Meta-substituted phenylene sulphonamide derivatives

Abstract

The present invention relates to a class of compounds represented by the Formula I or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising compounds of the Formula I, and methods of selectively inhibiting or antagonizing the α v β 3 integrin.

1 - 26 . (canceled)  
     
     
         27 . A method for treating diabetic retinopathy in a mammal in need of such treatment, wherein: 
 the method comprises administering an effective α v β 3  inhibiting amount comprising from about 0.01 mg to about 1000 mg per kilogram of body weight of a compound or pharmaceutically acceptable salt thereof to the mammal;    the compound corresponds in structure to the formula:                          B is selected from the group consisting of —CONR 50 — and —SO 2 NR 50 —;    A is selected from the group consisting of:                          Y 1  is selected from the group consisting of N—R 2 , O, and S;    as to R 2 : 
 R 2  is selected from the group consisting of H; alkyl; aryl; hydroxy; alkoxy; cyano; nitro; amino; alkenyl; alkynyl; alkyl substituted with one or more substituents selected from the group consisting of lower alkyl, halogen, hydroxyl, haloalkyl, cyano, nitro, carboxyl, amino, alkoxy, aryl, aryl substituted with one or more halogen, haloalkyl, lower alkyl, alkoxy, cyano, alkylsulfonyl, alkylthio, nitro, carboxyl, amino, hydroxyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, and fused monocyclic heterocycles; aryl substituted with one or more substituents selected from the group consisting of halogen, haloalkyl, hydroxy, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, cyano, nitro, alkylthio, alkylsulfonyl, sulfonic acid, sulfonamide, carboxyl derivatives, amino, aryl, fused aryl, monocyclic heterocycles, and fused monocyclic heterocycles; monocyclic heterocycles; and monocyclic heterocycles substituted with one or more substituents selected from the group consisting of halogen, haloalkyl, lower alkyl, alkoxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, sulfonic acid, sulfonamide, aryl, and fused aryl; or  
 R 2  and R 7 , together with the atoms to which they are bonded, form: 
 a 4-12 membered dinitrogen containing heterocycle optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, and phenyl;  
 a 5 membered heteroaromatic ring; or  
 a 5 membered heteroaromatic ring fused with a phenyl group;  
 
   as to R 7 : 
 R 7  is selected from the group consisting of H; alkyl; alkenyl; alkynyl; aralkyl; cycloalkyl; bicycloalkyl; aryl; acyl; benzoyl; alkyl substituted with one or more substituents selected from the group consisting of lower alkyl, halogen, hydroxy, haloalkyl, cyano, nitro, carboxyl derivatives, amino, alkoxy, thio, alkylthio, sulfonyl, aryl, aralkyl, aryl substituted with one or more substituents selected from the group consisting of halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethyl, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles; aryl substituted with one or more substituents selected from the group consisting of halogen, haloalkyl, lower alkyl, alkoxy, aryloxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, aryl, and fused aryl; monocyclic and bicyclic heterocyclicalkyls; —SO 2 R 10 ; and  
                     
 R 7  and R 8 , together with the nitrogen to which they are bonded, form a 4-12 membered mononitrogen containing monocyclic or bicyclic ring, wherein the ring: 
 is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, carboxyl derivatives, aryl, and hydroxy; and  
 optionally contains (in addition to the nitrogen) a heteroatom selected from the group consisting of O, N, and S; or  
 
 R 7  and R 2 , together with the atoms to which they are bonded, form: 
 a 4-12 membered dinitrogen containing heterocycle optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, and phenyl;  
 a 5 membered heteroaromatic ring; or  
 a 5 membered heteroaromatic ring fused with a phenyl group;  
 
   as to R 8 : 
 R 8  is selected from the group consisting of H; alkyl; alkenyl; alkynyl; aralkyl; cycloalkyl; bicycloalkyl; aryl; acyl; benzoyl; alkyl substituted with one or more substituents selected from the group consisting of lower alkyl, halogsen, hydroxy, haloalkyl, cyano, nitro, carboxyl derivatives, amino, alkoxy, thio, alkylthio, sulfonyl, aralkyl, aryl optionally substituted with one or more substituents selected from the group consisting of halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy. ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethyl, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles; aryl substituted with one or more substituents selected from the group consisting of halogen, haloalkyl, lower alkyl, alkoxy, aryloxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, aryl, and fused aryl; monocyclic and bicyclic heterocyclicalkyls; —SO 2 R 10 ; and  
                     
 or  
 R 8  and R 7 , together with the nitrogen to which they are bonded, form a 4-12 membered mononitrogen containing monocyclic or bicyclic ring, wherein the ring: 
 is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, carboxyl derivatives, aryl, and hydroxy; and  
 optionally contains (in addition to the nitrogen) a heteroatom selected from the group consisting of O, N, and S;  
 
   R 10  is selected from the group consisting of alkyl, aryl, and monocyclic heterocycles, wherein: 
 any such group is optionally substituted with one or more substituents selected from the group consisting of halogen, haloalkyl alkyl, alkoxy, cyano, nitro, amino, acylamino, trifluoroalkyl, amido, alkylaminosulfonyl, alkylsulfonyl, alkylsulfonylamino, alkylamino, dialkylamino, trifluoromethylthio, trifluoroalkoxy, trifluoromethylsulfonyl, aryl, aryloxy, thio, alkylthio, and monocyclic heterocycles;  
   R 5  is selected from the group consisting of H, alkyl, alkenyl, alkynyl, benzyl, and phenylethyl; or    as to Y 2 and R 7A : 
 Y 2  and R 7A  are independent substituents such that: 
 Y 2  is selected from the group consisting of alkyl; cycloalkyl; bicycloalkyl; aryl; monocyclic heterocycles; alkyl substituted with aryl which can also be optionally substituted with one or more substituents selected from the group consisting of halo, haloalkyl, alkyl, nitro, hydroxy, alkoxy, aryloxy, aryl, and fused aryl; aryl substituted with one or more substituents selected from the group consisting of halo, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, fused aryl, nitro, methylenedioxy, ethylenedioxy, and alkyl; alkynyl; alkenyl; —SR 9 . and —OR 9 —; and  
 R 7A  is selected from the group consisting of H; alkyl; alkenyl; alkynyl; aralkyl; cycloalkyl; bicycloalkyl; aryl; acyl; benzoyl; alkyl substituted with one or more substituents selected from the group consisting of lower alkyl, halogen, hydroxy, haloalkyl, cyano, nitro, carboxyl derivatives, amino, alkoxy, thio, alkylthio, sulfonyl, aryl, aralkyl, aryl substituted with one or more substituents selected from the group consisting of halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethyl, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles; aryl substituted with one or more substituents selected from the group consisting of halogen, haloalkyl, lower alkyl, alkoxy, aryloxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, aryl, and fused aryl; monocyclic and bicyclic heterocyclicalkyls; —SO 2 R 10 ; and  
                     
 
 Y 2  is —SR 9  and —OR 9 — such that R 7A  and R 9 , together with the atoms to which they are bonded, form a 4-12 membered mononitrogen containing sulfur or oxygen containing heterocyclic ring; or  
 Y 2  is carbon such that Y 2  and R 7A , together with the atoms to which they are bonded, form a 4-12 membered mononitrogen containing ring optionally substituted with alkyl, aryl, or hydroxy;  
   as to R 9 : 
 R 9  is selected from the group consisting of H; alkyl; aralkyl; aryl; alkenyl; and alkynyl; or  
 R 9  and R 7A , together with the atoms to which they are bonded, form a 4-12 membered mononitrogen containing sulfur or oxygen containing heterocyclic ring;  
   Z 1 , Z 2 , Z 4 , and Z 5  are independently selected from the group consisting of H; alkyl; hydroxy; alkoxy; aryloxy; arylalkoxy; halogen; haloalkyl; haloalkoxy; nitro; amino; aminoalkyl; alkylamino; dialkylamino; cyano; alkylthio; alkylsulfonyl; carboxyl derivatives; acetamide; aryl; fused aryl; cycloalkyl; thio; monocyclic heterocycles; fused monocyclic heterocycles; and A;    R 50  is selected from the group consisting of H and alkyl;    R 1  is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, and aryl, optionally substituted with one or more substituents selected from the group consisting of halogen, haloalkyl, hydroxy, alkoxy, aryloxy, aralkoxy, amino, aminoalkyl, carboxyl derivatives, cyano, and nitro;    t is zero, 1, or 2;    R is X—R 3 ;    X is selected from the group consisting of O, S, and NR 4 ;    R 3  and R 4  are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; haloalkyl; aryl; arylalkyl; sugars; and steroids; and    Y 3  and Z 3  are independently selected from the group consisting of H, alkyl, aryl, cycloalkyl, and aralkyl.    
     
     
         28 . A method according to  claim 27 , wherein the compound corresponds in structure to Formula II:  
       
         
           
           
               
               
           
         
       
     
     
         29 . A method according to  claim 28 , wherein A is:  
       
         
           
           
               
               
           
         
       
     
     
         30 . A method according to  claim 28 , wherein A is:  
       
         
           
           
               
               
           
         
       
     
     
         31 . A method according to  claim 27 , wherein the compound corresponds in structure to Formula III:  
       
         
           
           
               
               
           
         
       
     
     
         32 . A method according to  claim 31 , wherein A is:  
       
         
           
           
               
               
           
         
       
     
     
         33 . A method according to  claim 31 , wherein A is:  
       
         
           
           
               
               
           
         
       
     
     
         34 . A method according to  claim 27 , wherein A is:  
       
         
           
           
               
               
           
         
       
     
     
         35 . A method according to  claim 27 , wherein A is: