Gem-substituted alpha v beta 3 antagonists

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 and/or the α v β 5 integrin.

What is claimed is:  
     
         1 . A compound of the Formula:  
       
         
           
           
               
               
           
         
         wherein:  
         
           
             
             
                 
                 
             
           
         
          is a 4-8 membered monocyclic or a 7-12 membered bicyclic ring, optionally saturated or unsaturated, optionally substituted with one or more substituent selected from the group consisting of alkyl, haloalkyl, aryl, heteroaryl, halogen, alkoxyalkyl, aminoalkyl, hydroxy, nitro, alkoxy, hydroxyalkyl, thioalkyl, amino, alkylamino, arylamino, alkylsulfonamide, acyl, acylamino, alkylsulfone, sulfonamide, allyl, alkenyl, methylenedioxy, ethylenedioxy, alkynyl, carboxamide, cyano, and —(CH 2 ) n —COR wherein n is 0-2 and R is hydroxy, alkoxy, alkyl or amino; 
 A 1  is a 7-12 membered polycyclic heterocycle of the formula  
                     
 containing at least one nitrogen atom and optionally 1 to 5 heteroatoms or groups selected from O, N, S, SO 2  or CO; optionally saturated or unsaturated; optionally substituted by one or more R k  selected from the group consisting of hydroxy, alkyl, alkoxy, alkoxyalkyl, thioalkyl, haloalkyl, cyano, amino, alkylamino, halogen, acylamino, sulfonamide and —COR wherein R is hydroxy, alkoxy, alkyl or amino;  
 or A 1  is  
                     
 
         wherein Y 1  is selected from the group consisting of N—R 2 , O, and S;  
         R 2  is selected from the group consisting of H; alkyl; aryl; hydroxy; alkoxy; cyano; alkenyl; alkynyl; amido; alkylcarbonyl; arylcarbonyl; alkoxycarbonyl; aryloxycarbonyl; haloalkylcarbonyl; haloalkoxycarbonyl; al kylthiocarbonyl; arylthiocarbonyl; acyloxymethoxycarbonyl;  
         R 2  taken together with R 7  forms a 4-12 membered dinitrogen containing heterocycle optionally substituted with one or more substituent selected from the group consisting of lower alkyl, thioalkyl, alkylamino, hydroxy, keto, alkoxy, halo, phenyl, amino, carboxyl or carboxyl ester, and fused phenyl;  
         or R 2  taken together with R 7  forms a 5-9 membered heteroaromatic ring optionally substituted with one or more substituent selected from lower alkyl, phenyl, alkoxy and hydroxy;  
         or R 2  taken together with R 7  forms a 5 membered heteroaromatic ring fused with a aryl or heteroaryl ring;  
         R 7  (when not taken together with R 2 ) and R 8  are independently selected from the group consisting of H; alkyl; alkenyl; alkynyl; aralkyl; amino; alkylamino; hydroxy; alkoxy; arylamino; amido, alkylcarbonyl, arylcarbonyl; alkoxycarbonyl; aryloxy; aryloxycarbonyl; haloalkylcarbonyl; haloalkoxycarbonyl; alkylthiocarbonyl; arylthiocarbonyl; acyloxymethoxycarbonyl; cycloalkyl; bicycloalkyl; aryl; acyl; benzoyl;  
         or NR 7  and R 8  taken together form a 4-12 membered mononitrogen containing monocyclic or bicyclic ring optionally substituted with one or more substituent selected from lower alkyl, carboxyl derivatives, aryl or hydroxy and wherein said ring optionally contains a heteroatom selected from the group consisting of O, N and S;  
         R 5  is selected from the group consisting of H and alkyl;  
         or  
         
           
             
             
                 
                 
             
           
         
         wherein Y 2  is selected from the group consisting of alkyl; cycloalkyl; bicycloalkyl; aryl; monocyclic heterocycles;  
         Z 1  is selected from the group consisting of CH 2 , O, CH 2 O, NH, CO, S, SO, CH(OH) and SO 2 ;  
         Z 2  is a 1-5 carbon linker containing 0-3 heteroatom selected from the group consisting of O, S and N; alternatively Z 1 -Z 2  may further contain a carboxamide, sulfone, sulfonamide, alkenyl, alkynyl, or acyl group; wherein the carbon and nitrogen atoms of Z 1 -Z 2  are optionally substituted by alkyl, alkoxy, thioalkyl, alkylsulfone, aryl, alkoxyalkyl, alkylamino, heteroaryl, hydroxy, alkenyl, alkynyl, carboxyalkyl, halogen, haloalky or acylamino;  
         Z 2 -Z 1  is attached to the ring A at the meta- or para-position relative to the X-substituent;  
         n is an integer 1 or 2;  
         R c  is selected from the group consisting of hydrogen; alkyl; halogen, hydroxy, nitro, alkoxy, amino, haloalkyl, aryl, heteroaryl, alkoxyalkyl, aminoalkyl, hydroxyalkyl, thioalkyl, alkylamino, arylamino, alkylsulfonylamino, acyl, acylamino, sulfonyl, sulfonamide, allyl, alkenyl, methylenedioxy, ethylenedioxy, alkynyl, alkynylalkyl, carboxy, alkoxycarbonyl, carboxamido, cyano, and —(CH 2 ) n COR wherein n is 0-2 and R is selected from hydroxy, alkoxy, alkyl and amino;  
         X is selected from the group consisting of —CHR e —, —NHR f —, —O—, —S—, —SO 2 -, and CO wherein R e  is H, lower alkyl, alkoxy, cycloalkyl, alkoxyalkyl, hydroxy, alkynyl, alkenyl, haloalkyl, thioalkyl, aralkyl or aryl; wherein when R e  is hydroxy the hydroxy can optionally form a lactone with the carboxylic acid function of the chain; wherein R f  is selected from the group consisting of H, alkyl, aryl, benzyl and haloalkyl;  
         Y is selected from the group consisting of (CH 2 ) p , —CR 9 —, —NR 9 , CO and SO 2 , wherein R 9  is selected from the group consisting of H, alkyl, haloalkyl, alkoxyalkyl, alkynyl, aryl, heteroaryl, aralkyl, hydroxy, alkoxy, and carboxyalkyl; wherein p is 0 or 1;  
         or the group X-Y can contain a moiety selected from the group consisting of acyl, alkyl, sulfonyl, amino, ether, thioether, carboxamido, sulfonamido and olefin;  
         Y 3  and Y 4  are independently selected from the group consisting of alkyl, haloalkyl, hydroxy, alkoxy, cyano, halogen, aralkyl, heteroaralkyl, alkoxyalkyl, hydroxyalkyl, aryloxyalkyl, alkylsulfone, alkene or alkyne; wherein the alkyl group optionally contains 0-4 heteroatoms selected from the group consisting of N, O, and S and SO 2 ;  
         or when Y 3  is an aryl or a heteroaryl, Y 4  may be an aryl, heteroaryl, alkene, alkyne, alkoxy, hydroxy, cyano, alkoxyalkyl or an alkylsulfone;  
         Y 5  is C  
         optionally, Y 3 , Y 4  and Y 5  may form a sulfone (SO 2 ) group; or  
         Y 3  taken together with Y 4  forms a 3-8 membered monocyclic or a 7-11 membered bicyclic ring, containing 2-3 double bonds, containing 0-4 heteroatoms or functional groups selected from O, NR 9 , S, CO or SO 2 , optionally substituted with one or more substituent selected from the group consisting of alkyl, haloalkyl, halogen, haloalkyl, alkoxy, alkyne, cyano, alkylsulfone, sulfonamide, carboalkoxy and carboxyalkyl;  
         R b  is X 2 —R h  wherein X 2  is selected from the group consisting of O, S and NR j  wherein R h  and R j  are independently selected from the group consisting of H, alkyl, aryl, aralkyl, acyl and alkoxyalkyl.  
       
     
     
         2 . The compound of  claim 1  wherein A 1  is a naphthyridine.  
     
     
         3 . The compound according to  claim 2  wherein 
 n=1;  
 A is a phenyl ring substituted with R c ;  
 Y is (CH 2 ) p ; wherein p=0;  
 Y 5  is C.  
 
     
     
         4 . The compound according to  claim 3   wherein: 
 Y 3  taken together with Y 4  forms a monocyclic or a bicyclic ring B.  
   
     
     
         5 . The compound according to  claim 4  wherein: 
 the ring B is one of the following ring systems:  
                     
  wherein Rd is selected from the group consisting of hydrogen, alkyl, acyl, alkoxyalkyl, haloalkyl, alkylsulfone, aryl, heteroaryl, aralkyl and heteroaralkyl.  
 
     
     
         6 . The compound according to  claim 2  wherein Y 5  taken together with Y 3  and Y 4  forms a sulfone (SO 2 ) group.  
     
     
         7 . The compound according to  claim 2  comprising 
 3,3-dimethyl-4-{4-[2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy] phenyl}butanoic acid;  
 and pharmaceutically acceptable salts thereof.  
 
     
     
         8 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 2 .  
     
     
         9 . A method for treating conditions mediated by the α v β 3  integrin in a mammal in need of such treatment comprising administering an effective α v β 3  inhibiting amount of a compound of  claim 2 .  
     
     
         10 . The method according to  claim 9  wherein the condition treated is selected from the group consisting of tumor metastasis, tumor growth, solid tumor growth, angiogenesis, osteoporosis, humoral hypercalcemia of malignancy, smooth muscle cell migration, restenosis, atheroscelorosis, macular degeneration, retinopathy, and arthritis.  
     
     
         11 . A method for treating conditions mediated by the α v β 5  integrin in a mammal in need of such treatment comprising administering an effective α v β 5  inhibiting amount of a compound of  claim 2 .  
     
     
         12 . The method according to  claim 11  wherein the condition treated is selected from the group consisting of tumor metastasis, tumor growth, solid tumor growth, angiogenesis, osteoporosis, humoral hypercalcemia of malignancy, smooth muscle cell migration, restenosis, atheroscelorosis, macular degeneration, retinopathy, and arthritis.  
     
     
         13 . A method of treating neoplasia in a patient in need thereof comprising administering a compound of  claim 2  in combination with a chemotherapeutic agent.  
     
     
         14 . A compound of  claim 2  that selectively antagonizes the α v β 3  and the α v β 5  integrins, over the α v β 6  integrin.