Modulators of acetylcholine receptors

Abstract

Compounds comprising an aza-bicyclic portion and an aromatic portion linked via an optionally oxidized sulphur atom are disclosed. The compounds disclosed are useful for the treatment of dysfunctions of the central and autonomic nervous systems.

1 . A compound represented by Formula (I) or pharmaceutically acceptable salts thereof:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  is —H, 
 C 1-2 alkyl optionally substituted with 1, 2 or 3 groups independently selected from halogen, hydroxyl, thiol, C 1-4 alkoxy or C 1-4 alkylthio, or aryl-C 1-4 alkyl;  
 
 R 2  is —H, 
 —OH,  
 —NH 2 ,  
 —NH-Q-V-T, wherein Q is —C(O)—, —C(O)—NH—, —C(O)O—, or —SO 2 —; 
 V is H, aryl, aryl-C 1-12 alkyl, diaryl-C 1-12 alkyl, lactonyl, or C 1-18 alkyl optionally substituted with halogen, hydroxyl, C 1-4 alkoxy, —C(O)OC 1-4 alkyl, —OC(O)C 1-4 alkyl, aryl-C 1-4 alkoxy, aryloxy, or SO 2 C 1-4 alkyl; and  
 T is H, halogen, C 1-5 alkyl, C 1-4 alkoxy, nitro, aryl, aryl-C 1-4 alkyl, or aryloxy unless V is H in which case T is absent,  
 
 aryl,  
 -(L) a -Z, wherein L is CH 2 , CO, O, NH or N(C 1-4 alkyl) and a is 0 or 1; 
 and  
 Z is C 1-3 alkyl-F, C 0-3 alkyl-aryl-R 6 , C 0-3 alkyl-CO—R 6 , C 0-3 alkyl-CO—NR 6   2 , C 0-3 alkyl-CO 2 —R 6 , C 0-3 alkyl-SO 2 —R 6 , C 0-3 alkyl-SO 2 —NR 6   2 , C 1-3 alkyl-OR 6 , C 1-3 alkyl-CN or C 1-3 alkyl-NR 6   2 , wherein each C 0-3 alkyl or C 1-3 alkyl portion is optionally substituted with from 1 to 6 groups selected from F and C 1-5 alkyl,  
 
 linked back to the aromatic ring so as to form a fused bicyclic compound represented by Formula (Ia)  
                     
  wherein D is O or S; and 
 E is O, S, NR 5 , C(R 5 ) 2 , O—CR 5   2 , NR 5 —CR 5   2 , NR 5 —CO, CR 5   2 —O, CR 5   2 —S(O) r , CR 5   2 —NR 5 , CR 5   2 —CR 5   2 , CO—NR 5 , or CR 5 ═CR 5 ; or  
 
 linked back to the aromatic ring so as to form a fused bicyclic compound represented by Formula (Ib)  
                     
  wherein G is CR 5  or N; and 
 J is CR 5  or N;  
 
 
 unless X is N in which case R 2  is absent  
 R 3  is H, halogen, C 1-4 alkyl optionally substituted with from 1 to 3 fluorine atoms, cyano, CF 3 , OC 1-4 alkyl, aryloxy, arylC 1-4 alkyl, arylC 1-4 alkoxy, C 3-10 cycloalkoxy, carboxy, carbonamido, —CO—NH—C 1-4 alkyl, aryl, hydroxy, —SO 2 NH 2 , —SO 2 NHC 1-4 alkyl, or —C 1-4 alkyl-OH;  
 R 4  is H, halogen, C 1-4 alkyl optionally substituted with from 1 to 3 fluorine atoms, cyano, CF 3 , OC 1-4 alkyl, aryloxy, arylC 1-4 alkyl, arylC 1-4 alkoxy, C 3-10 cycloalkoxy, carboxy, carbonamido, —CO—NH—C 1-4 alkyl, aryl, hydroxy, —SO 2 NH 2 , —SO 2 NHC 1-4 alkyl, or —C 1-4 alkyl-OH;  
 R 5  is each independently H or C 1-4 alkyl;  
 R 6  is each independently H, C 1-6 alkyl, aryl or arylC 1-4 alkyl, each of which (except H) may be optionally substituted with from 1 to 3 fluorine atoms;  
 X is C or N;  
 W is C or N;  
 W′ is C or N;  
 Y is C or N;  
 Y′ is C or N;  
 provided that there are no more than two N atoms in the aryl ring;  
 A is a double bond;  
 m, n, o and p are independently 0, 1, 2 or 3;  
 q is optionally 1, 2 or 3;  
 r is 0, 1 or 2.  
 provided that  
 when X, W, W′, Y and Y′ are all C, R 3  is H, R 4  is H or Cl positioned meta to the sulphur atom, A is (CH 2 ) q  and R 1  is selected from H, unsubstituted C 1-4 alkyl and unsubstituted C 3-4 cycloalkyl; then R 2  may not be H or —OH, and that  
 when one of X, Y and Y′ is N, R 3  is H, R 4  is H or Cl positioned meta to the sulphur atom, A is (CH 2 ) q  and R 1  is selected from H, unsubstituted C 1-4 alkyl and unsubstituted C 3-4 cycloalkyl; then R 2  may not be H or —OH.  
 
