Aryl fused azapolycyclic compounds

Abstract

Compounds of the formula and their pharmaceutically acceptable salts, wherein R 1 , R 2 , R 3 and n are defined as in the specification, intermediates in the synthesis of such compounds, pharmaceutical compositions containing such compounds and methods of using such compounds in the treatment of neurological and psychological disorders are claimed.

1 . A pharmaceutical composition for use in treating addiction to alcohol in a mammal, comprising a compound of the formula  
     
       
         
         
             
             
         
       
       R 1  is hydrogen, (C 1 -C 6 )alkyl, unconjugated (C 3 -C 6 )alkenyl, XC(═O)R 13  or —CH 2 CH 2 —O—(C 1 -C 4 )alkyl;  
       R 2  and R 3  are selected, independently, from hydrogen, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, hydroxy, nitro, amino, halo, cyano, —SO q (C 1 -C 6 )alkyl wherein q is zero, one or two, (C 1 -C 6 )alkylamino-, [(C 1 -C 6 )alkyl] 2 amino-, —CO 2 R 4 , —CONR 5 R 6 , —SO 2 NR 7 R 8 , —C(═O)R 13 , —XC(═O)R 13 , aryl-(C 0 -C 3 )alkyl- or aryl-(C 0 -C 3 )alkyl-O—, wherein said aryl is selected from phenyl and naphthyl, heteroaryl-(C 0 -C 3 )alkyl- or heteroaryl-(C 0 -C 3 )alkyl-O—, wherein said heteroaryl is selected from five to seven membered aromatic rings containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur, and X 2  (C 0 -C 6 )alkoxy-(C 0 -C 6 )alkyl-, wherein X 2  is absent or X 2  is (C 1 -C 6 )alkylamino- or [(C 1 -C 6 )alkyl] 2 amino-, and wherein the (C 0 -C 6 )alkoxy-(C 0 -C 6 )alkyl- moiety of said X 2  (C 0 -C 6 )alkoxy-(C 0 -C 6 )alkyl- contains at least one carbon atom, and wherein from one to three of the carbon atoms of said (C 0 -C 6 )alkoxy-(C 0 -C 6 )alkyl- moiety may optionally be replaced by an oxygen, nitrogen or sulfur atom, with the proviso that any two such heteroatoms must be separated by at least two carbon atoms, and wherein any of the alkyl moieties of said (C 0 -C 6 )alkoxy-(C 0 -C 6 )alkyl- may be optionally substituted with from two to seven fluorine atoms, and wherein one of the carbon atoms of each of the alkyl moieties of said aryl-(C 0 -C 3 )alkyl- and said heteroaryl-(C 0 -C 3 )alkyl- may optionally be replaced by an oxygen, nitrogen or sulfur atom, and wherein each of the foregoing aryl and heteroaryl groups may optionally be substituted with one or more substituents, preferably from zero to two substituents, independently selected from (C 1 -C 6 )alkyl optionally substituted with from one to seven fluorine atoms, (C 1 -C 6 )alkoxy optionally substituted with from two to seven fluorine atoms, halo (e.g., chloro, fluoro, bromo or iodo), (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, hydroxy, nitro, cyano, amino, (C 1 -C 6 )alkylamino-, [(C 1 -C 6 ) alkyl] 2 amino-, —CO 2 R 4 , —CONR 5 R 6 , —SO 2 NR 7 R 8 , —C(═O)R 13  and —XC(═O)R 13 ;  
       or R 2  and R 3 , together with the carbons to which they are attached, form a four to seven membered monocyclic, or ten to fourteen membered bicyclic, carbocyclic ring that can be saturated or unsaturated, wherein from one to three of the nonfused carbon atoms of said monocyclic rings, and from one to five of the carbon atoms of said bicyclic rings that are not part of the benzo ring shown in formula I, may optionally and independently be replaced by a nitrogen, oxygen or sulfur, and wherein said monocyclic and bicyclic rings may optionally be substituted with one or more substituents, preferably from zero to two substituents for the monocyclic rings and from zero to three substituents for the bicyclic rings, that are selected, independently, from (C 1 -C 6 ) alkyl optionally substituted with from one to seven fluorine atoms, (C 1 -C 6 ) alkoxy optionally substituted with from one to seven fluorine atoms, nitro, cyano, halo, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, hydroxy, amino, (C 1 -C 6 )alkylamino and [(C 1 -C 6 ) alkyl] 2 amino, —CO 2 R 4 , —CONR 5 R 6 , —SO 2 NR 7 R 8 , —C(═O)R 13  and —XC(═O)R 13 ;  
       each R 4 , R 5 , R 6 , R 7 , R 8  and R 13  is selected, independently, from hydrogen and (C 1 -C 6 ) alkyl, or R 5  and R 6 , or R 7  and R 8  together with the nitrogen to which they are attached, form a pyrrolidine, piperidine, morpholine, azetidine, piperizine, N—(C 1 -C 6 )alkylpiperizine or thiomorpholine ring, or a thiomorpholine ring wherein the ring sulfur is replaced with a sulfoxide or sulfone; and  
       each X is, independently, (C 1 -C 6 )alkylene;  
       with the proviso that: (a) at least one of R 1 , R 2  and R 3  must be the other than hydrogen, and (b) when R 2  and R 3  are both hydrogen, R 1  cannot be hydrogen or methyl;  
       or a pharmaceutically acceptable salt thereof;  
       said compound being present in an amount that is effective in treating addiction to alcohol, and a pharmaceutically acceptable carrier.  
     
