Muscarinic receptor antagonists

Abstract

Disclosed are multibinding compounds which are muscarinic receptor antagonists. The multibinding compounds of this invention containing from 2 to 10 ligands covalently attached to one or more linkers. Each ligand is, independently of each other, a muscarinic receptor antagonist or an allosteric modulator provided that at least one of said ligand is a muscarinic receptor antagonist. The multibinding compounds of this invention are useful in the treatment and prevention of diseases such as chronic obstructive pulmonary disease, chronic bronchitis, irritable bowel syndrome, urinary incontinence, and the like.

1 - 50 . (canceled) 
   
   
       51 . A compound of the formula: 
     
       
         
         
             
             
         
       
     
     wherein:
 L b  is a group of formula (h): 
 
     
       
         
         
             
             
         
       
       n 11  is an integer from 1 to 7; 
       n 12  is 0 or an integer from 1 to 7; 
       F is selected from —NR 40 —, —O—, —S—, and —CHR 41 —; and R 40  and R 41  are independently selected from hydrogen, alkyl, and substituted alkyl; 
       F″ is selected from a covalent bond, —OR 43 , —NR 42 R 43 , and —N + R 43 R 44 R 45 ; R 42  is hydrogen or alkyl; R 44  and R 45  are independently alkyl; and R 43  is a covalent bond attaching the group of formula (h) to X; 
       R 36  is selected from hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono- or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, and alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, and substituted amino; 
       R 37  is selected from hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, and alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, and substituted amino; 
       R 38  is selected from hydrogen, alkyl, halo, hydroxy, alkoxy, and a covalent bond attaching the group of formula (h) to X, provided that at least one of R 38  and R 43  attaches the group of formula (h) to X; 
       R 39  is selected from hydrogen, alkyl, halo, hydroxy, alkoxy, and substituted alkyl; 
       X is a group of the formula:
   —X a -Z-(Y a -Z) n -Y b -Z-X a — 
 
       m is an integer from 0 to 20; 
       X a  at each separate occurrence is selected from a covalent bond, —O—, —S—, —NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(S)—, —C(S)O—, and —C(S)NR—; 
       Z at each separate occurrence is selected from a covalent bond, alkylene, substituted alkylene, cycloalkylene, substituted cycloalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, and heterocyclene; 
       Y a  and Y b  at each separate occurrence are selected from a covalent bond, —O—, —C(O)—, —OC(O)—, —C(O)O—, —NR—, —S(O) n —, —C(O)NR′—, —NR′C(O)—, —NR′C(O)NR′—, —NR′C(S)NR′—, —C(═NR′)NR′—, —NR′C(═NR′)—, —OC(O)NR′—, —NR′C(O)O—, —P(O)(OR′)O—, —OP(O)(OR′)—, —S(O) n CR′R″—, —S(O) n NR′—, —NR′S(O) n —, and —S—S—; 
       n is 0, 1 or 2; and 
       R, R′ and R″ at each separate occurrence are selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and heterocyclic; 
       or a pharmaceutically-acceptable salt thereof. 
     
   
   
       52 . The compound of  claim 51 , wherein n 11  is 1 or 2. 
   
   
       53 . The compound of  claim 51 , wherein n 12  is 0 or 6. 
   
   
       54 . The compound of  claim 51 , wherein F is —NR 40 —, —O— or —CHR 41 —; and R 40  and R 41  are independently selected from hydrogen and alkyl. 
   
   
       55 . The compound of  claim 51 , wherein F″ is a covalent bond, —NR 42 R 43 , or —N + R 43 R 44 R 45 . 
   
   
       56 . The compound of  claim 51 , wherein R 36  is hydrogen, halo, nitro, hydroxy, or alkoxy. 
   
   
       57 . The compound of  claim 51 , wherein R 37  is hydrogen, halo, hydroxy, or alkoxy. 
   
   
       58 . The compound of  claim 51 , wherein R 38  is hydrogen or hydroxy. 
   
   
       59 . The compound of  claim 51 , wherein R 39  is hydrogen. 
   
   
       60 . A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and the compound of  claim 51 .