, wherein phenyl and heteroaryl may also carry a phenyl group or an aromatic 5- or 6-membered C-bound heteroaromatic radical, comprising 1 nitrogen atom as ring member and 0, 1, 2 or 3 further heteroatoms, independently of each other, selected from O, S and N, wherein the last two mentioned radicals may carry 1, 2, 3 or 4 of the aforementioned radicals R a ; 
 
         R 1a  is hydrogen or C 1 -C 4 -alkyl; 
         R 2  is C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, fluorinated C 1 -C 6  alkyl or fluorinated C 3 -C 6  cycloalkyl; 
         R 3 , R 4 , R 5 , R 6 , and R 7  independent of each other are H, C 1 -C 6  alkyl, optionally substituted with OH, C 1 -C 4  alkoxy or phenyl, C 1 -C 4  haloalkyl or phenyl, which may carry 1, 2 or 3 radicals selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkoxy, NR 3a R 4 a, CN, C 1 -C 2  fluoroalkyl and halogen, wherein R 3a  and R 4a  are independent of each other H, C 1 -C 6  alkyl, optionally substituted with OH, C 1 -C 4  alkoxy or phenyl, C 1 -C 4  haloalkyl or phenyl, which may carry 1, 2 or 3 radicals selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkoxy, amino, NH(C 1 -C 4  alkyl) and N(C 1 -C 4  alkyl) 2 , R 4  may also be a radical COR 8 , wherein R 8  is hydrogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy or phenyl, which may carry 1, 2 or 3 radicals selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkoxy, NR 3 R 4 , CN, C 1 -C 2  fluoroalkyl and halogen, R 3  and R 4  may together with the nitrogen atom to which they are bound form a N-bound 5 or 6 membered saturated heterocyle, which 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 6  alkyl groups 
       
       and the physiologically tolerated acid addition salts of these compounds. 
     
     
         2 . A compound as claimed in  claim 1 , wherein Ar is a radical of the formula Ar-1, 
       
         
           
           
               
               
           
         
         wherein # denotes the binding position to the Sulfur atom of the group S(O) n  and R 1  is as defined in  claim 1 . 
       
     
     
         3 . A compound as claimed in  claim 1 , wherein Ar is a radical of the formula Ar-2, 
       
         
           
           
               
               
           
         
         wherein # denotes the binding position to the Sulfur atom of the group S(O) n  and R 1  and R 1a  are as defined in  claim 1 . 
       
     
     
         4 . A compound as claimed in  claim 1 , wherein Ar is a radical of the formula Ar-3, 
       
         
           
           
               
               
           
         
         wherein # denotes the binding position to the Sulfur atom of the group S(O) n  and R 1 R 1  and R 1a  are as defined in  claim 1 . 
       
     
     
         5 . A compound as claimed in any of  claim 1 ,  2 ,  3  or  4 , wherein R 1  is selected from the group consisting of hydrogen, C 1 -C 4  alkyl, C 3 -C 5  cycloalkyl, C 1 -C 4  alkoxymethyl and trifluoromethyl. 
     
     
         6 . A compound as claimed in any of  claim 1 ,  2 ,  3  or  4 , wherein R 1  is hydrogen or methyl. 
     
     
         7 . A compound as claimed in any of  claim 1 ,  2 ,  3  or  4 , wherein R 2  is selected from the group consisting of C 3 -C 4  alkyl or fluorinated C 1 -C 2  alkyl. 
     
     
         8 . A compound as claimed in any of  claim 1 ,  2 ,  3  or  4 , wherein R 2  is selected from the group consisting of n-propyl, isopropyl and tert-butyl. 
     
     
         9 . A compound as claimed in any of  claim 1 ,  2 ,  3  or  4 , wherein R 2  is tert-butyl. 
     
     
         10 . A compound as claimed in  claim 9 , wherein R 1  is hydrogen. 
     
     
         11 . A compound as claimed in  claim 9 , wherein R 1  is methyl. 
     
     
         12 . A compound as claimed in any of  claim 1 ,  2 ,  3  or  4 , wherein R 2  is selected from the group consisting of trifluoromethyl and difluoromethyl. 
     
     
         13 . A compound as claimed any of  claim 1 ,  2 ,  3  or  4 , wherein R 2  is trifluoromethyl. 
     
     
         14 . A compound as claimed in  claim 13 , wherein R 1  is hydrogen. 
     
     
         15 . A compound as claimed in  claim 13 , wherein R 1  is methyl. 
     
     
         16 . A compound as claimed in any of  claim 1 ,  2 ,  3  or  4 , wherein R 2  is C 3 -C 4  cycloalkyl or fluorinated C 3 -C 4  cycloalkyl. 
     
     
         17 . A compound as claimed in  claim 16 , wherein R 1  is hydrogen. 
     
     
         18 . A compound as claimed in  claim 16 , wherein R 1  is methyl. 
     
     
         19 . A pharmaceutical composition comprising at least one compound as claimed in any of  claim 1 ,  2 ,  3  or  4  together with at least one physiologically acceptable carrier or auxiliary substance. 
     
     
         20 . A method for treating a medical disorder of the central nervous system 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 as claimed in any of  claim 1 ,  2 ,  3  or  4  to a subject in need thereof. 
     
     
         21 . The method as claimed in  claim 20 , wherein the medical disorder is schizophrenia. 
     
     
         22 . Triazole compounds of the formula IIa 
       
         
           
           
               
               
           
         
         wherein 
         Ar is a C-bound 1,2,4-triazol radical which carries a radical R 1  on the remaining carbon atom and a radical R 18  on one of the nitrogen atoms; 
         R 1  is selected from the group consisting of C 2 -C 6 -alkyl, fluorinated C 1 -C 6 -alkyl, C 3 -C 6  cycloalkyl, C 1 -C 4  alkoxymethyl, fluorinated C 3 -C 6  cycloalkyl and fluorinated C 1 -C 4  alkoxymethyl; 
         R 1a  is hydrogen or C 1 -C 4  alkyl; and 
         R 2  is C 1 -C 6  alkyl or fluorinated C 1 -C 6  alkyl; 
         and the physiologically tolerated acid addition salts of these compounds. 
       
     
     
         23 . The compound as claimed in  claim 22 , wherein Ar is a radical of the formula Ar-1, 
       
         
           
           
               
               
           
         
         wherein # denotes the binding position to the Sulfur atom of the group S(O) n  and R 1  is as defined in  claim 22 . 
       
     
     
         24 . A compound as claimed in  claim 22 , wherein Ar is a radical of the formula Ar-2, 
       
         
           
           
               
               
           
         
         wherein # denotes the binding position to the Sulfur atom of the group S(O) r , and R 1  and R 1a  are as defined in  claim 22 . 
       
     
     
         25 . A compound as claimed in  claim 22 , wherein Ar is a radical of the formula Ar-3, 
       
         
           
           
               
               
           
         
         wherein # denotes the binding position to the Sulfur atom of the group S(O) n  and R 1 R 1  and R 1a  are as defined in  claim 22 . 
       
     
     
         26 . A compound as claimed in any of  claim 22 ,  23 ,  24  or  25 , wherein R 1  is selected from the group consisting of C 2 -C 4 -alkyl, trifluoromethyl, C 3 -C 5  cycloalkyl and C 1 -C 4  alkoxymethyl. 
     
     
         27 . A compound as claimed in any of  claim 22 ,  23 ,  24  or  25 , wherein R 2  is selected from the group consisting of C 3 -C 4  alkyl or fluorinated C 1 -C 2  alkyl. 
     
     
         28 . A compound as claimed in any of  claim 22 ,  23 ,  24  or  25 , wherein R 2  is selected from the group consisting of n-propyl, isopropyl and tert-butyl. 
     
     
         29 . A compound as claimed in any of  claim 22 ,  23 ,  24  or  25 , wherein R 2  is tert-butyl. 
     
     
         30 . A compound as claimed in any of  claim 22 ,  23 ,  24  or  25 , wherein R 2  is selected from the group consisting of trifluoromethyl and difluoromethyl. 
     
     
         31 . A compound as claimed in any of  claim 22 ,  23 ,  24  or  25 , wherein R 2  is trifluoromethyl. 
     
     
         32 . A pharmaceutical composition comprising at least one compound as claimed in any of  claim 22 ,  23 ,  24  or  25  together with at least one physiologically acceptable carrier or auxiliary substance. 
     
     
         33 . A method for treating a medical disorder of the central nervous system 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 as claimed in claim any of  claim 22 ,  23 ,  24  or  25  to a subject in need thereof. 
     
     
         34 . The method as claimed in  claim 33 , wherein the medical disorder is schizophrenia.