   
   
       2 . The pharmaceutical composition according to  claim 1 , wherein R 2  and R 3 , together with the benzo ring of formula I, form a bicyclic ring system selected from the following:  
     
       
         
         
             
             
         
       
       wherein R 10  and R 17  are selected, independently, from (C 0 -C 6 )alkoxy-(C 0 -C 6 )alkyl- wherein the total number of carbon atoms does not exceed six and wherein any of the alkyl moieties may optionally be substituted with from one to seven fluorine atoms; nitro, cyano, halo, amino, (C 1 -C 6 )alkylamino-, [(C 1 -C 6 )alkyl] 2 amino-, —CO 2 R 4 , —CONR 5 R 6 , —SO 2 NR 7 R 8 , —C(═O)R 13 —XC(═O)R 13 , phenyl and monocyclic heteroaryl, wherein said heteroaryl is selected from five to seven membered aromatic rings containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur.  
     
   
   
       3 . The pharmaceutical composition according to  claim 1 , wherein the compound is: 
 5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9 ]hexadeca-2(11),3,5,7,9-pentaene; or, a pharma-ceutically acceptable salt thereof.    
   
   
       4 . The pharmaceutical composition according to  claim 1 , wherein the pharmaceutically acceptable salt is the citrate or tartrate salt.  
   
   
       5 . A pharmaceutical composition for use in treating attention deficit hyperactivity disorder in a mammal, comprising a compound of the formula  
     
       
         
         
             
             
         
       
       R 1  is hydrogen, (C 1 -C 6 )alkyl, unconjugated (C 3 -C 6 )alkenyl, XC(═O)R 13  or —CH 2 CH 2 —O—(C 1 -C 4 )alkyl;  
       R 2  and R 3  are selected, independently, from hydrogen, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, hydroxy, nitro, amino, halo, cyano, —SO q (C 1 -C 6 )alkyl wherein q is zero, one or two, (C 1 -C 6 )alkylamino-, [(C 1 -C 6 )alkyl] 2 amino-, —CO 2 R 4 , —CONR 5 R 6 , —SO 2 NR 7 R 8 , —C(═O)R 13 —XC(═O)R 13 , aryl-(C 0 -C 3 )alkyl- or aryl-(C 0 -C 3 )alkyl-O—, wherein said aryl is selected from phenyl and naphthyl, heteroaryl-(C 0 -C 3 )alkyl- or heteroaryl-(C 0 -C 3 )alkyl-O—, wherein said heteroaryl is selected from five to seven membered aromatic rings containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur, and X 2  (C 0 -C 6 )alkoxy-(C 0 -C 6 )alkyl-, wherein X 2  is absent or X 2  is (C 1 -C 6 )alkylamino- or [(C 1 -C 6 )alkyl] 2 amino-, and wherein the (C 0 -C 6 )alkoxy-(C 0 -C 6 )alkyl- moiety of said X 2  (C 0 -C 6 )alkoxy-(C 0 -C 6 )alkyl- contains at least one carbon atom, and wherein from one to three of the carbon atoms of said (C 0 -C 6 )alkoxy-(C 0 -C 6 )alkyl- moiety may optionally be replaced by an oxygen, nitrogen or sulfur atom, with the proviso that any two such heteroatoms must be separated by at least two carbon atoms, and wherein any of the alkyl moieties of said (C 0 -C 6 )alkoxy-(C 0 -C 6 )alkyl- may be optionally substituted with from two to seven fluorine atoms, and wherein one of the carbon atoms of each of the alkyl moieties of said aryl-(C 0 -C 3 )alkyl- and said heteroaryl-(C 0 -C 3 )alkyl- may optionally be replaced by an oxygen, nitrogen or sulfur atom, and wherein each of the foregoing aryl and heteroaryl groups may optionally be substituted with one or more substituents, preferably from zero to two substituents, independently selected from (C 1 -C 6 )alkyl optionally substituted with from one to seven fluorine atoms, (C 1 -C 6 )alkoxy optionally substituted with from two to seven fluorine atoms, halo (e.g., chloro, fluoro, bromo or iodo), (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, hydroxy, nitro, cyano, amino, (C 1 -C 6 )alkylamino-, [(C 1 -C 6 ) alkyl] 2 amino-, —CO 2 R 4 , —CONR 5 R 6 , —SO 2 NR 7 R 8 , —C(═O)R 13  and —XC(═O)R 13 ;  
       or R 2  and R 3 , together with the carbons to which they are attached, form a four to seven membered monocyclic, or ten to fourteen membered bicyclic, carbocyclic ring that can be saturated or unsaturated, wherein from one to three of the nonfused carbon atoms of said monocyclic rings, and from one to five of the carbon atoms of said bicyclic rings that are not part of the benzo ring shown in formula I, may optionally and independently be replaced by a nitrogen, oxygen or sulfur, and wherein said monocyclic and bicyclic rings may optionally be substituted with one or more substituents, preferably from zero to two substituents for the monocyclic rings and from zero to three substituents for the bicyclic rings, that are selected, independently, from (C 1 -C 6 ) alkyl optionally substituted with from one to seven fluorine atoms, (C 1 -C 6 ) alkoxy optionally substituted with from one to seven fluorine atoms, nitro, cyano, halo, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, hydroxy, amino, (C 1 -C 6 )alkylamino and [(C 1 -C 6 ) alkyl] 2 amino, —CO 2 R 4 , —CONR 5 R 6 , —SO 2 NR 7 R 8 , —C(═O)R 13  and —XC(═O)R 13 ;  
       each R 4 , R 5 , R 6 , R 7 , R 8  and R 13  is selected, independently, from hydrogen and (C 1 -C 6 ) alkyl, or R 5  and R 6 , or R 7  and R 8  together with the nitrogen to which they are attached, form a pyrrolidine, piperidine, morpholine, azetidine, piperizine, N—(C 1 -C 6 )alkylpiperizine or thiomorpholine ring, or a thiomorpholine ring wherein the ring sulfur is replaced with a sulfoxide or sulfone; and  
       each X is, independently, (C 1 -C 6 )alkylene;  
       with the proviso that: (a) at least one of R 1 , R 2  and R 3  must be the other than hydrogen, and (b) when R 2  and R 3  are both hydrogen, R 1  cannot be hydrogen or methyl;  
       or a pharmaceutically acceptable salt thereof;  
       said compound being present in an amount that is effective in treating attention deficit hyperactivity disorder, and a pharmaceutically acceptable carrier.  
     
   
   
       6 . The pharmaceutical composition according to  claim 5 , wherein the compound is: 
 5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9 ]hexadeca-2(11),3,5,7,9-pentaene; or a pharmaceutically acceptable salt thereof.    
   
   
       7 . The pharmaceutical composition according to  claim 5 , wherein the pharmaceutically acceptable salt is the citrate or tartrate salt.  
   
   
       8 . A method for treating addiction to alcohol in a mammal, comprising administering to said mammal an amount of a composition according to  claim 1  that is effective in treating addiction to alcohol.  
   
   
       9 . The method according to  claim 8  for treating addiction to alcohol in a mammal wherein the compound is 5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9 ]hexadeca-2(11),3,5,7,9-pentaene; or a pharmaceutically acceptable salt thereof.  
   
   
       10 . The method according to  claim 8 , wherein the pharmaceutically acceptable salt is the citrate or tartrate salt.  
   
   
       11 . A method for treating attention deficit hyperactivity disorder in a mammal, comprising administering to said mammal an amount of a composition according to  claim 5  that is effective in treating attention deficit hyperactivity disorder.  
   
   
       12 . The method according to  claim 11 , wherein the compound is 5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9 ]hexadeca-2(11),3,5,7,9-pentaene; or a pharmaceutically acceptable salt thereof.  
   
   
       13 . The method according to  claim 11 , wherein the pharmaceutically acceptable salt is the citrate or tartrate salt.