VLA-4 inhibitor compounds

Abstract

Compounds that selectively inhibit the binding of ligands to α4β1 integrin (VLA-4) and methods for their preparation are disclosed. In one embodiment, compounds of the invention are represented by Formula I: As selective inhibitors of VLA-4 mediated cell adhesion, compounds of the present invention are useful in the treatment of conditions associated with such adhesion, including, but not limited to, such conditions as inflammatory and autoimmune responses, diabetes, asthma, psoriasis, inflammatory bowel disease, transplantation rejection, and tumor metastasis. Also disclosed are methods of inhibiting VLA-4 mediated cell adhesion and methods of treating conditions associated with LA-4 mediated cell adhesion.

1 . A compound represented by Formula I, or a salt thereof,  
       
         
           
           
               
               
           
         
         wherein  
         W is chosen from aryl group, substituted aryl group, heteroaryl group and substituted heteroaryl group;  
         W 1  is chosen from arylene group, substituted arylene group, heteroarylene group and substituted heteroarylene group;  
         A is chosen from ═O, ═S and ═NH;  
         R is chosen from a direct bond, alkyenylene group and —(CH 2 ) n —,  
          wherein 
 n is chosen from 1 and 2;  
 
         X is chosen from —C(O)—, —CH 2 — and S(O) 2 ;  
         M is chosen from  
         
           
             
             
                 
                 
             
           
         
          wherein  
         
           
             
             
                 
                 
             
           
         
          is a divalent 4-, 5-, 6- or 7-membered heterocyclic moiety, other than pyrrolidine or thiazolidine, wherein the nitrogen atom is the point of attachment to X; 
 R 1 , R 2  and R 3  are independently chosen from —H, —OH, —NH 2 , halogen atom, alkyl group, substituted alkyl group, aryl group, substituted aryl group, alkoxy group, substituted alkoxy group, monoalkylamino group, substituted monoalkylamino group, dialkylamino group, substituted dialkylamino group, cycloalkylamino group, substituted cycloalkylamino group, alkylsulfonylamino group, substituted alkylsulfonylamino group, arylsulfonylamino group, substituted arylsulfonylamino group, aryloxy group, substituted aryloxy group, heteroaryloxy group, substituted heteroaryloxy group, benzyloxy group and substituted benzyloxy group, or  
 two of R 1 , R 2  and R 3  taken together may form a 3-, 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic residues optionally substituted with from 1 to 3 substituents chosen independently from —OH, halogen atom, —NH 2 , alkyl group, alkoxy group, aryl group, aryloxy group, alkylamino group, benzyloxy group and heteroaryl group;  
 R 4  is chosen from —H and lower alkyl group;  
 Y is a direct bond or a divalent radical chosen from —C(O)—, —C(O)NH—, alkenylene group, alkynylene group and —(CH 2 ) k Y 2 ,  
  wherein 
 k is chosen from 1, 2 and 3; and  
 Y 2  is a direct bond or a divalent radical chosen from —O—, —S—, —S(O), —S(O) 2 — and —NY 3 —,  
  wherein 
 Y 3  is chosen from —H and lower alkyl group;  
 Z is chosen from arylene group, substituted arylene group, heterocyclylene group, substituted heterocyclylene group, cycloalkylene group and substituted cycloalkylene group;  
 
 
 A 1  is a direct bond or a divalent radical chosen from alkenylene group, alkynylene group, —(CH 2 ) t — and —O(CH 2 ),  
  wherein 
 t is chosen from 1, 2 and 3; and  
 v is chosen from 0, 1, 2, and 3; and  
 
 R 5  is chosen from —OH, lower alkoxy group, —N(H)OH,  
                     
  wherein  
                     
  is a divalent 4-, 5-, 6- or 7-membered heterocyclic moiety, other than pyrrolidine or thiazolidine, wherein the nitrogen atom is the point of attachment to X;  
 R 6  and R 7  are independently chosen from —H, —OH, halogen atom, alkyl group and alkoxy group;  
 Y 1  is a divalent radical chosen from —O—, —S—, —S(O)—, —S(O) 2 — and —NY 4 —,  
  wherein 
 Y 4  is chosen from —H and lower alkyl group;  
 
