Novel muscarinic receptor agonists

Abstract

This invention relates to a novel class of partial or full muscarinic receptor agonists intermediates for their preparation, and pharmaceutical compositions and methods of use for the treatment or prevention of diseases the treatment or prevention of which is mediated by muscarinic receptor agonism

1 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein X is NR 4 R 5 , (C 1 -C 10 )alkyl or (C 3 -C 10 )cycloalkyl, wherein said (C 3 -C 10 )cycloalkyl may optionally be substituted with from one to three substituents independently selected from the group consisting of —OR 6 , (C 1 -C 4 )alkyl, oxo and a ketal of the formula —O—(CH 2 )n—O—; 
 n is an integer from one to three;  
 m is an integer from one to three;  
 p is an integer from one to three;  
 Y is N or CH;  
 Z is NR 7 R 8 , (C 3 -C 10 )cycloalkyl, (C 1 -C 10 )alkyl, pyridyl or phenyl; wherein said phenyl or (C 3 -C 10 )cycloalkyl may optionally be substituted with from one to three substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo, hydroxy, (C 1 -C 6 )alkoxy, amino, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )-alkylamino and trifluoromethoxy;  
 R 2  is phenyl optionally substituted with from one to three substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo, hydroxy, (C 1 -C 6 )alkoxy, amino, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )-alkylamino, —CF 3 , —CN, —CORR 6 , NHCOR 6  and trifluoromethoxy;  
 R 3  is phenyl optionally substituted with from one to three substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo, hydroxy, (C 1 -C 6 )alkoxy, amino, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )-alkylamino and trifluoromethoxy;  
 R 4  and R 5  are independently (C 1 -C 10 )alkyl or R 4  and R 5  taken together with the nitrogen atom to which they are attached form a (five to nine)-membered saturated heterocyclic ring in which one of the ring atoms may optionally be replaced with a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, wherein said (five to nine)-membered saturated heterocyclic ring may optionally be substituted with from one to three substituents independently selected from the group consisting of —OR 6 , (C-C 4 )alkyl, oxo and a ketal of the formula —O—(CH 2 ) m —O—; with the proviso that said substituted heterocycles may not be substituted next to a heteroatom by hydroxy or a ketal;  
 R 6  is hydrogen or (C 1 -C 8 )alkyl; and  
 R 7  and R 8  are independently (C 1 -C 10 )alkyl or R 7  and R 8  taken together with the nitrogen atom to which they are attached form a (five to seven)-membered saturated heterocyclic ring in which one of the ring atoms may optionally be replaced with a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, wherein said (five to seven)-membered saturated heterocyclic ring may optionally be substituted with from one to three substituents independently selected from the group consisting of —OR 6 , (C 1 -C 4 )alkyl, oxo and a ketal of the formula —O—(CH 2 ) p —O—; with the proviso that said substituted heterocycles may not be substituted in the two position by hydroxy or a ketal;  
 and the pharmaceutically acceptable salts thereof.  
 
     
     
         2 . A compound according to  claim 1 , wherein Z is pyridyl, or phenyl optionally substituted with from one to three substituents independently selected from the group consisting of (C-C 6 )alkyl, halo, hydroxy, (C 1 -C 6 )alkoxy, amino, (C 1 -C 6 ,)alkylamino, di(C 1 -C 6 )-alkylamino and trifluoromethoxy.  
     
     
         3 . A compound according to  claim 2 , wherein X is NR 4 R 5  and R 4  and R 5  are taken together with the nitrogen atom to which they are attached to form an optionally substituted (five to nine)-membered saturated heterocyclic ring selected from piperidine, pyrrolidine, thiomorpholine, hexamethylenimine, morpholine, thiazolidine and 1,2-tetrahydrooxazine.  
     
     
         4 . A compound according to  claim 3 , wherein X is an optionally substituted heterocycle selected from the group consisting of piperidine and 1,2-tetrahydrooxazine.  
     
     
         5 . A compound according to  claim 3 , wherein R 2  is phenyl optionally substituted with halo, hydroxy or methoxy.  
     
     
         6 . A compound according to  claim 4 , wherein R 2  is phenyl optionally substituted with halo, hydroxy or methoxy.  
     
     
         7 . A compound according to  claim 6 , wherein R 2  is phenyl substituted in the 4-position of the phenyl ring with fluoro or methoxy.  
     
     
         8 . A compound according to  claim 3 , wherein R 3  is phenyl substituted with two substituents independently selected from (C-C 6 )alkyl, halo, hydroxy, (C-C 6 )alkoxy, amino, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )-alkylamino and trifluoroalkoxy.  
     
     
         9 . A compound according to  claim 4 , wherein R 3  is phenyl substituted with two substituents independently selected from (C 1 -C 6 )alkyl, halo, hydroxy, (C 1 -C 6 )alkoxy, amino, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )-alkylamino and trifluoroalkoxy.  
     
     
         10 . A compound according to  claim 6 , wherein R 3  is phenyl substituted with two substituents independently selected from (C 1 -C 6 )alkyl, halo, hydroxy, (C 1 -C 6 )alkoxy, amino, (C 1 -C 6 )alkylamino di(C 1 -C 6 )-alkylamino and trifluoroalkoxy.  
     
     
         11 . A compound according to  claim 4  wherein said piperidine is substituted in the two position with (C 1 -C 4 )alkyl.  
     
     
         12 . A compound according to  claim 8  wherein said piperidine is substituted in the two position with (C 1 -C 4 )alkyl.  
     
     
         13 . A compound according to  claim 10  wherein said piperidine is substituted in the two position with (C 1 -C 4 )alkyl.  
     
     
         14 . A compound according to  claim 11 , wherein R 3  is 2,6-dimethylphenyl.  
     
     
         15 . A compound according to  claim 12 , wherein R 3  is 2,6-dimethylphenyl.  
     
     
         16 . A compound according to  claim 13 , wherein R 3  is 2,6-dimethylphenyl.  
     
     
         17 . A pharmaceutical composition for treating or preventing a disease or condition, the treatment or prevention of which can be effected or facilitated by enhancing cholinergic neurotransmission in a mammal, comprising a muscarinic receptor binding effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.  
     
     
         18 . A method of treating or preventing a disease or condition, the treatment or prevention of which can be effected or facilitated by enhancing cholinergic neurotransmission in a mammal, comprising administering to said mammal a muscarinic receptor binding effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof.  
     
     
         19 . A pharmaceutical composition for treating or preventing a disease or condition, the treatment or prevention of which can be effected or facilitated by enhancing cholinergic neurotransmission in a mammal, comprising administering to said mammal an amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof that is effective in treating or preventing such condition.  
     
     
         20 . A method of treating or preventing a disease or condition, the treatment or prevention of which can be effected or facilitated by enhancing cholinergic neurotransmission in a mammal, comprising administering to said mammal an amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof that is effective in treating or preventing such condition.  
     
     
         21 . A method of treating, preventing or diagnosing a disease or condition selected from the group consisting of psychotic disorders, pain, sleep disorders, depression, Alzheimer's disease, tardive dyskinesia, Picks disease, Huntington's chores, Friederich's ataxia, Gilles de la Tourette's disease, Down's Syndrome, attention-deficit disorder, multi-infarct dementia, and age-related cognitive decline (ARCD) in a mammal, comprising administering to a mammal in need of such treatment, prevention or diagnosis an amount of a compound according to  claim 1  effective in treating, preventing or diagnosing such condition.  
     
     
         22 . A pharmaceutical composition for treating, preventing or diagnosing a disease or condition selected from the group consisting of psychotic disorders, pain, sleep disorders, depression, Alzheimer's disease, tardive dyskinesia, Picks disease, Huntington's chorea, Friederich's ataxia, Gilles de la Tourette's disease, Down's Syndrome, attention-deficit disorder, multi-infarct dementia, and age-related cognitive decline (ARCD) in a mammal, comprising an amount of a compound according to  claim 1  effective in treating, preventing or diagnosing such condition and a pharmaceutically acceptable carrier.