   
   
       2 . A compound as claimed in  claim 1  wherein: 
 R 2  is —H, 
 —NH 2 ,  
 —NH-Q-V-T as defined in  claim 1 ,  
 aryl,  
 -(L) a -Z as defined in  claim 1 ,  
 linked back to the aromatic ring so as to form a fused bicyclic compound represented by Formula (Ia) as defined in  claim 1 , or  
 linked back to the aromatic ring so as to form a fused bicyclic compound represented by Formula (Ib) as defined in  claim 1;   
   unless X is N in which case R 2  is absent.    
   
   
       3 . A compound as claimed in  claim 1  wherein: 
 R 2  is —NH-Q-V-T as defined in  claim 1 , 
 aryl,  
 -(L) a -Z as defined in  claim 1 ,  
 linked back to the aromatic ring so as to form a fused bicyclic compound represented by Formula (Ia) as defined in  claim 1 , or  
 linked back to the aromatic ring so as to form a fused bicyclic compound represented by Formula (Ib) as defined in  claim 1;   
   unless X is N in which case R 2  is absent.    
   
   
       4 . A compound as claimed in  claim 1  wherein: 
 R 2  is —NH-Q-V-T wherein Q is —C(O)—NH—, or —C(O)O—; 
 V is as defined in  claim 1;  and  
 T is as defined in  claim 1;   
    aryl,     -(L) a -Z as defined in  claim 1 ,     linked back to the aromatic ring so as to form a fused bicyclic compound represented by Formula (Ia) as defined in  claim 1 , or     linked back to the aromatic ring so as to form a fused bicyclic compound represented by Formula (Ib) as defined in  claim 1;     unless X is N in which case R 1  is absent.    
   
   
       5 . A compound as claimed in  claim 1  wherein: 
 R 1  is —H, 
 C 1-12 alkyl optionally substituted with 1, 2 or 3 groups independently selected from halogen, hydroxyl, thiol, C 1-4 alkoxy or C 1-4 alkylthio, or aryl-C 1-4 alkyl;  
   R 2  is —H, 
 —OH,  
 —NH 2 ,  
 —NH-Q-V-T, wherein Q is —C(O)—, —C(O)—NH—, —C(O)O—, or —SO 2 —; 
 V is aryl, aryl-C 1-12 alkyl, diaryl-C 1-12 alkyl, lactonyl, or C 1-18 alkyl optionally substituted with halogen, hydroxyl, C 1-4 alkoxy, —C(O)OC 1-4 alkyl, —OC(O)C 1-4 alkyl, aryl-C 1-4 alkoxy, aryloxy, or SO 2 C 1-4 alkyl; and  
 T is H, halogen, aryl, aryl-C 1-4 alkyl, or aryloxy,  
 
   unless X is N in which case R 2  is absent    R 3  is H, halogen, C 1-4 alkyl, cyano, CF 3 , OC 1-4 alkyl, aryloxy, arylC 1-4 alkoxy, C 3-10 cycloalkoxy, carboxy, carbonamido, —CO—NH—C 1-4 alkyl, aryl, hydroxy, —SO 2 NH 2 , —SO 2 NHC 1-4 alkyl, or —C 1-4 alkyl-OH,    R 4  is H, halogen, C 1-4 alkyl, cyano, CF 3 , OC 1-4 alkyl, aryloxy, arylC 1-4 alkoxy, C 3-10 cycloalkoxy, carboxy, carbonamido, —CO—NH—C 1-4 alkyl, aryl, hydroxy, —SO 2 NH 2 , —SO 2 NHC 1-4 alkyl, or —C 1-4 alkyl-OH,    X is C or N,    W is C or N, provided that both X and Y are not N,    W′is C    Y is C or N    Y′is C    A is a double bond;    m, n, o and p are independently 0, 1, 2 or 3    q is optionally 1, 2 or 3    r is 0.    
   
   
       6 . A compound as claimed in  claim 5  wherein R 1  is H, C 1-6 alkyl optionally substituted with 1 or 2 hydroxyl groups, or aryl-C 1-4 alkyl.  
   
   
       7 . A compound as claimed in  claim 6  wherein R 1  is benzyl, p-methoxybenzyl, furanylmethyl, imidazolylmethyl, pyridinylmethyl, thienylmethyl, pyridylmethyl, N-hydroxypyridylmethyl or thiazolylmethyl.  
   
   
       8 . A compound as claimed in  claim 5  wherein R 2  is H, R 3  is carbonamido (—CONH 2 ) or C 1-4 alkyl-OH, and R 4  is H, C 1-4 alkyl, CF 3 , halogen or cyano.  
   
   
       9 . A compound as claimed in  claim 5  wherein R 2  is OH, and R 3  and R 4  each independently represent H, C 1-4 alkyl, CF 3 , cyano or halogen.  
   
   
       10 . A compound as claimed in  claim 5  wherein R 2  is of formula —NH-Q-V-T; T is H and R 3  and R 4  each independently represent H, methyl, CF 3 , chloro- or cyano-.  
   
   
       11 . A compound as claimed in  claim 5  wherein R 2  is of formula —NH—SO 2 —V-T; V is aryl, —C 1-12 alkyl or aryl-C 1-12 alkyl; R 3  is H, methyl, CF 3 , Cl or cyano and R 4  is H.  
   
   
       12 . A compound as claimed in  claim 5  wherein R 2  is of formula —NH—SO 2 —V-T, V is selected from C 1-12 alkyl, phenyl, naphthyl, thienyl, oxazolyl, isoxazolyl, or phenyl(CH═CH), optionally substituted with 1, 2, 3 or 4 substituents selected from: 
 —NO 2 ;    halogen;    —CF 3 ;    C 1-12 alkoxy;    C 1-12 alkylthio;    C 1-12 alkyl;    C 1-4 alkylsulfonyl;    —CN;    —OCF 3 ;    —C(O)OC 1-4 alkyl;    —OCH 2 CF 3 ;    —NHC(O)C 1-4 alkyl.    
   
   
       13 . a compound as claimed in  claim 5  wherein R 2  is of formula —NH—SO 2 —V-T, T is selected from H; or diazole, oxazole, isoxazole, phenyl or phenoxy, optionally substituted with 1, 2, 3 or 4 substituents selected from 
 —NO 2 ;    halogen;    —CF 3 ;    C 1-12 alkoxy;    C 1-12 alkylthio;    C 1-12 alkyl;    C 1-4 alkylsulfonyl;    —CN;    —OCF 3 ;    —C(O)OC 1-4 alkyl;    —OCH 2 CF 3 ;    —NHC(O)C 1-4 alkyl.    
   
   
       14 . A compound as claimed in  claim 5  wherein R 2  is of formula —NH—SO 2 —V-T, V is selected from 3-chloro-4-methylphenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-bromophenyl, 4-methoxyphenyl, 4-methylphenyl, naphthyl, 2,4,6-trimethylphenyl, phenyl(CH═CH)—, 4-chlorophenyl, 2-chlorophenyl, 2,5-dichlorothien-3-yl, 2,5,6-trimethyl-4-methoxyphenyl, 4-methoxyphenyl, 2,3,4-trifluorophenyl, 3-cyanophenyl, 2-methoxycarbonylthien-3-yl or 4-pentylphenyl and T is H.  
   
   
       15 . A compound as claimed in  claim 5  wherein R 2  is of formula —NH—SO 2 —V-T, T is 2-chloro-5-nitrophenoxy and V is phenyl.  
   
   
       16 . A compound as claimed in  claim 5  wherein R 2  is of formula —NH—C(O)—V-T wherein V is selected from aryl; aryl-C 1-12 alkyl; diaryl-C 1-12 alkyl; lactonyl; or Cl 1-8 alkyl optionally substituted with halogen, hydroxyl, C 1-4 alkoxy, C(O)OC 1-4 alkyl, OC(O)C 1-4 alkyl, aryl-C 1-4 alkoxy or aryloxy.  
   
   
       17 . A compound as claimed in  claim 5  wherein R 2  is of formula —NH—C(O)—V-T, and V is selected from C 1-12 alkyl, phenyl, phenyl-C 1-12 alkyl, diphenylmethyl, naphthyl, furanyl, thienyl, diazolyl, pyridinyl, thiazolyl, benzothienyl, fluorenyl, oxazolyl or isoxazolyl, optionally substituted with 1, 2, 3 or 4 substituents independently selected from 
 —NO 2 ;    halogen;    —CF 3 ;    C 1-12 alkoxy;    C 1-12 alkylthio;    C 1-12 alkyl;    C 1-4 alkylsulfonyl;    —CN;    —OCF 3 ;    —C(O)O—C 1-4 alkyl;    —OCH 2 CF 3 .    
   
   
       18 . A compound as claimed in  claim 5  wherein R 2  is of formula —NH—C(O)—V-T, T is selected from H; halogen; or diazole, oxazole, isoxazole, phenyl, phenoxy or benzodioxanyl optionally substituted with 1, 2, 3 or 4 substituents selected from 
 —NO 2 ;    halogen;    —CF 3 ;    C 1-12 alkylthio;    C 1-12 alkoxy;    C 1-12 alkyl;    C 1-4 alkylsulfonyl;    —CN;    —OCF 3 ;    —C(O)O—C 1-4 alkyl.    
   
   
       19 . A pharmaceutical composition comprising a compound as claimed in  claim 1  with a pharmaceutically acceptable diluent or carrier.  
   
   
       20 . A method of treatment of dysfunctions of the central and autonomic nervous systems comprising administering an effective amount of a compound of  claim 1  to a patient in need thereof.