 Z 1  is a divalent radical chosen from arylene group, substituted arylene group, heterocyclylene group, substituted heterocyclylene group, cycloalkylene group and substituted cycloalkylene group;  
 A 2  is a direct bond or a divalent radical chosen from alkenylene group, alkynylene group and —(CH 2 ) e    
  wherein 
 e is chosen from 1, 2 and 3; and  
 
 R 8  is chosen from —OH, lower alkoxy group, —N(H)OH,  
                     
  wherein  
 L is  
                     
  wherein  
                     
  is a divalent 4-, 5-, 6- or 7-membered heterocyclic moiety, other than pyrrolidine or thiazolidine, optionally substituted with from 1 to 3 substitutents chosen independently from alkyl group, alkoxy group, hydroxyalkyl group, —OH, benzyloxy group, —NH 2 , halogen atom, aryl group and heteroaryl group, said moiety may be fused to 1 or 2 additional carbocyclic or heterocyclic residues optionally substituted with from 1 to 3 substitutents chosen independently from alkyl group, aryloxy group, alkoxy group, hydroxyalkyl group, —OH, benzyloxy group, —NH 2 , halogen atom, aryl group and heteroaryl group;  
 m and q are independently chosen from 0, 1, 2 and 3;  
 X 1  is chosen from —CH═ and —N═;  
 R 9  is chosen from —H and lower alkyl group;  
 R 10  is chosen from —COOH, lower alkoxycarbonyl group,  
                     
  and  
 Z 2  is chosen from —H, COOH and lower alkoxycarbonyl group; and  -R 11 -Z 3 -Q 2 -L 1 ,  
  wherein 
 R 11  is chosen from —O—,  
                     
  and —NR 12 —
  wherein  
 R 12  is chosen from —H, alkyl group, substituted alkyl group, cycloalkyl group, substituted cycloalkyl group, aryl group, substituted aryl group, benzyl group, substituted benzyl group, lower alkenyl group, substituted lower alkenyl group and lower alkynyl group and  
 
 the left hand bond is the point of attachment to —X— and the right hand bond is the point of attachment to -Z 3 ;  
 
 Z 3  is chosen from a direct bond, a divalent aliphatic hydrocarbon moiety having 1 to 12 carbon atoms,  
  wherein 
 one or more carbon atoms may be replaced with —O— or —NR 13 —,  
  wherein 
 R 13  is chosen from —H and lower alkyl group, and  
 
 one or more hydrogen atoms attached to an aliphatic carbon atom may be replaced with lower alkyl group; and  
                     
  wherein 
 x is chosen from 0 and 1;  
 y is chosen from 1, 2, and 3; and  
 R 14  is chosen from —H, —OH and halogen atom,  
                     
 
 when R 11  is —NR 2 ,  -Z 4 -   
  wherein  
 
 Z 4  is chosen from  
                     
  wherein 
 R 14a  is chosen from —H, —OH, lower alkyl group and halogen atom;  
                     
 ′wherein the left hand bond is the point of attachment to R 11  and the right hand bond is the point of attachment to Q 2 ;  
 
 Q 2  is a divalent radical chosen from arylene group, substituted arylene group, heterocyclylene group, substituted heterocyclylene group, cycloalkylene group, substituted cycloalkylene group,  
                     
  wherein R 15  and R 16  are independently chosen from —H, halogen atom and lower alkyl group; and  
                     
  wherein R 17  and R 18  are independently chosen from —H, lower alkyl group, substituted lower alkyl group and lower alkenyl group; and  
 L 1  is chosen from —COOH and —COOR 19    
  wherein 
 R 19  is a lower alkyl group.  
 
 
       
     
     
         2 . A compound according to  claim 1 , or a salt thereof, wherein M is  
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound according to  claim 1 , or a salt thereof, wherein M is  
       
         
           
           
               
               
           
         
       
     
     
         4 . A compound according to  claim 1 , or a salt thereof, wherein M is  
       
         
           
           
               
               
           
         
       
     
     
         5 . A compound according to  claim 1 , or a salt thereof, wherein M is 
   -R 11 -Z 3 -Q 2 -L 1 .    
     
     
         6 . A compound according to  claim 2 , or a salt thereof, wherein at least one radical of R 1 , R 2  and R 3  is —OH or halogen atom.  
     
     
         7 . A compound according to  claim 6 , or a salt thereof, wherein A is ═O, R is —(CH 2 ) n — and X is —C(O)—.  
     
     
         8 . A compound according to  claim 7 , or a salt thereof, wherein Y is chosen from alkenylene group, alkynylene group and —(CH 2 ) k Y 2 ; Y 2  is chosen from a direct bond, —O—, —S(O) and —NY 3 —; and Y 3  is —H.  
     
     
         9 . A compound according to  claim 8 , or a salt thereof, wherein Y is chosen from —O— and —NY 3 —.  
     
     
         10 . A compound according to  claim 2 , or a salt thereof, wherein W is unsubstituted phenyl group or phenyl group having one or two substituents chosen from lower alkyl group and halogen atom at the ortho positions thereof.  
     
     
         11 . A compound according to  claim 10 , or a salt thereof, wherein W 1  is unsubstituted phenylene group or phenylene group having a substituent chosen from methoxy group, lower alkyl group and halogen atom at the ortho position to the —NH— thereof.  
     
     
         12 . A compound according to  claim 2 , or a salt thereof, wherein W 1  is phenylene group having a substituent chosen from methoxy group, lower alkyl group and halogen atom at the ortho position to the —NH— thereof and having 1 to 3 substituents chosen from lower alkyl group and halogen atom.  
     
     
         13 . A compound according to  claim 2 , or a salt thereof, wherein A 1  is a direct bond or —(CH 2 ) t —.  
     
     
         14 . A compound according to  claim 13 , or a salt thereof, wherein A 1  is a direct bond.  
     
     
         15 . A compound according to  claim 14 , or a salt thereof, wherein R 5  is —OH.  
     
     
         16 . A compound according to  claim 2 , or a salt thereof, wherein W is unsubstituted phenyl group or phenyl group having one or two substituents chosen from lower alkyl group and halogen atom at the ortho positions thereof; W 1  is unsubstantiated phenylene group or phenylene group having a substituent chosen from methoxy group, lower alkyl group and halogen atom at the ortho position to the —NH— thereof; R is —CH 2 —; X is —C(O)— and R 5  is —OH.  
     
     
         17 . (canceled)  
     
     
         18 . (canceled)  
     
     
         19 . A compound according to  claim 2 , or a salt thereof, wherein R 5  is lower alkoxy group.  
     
     
         20 . A method of inhibiting cell adhesion in a mammal, said method comprising administering to said mammal an effective amount of a compound according to  claim 1 .  
     
     
         21 . A method of treating a condition associated with VLA-4 mediated cell adhesion in a mammal, aid method comprising administering to said mammal an effective amount of a compound according to  claim 1 .  
     
     
         22 . A method according to  claim 21 , wherein the condition associated with VLA-4 mediated cell adhesion is chosen from inflammatory responses, autoimmune responses and tumor metastasis.  
     
     
         23 . A method according to  claim 21 , wherein the condition associated with VLA-4 mediated cell adhesion is chosen from asthma, diabetes, arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease and transplantation rejection.  
     
     
         24 . (canceled)  
     
     
         25 . (canceled)  
     
     
         26 . A pharmaceutical composition comprising as a therapeutic agent, a compound according to  claim 1  and a pharmaceutically acceptable carrier or excipient.  
     
     
         27 . A pharmaceutical composition according to  claim 26 , further comprising one or more additional therapeutic agents.  
     
     
         28 . A pharmaceutical composition according to  claim 27 , wherein said one or more additional therapeutic agents are chosen from the group consisting of antiinflammatory, antirheumatic, corticosteroid, immunosuppressive, antipsoriatic, bronchodilator, antiasthmatic and antidiabetic agents.  
     
     
         29 . A pharmaceutical composition according to  claim 28 , wherein one of said one or more additional therapeutic agents is an antiinflammatory agent.  
     
     
         30 . A pharmaceutical composition according to  claim 29 , wherein said antiinflammatory agent is chosen from a steroid and an NSAID.  
     
     
         31 . A compound according to  claim 16 , or a salt thereof, wherein the compound is: