Muscarinic agonists

Abstract

Compounds and methods are provided for the treatment of disease conditions in which modification of cholinergic, especially muscarinic m1, m4, or both m1 and m4, receptor activity has a beneficial effect. In the method, an effective amount of a compound is administered to a patient in need of such treatment.

1 - 76 . (canceled)  
   
   
       77 . A compound of formula (I):  
     
       
         
         
             
             
         
       
       wherein:  
       Z 1  is CR 1 , Z 2  is CR 2 , Z 3  is CR 3 , and Z 4  is CR 4 ;  
       W 1  is S, W 2  is N or CR 6 , and W 3  is CG;  
       G is of formula (II):  
       
         
           
           
               
               
           
         
       
       Y is O, S, CHOH, —NHC(O)—, —C(O)NH—, —C(O)—, —OC(O)—, —(O)CO—, —NR 7 —, —CH═N—, or absent;  
       p is 1, 2, 3, 4 or 5;  
       Z is CR 8 R 9  or absent;  
       each t is 1, 2, or 3;  
       each R 1 , R 2 , R 3 , and R 4 , independently, is H, amino, hydroxyl, halo, or straight- or branched-chain C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  heteroalkyl, C 1-6  haloalkyl, —CN, —CF 3 , —OR 11 , —COR 11 , —NO 2 , —SR 11 , —NHC(O)R 11 , —C(O)NR 12 R 13 , —NR 12 R 13 , NR 11 C(O)NR 12 R 13 , —SO 2 NR 12 R 13 , —OC(O)R 11 , —O(CH 2 ) q NR 12 R 13 , or —(CH 2 ) q NR 12 R 13 , where q is an integer from 2 to 6, or R 1  and R 2  together form —NH—N═N— or R 3  and R 4  together form —NH—N═N—;  
       each R 5 , R 6 , and R 7 , independently, is H, C 1-6  alkyl; formyl; C 3-6  cycloalkyl; C 5-6  aryl, optionally substituted with halo or C 1-6  alkyl; or C 5-6  heteroaryl, optionally substituted with halo or C 1-6  alkyl;  
       each R 8  and R 9 , independently, is H or straight- or branched-chain C 1-8  alkyl;  
       R 10  is straight- or branched-chain C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 1-8  alkylidene, C 1-8  alkoxy, or C 1-8  heteroalkyl;  
       R 10 ′ is H, straight- or branched-chain C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 1-8  alkylidene, C 1-8  alkoxy, C 1-8  heteroalkyl, C 1-8  aminoalkyl, C 1-8  haloalkyl, C 1-8  alkoxycarbonyl, C 1-8  hydroxyalkoxy, C 1-8  hydroxyalkyl, or C 1-8  alkylthio;  
       each R 11 , independently, is H, straight- or branched-chain C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 2-8  heteroalkyl, C 2-8  aminoalkyl, C 2-8  haloalkyl, C 1-8  alkoxycarbonyl, C 2-8  hydroxyalkyl, —C(O)—C 5-6  aryl substituted with C 1-3  alkyl or halo, C 5-6  aryl, C 5-6  heteroaryl, C 5-6  cycloalkyl, C 5-6  heterocycloalkyl, —C(O)NR 12 R 13 , —CR 5 R 12 R 13 , —(CH 2 ) t NR 12 R 13 , t is an integer from 2 to 8; and  
       each R 12  and R 13 , independently, is H, C 1-6  alkyl; C 3-6  cycloalkyl; C 5-6  aryl, optionally substituted with halo or C 1-6  alkyl; or C 5-6  heteroaryl, optionally substituted with halo or C 1-6  alkyl;  
       or a pharmaceutically acceptable salt, ester or prodrug thereof.  
     
   
   
       78 . The compound of  claim 77 , wherein each t is 2.  
   
   
       79 . The compound of  claim 78 , wherein R 10  is n-butyl.  
   
   
       80 . The compound of  claim 78 , wherein each R 1 , R 2 , R 3 , and R 4 , independently, is H, hydroxyl, halo, C 1-6  heteroalkyl, CF 3 , —NO 2 , or straight- or branched-chain C 1-6  alkyl, or R 1  and R 2  together form —NH—N═N— or R 3  and R 4  together form —NH—N═N—.  
   
   
       81 . The compound of  claim 78 , wherein Y is absent or O, p is 0, 1, 2 or 3, and R 8  and R 9  are H.  
   
   
       82 . The compound of  claim 81 , wherein Z is absent, Y is absent and p is 3.  
   
   
       83 . The compound of  claim 82 , wherein R 10  is n-butyl.  
   
   
       84 . The compound of  claim 77 , wherein the compound is: 
 1-benzo[b]thiophen-2-yl-4-(4-butylpiperidin-1-yl)-butan-1-one;    4-(4-butylpiperidin-1-yl)-1-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-butan-1-one;    1-(3-bromo-benzo[b]thiophen-2-yl)-4-(4-butylpiperidin-1-yl)-butan-1-one    1-(3-benzo[b]thiophen-2-yl-propyl)-4-butylpiperidine;    4-butyl-1-[3-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-propyl]-piperidine;    1-(3-benzo [b]thiophen-2-yl-propyl)-4-methylpiperidine    1-(3-benzo[b]thiophen-2-yl-propyl)-4-benzylpiperidine; or    3-[3-(4-butyl-piperidin-1-yl)-propyl]-benzo[d]isothiazole.    
   
   
       85 . A pharmaceutical composition comprising an effective amount of a compound of formula (I):  
     
       
         
         
             
             
         
       
       wherein:  
       Z 1  is CR 1 , Z 2  is CR 2 ,Z 3  is CR 3 , and Z 4 is CR 4 ;  
       W 1  is S, W 2  is N or CR 6 , and W 3  is CG;  
       G is of formula (II):  
       
         
           
           
               
               
           
         
       
       Y is O, S, CHOH, —NHC(O)—, —C(O)NH—, —C(O)—, —OC(O)—, —(O)CO—, —NR 7 —, —CH═N—, or absent;  
       p is 1, 2, 3, 4 or 5;  
       Z is CR 8 R 9  or absent;  
       each t is 1, 2, or 3;  
       each R 1 , R 2 , R 3 , and R 4 , independently, is H, amino, hydroxyl, halo, or straight- or branched-chain C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  heteroalkyl, C 1-6  haloalkyl, —CN, —CF 3 , —OR 11 , —COR 11 , —NO 2 , —SR 11 , —NHC(O)R 11 , —C(O)NR 12 R 13 , —NR 12 R 13 , NR 11 C(O)NR 12 R 13 , —SO 2 NR 12 R 13 , —OC(O)R 11 , —O(CH 2 ) q NR 12 R 13 , or —(CH 2 ) q NR 12 R 13 , where q is an integer from 2 to 6, or R 1  and R 2  together form —NH—N═N— or R 3  and R 4  together form —NH—N═N—;  
       each R 5 , R 6 , and R 7 , independently, is H, C 1-6  alkyl; formyl; C 3-6  cycloalkyl; C 5-6  aryl, optionally substituted with halo or C 1-6  alkyl; or C 5-6  heteroaryl, optionally substituted with halo or C 1-6  alkyl;  
       each R 8  and R 9 , independently, is H or straight- or branched-chain C 1-8  alkyl;  
       R 10  is straight- or branched-chain C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 1-8  alkylidene, C 1-8  alkoxy, or C 1-8  heteroalkyl;  
       R 10 ′ is H, straight- or branched-chain C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 1-8  alkylidene, C 1-8  alkoxy, C 1-8  heteroalkyl, C 1-8  aminoalkyl, C 1-8  haloalkyl, C 1-8  alkoxycarbonyl, C 1-8  hydroxyalkoxy, C 1-8  hydroxyalkyl, or C 1-8  alkylthio;  
       each R 11 , independently, is H, straight- or branched-chain C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 2-8  heteroalkyl, C 2-8  aminoalkyl, C 2-8  haloalkyl, C 1-8  alkoxycarbonyl, C 2-8  hydroxyalkyl, —C(O)—C 5-6  aryl substituted with C 1-3  alkyl or halo, C 5-6  aryl, C 5-6  heteroaryl, C 5-6  cycloalkyl, C 5-6  heterocycloalkyl, —C(O)NR 12 R 13 , —CR 5 R 12 R 13 , —(CH 2 ) t NR 12 R 13 , t is an integer from 2 to 8; and  
       each R 12  and R 1-3 , independently, is H, C 1-6  alkyl; C 3-6  cycloalkyl; C 5-6  aryl, optionally substituted with halo or C 1-6  alkyl; or C 5-6  heteroaryl, optionally substituted with halo or C 1-6  alkyl;  
       or a pharmaceutically acceptable salt, ester or prodrug thereof.  
     
   
   
       86 . A pharmaceutical composition of  claim 85 , wherein each t is 2.  
   
   
       87 . A pharmaceutical composition of  claim 86 , wherein R 10  is n-butyl.  
   
   
       88 . A pharmaceutical composition of  claim 86 , wherein each R 1 , R 2 , R 3 , and R 4 , independently, is H, hydroxyl, halo, C 1-6 heteroalkyl, CF 3 , —NO 2 , or straight- or branched-chain C 1-6  alkyl, or R 1  and R 2  together form —NH—N═N— or R 3  and R 4  together form —NH—N═N—.  
   
   
       89 . A pharmaceutical composition of  claim 86 , wherein Y is absent or O, p is 0, 1, 2 or 3, and R 8  and R 9  are H.  
   
   
       90 . A pharmaceutical composition of  claim 89 , wherein Z is absent, Y is absent and p is 3.  
   
   
       91 . A pharmaceutical composition of  claim 90 , wherein R 10  is n-butyl.  
   
   
       92 . A pharmaceutical composition of  claim 86 , wherein the compound is: 
 1-benzo[b]thiophen-2-yl-4-(4-butylpiperidin-1-yl)-butan-1-one;    4-(4-butylpiperidin-1-yl)-1-(5-fluoro-3-methyl-benzo [b]thiophen-2-yl)-butan-1-one;    1-(3-bromo-benzo [b]thiophen-2-yl)-4-(4-butylpiperidin-1-yl)-butan-1-one    1-(3-benzo [b]thiophen-2-yl-propyl)-4-butylpiperidine;    4-butyl-1-[3-(5-fluoro-3-methyl-benzo [b]thiophen-2-yl)-propyl]-piperidine;    1-(3-benzo [b]thiophen-2-yl-propyl)-4-methylpiperidine;    1-(3-benzo[b]thiophen-2-yl-propyl)-4-benzylpiperidine; or    3-[3-(4-butyl-piperidin-1-yl)-propyl]-benzo[d]isothiazole.