4-Bromo or 4-iodo phenylamino benzhydroxamic acid derivatives and their use as MEK inhibitors

Abstract

Phenylamino benzhydroxamic acid derivatives of the formula where R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are hydrogen or substituent groups such as alkyl, and where R 7 is hydrogen or an organic radical, are potent inhibitors of MEK and, as such, are effective in treating cancer and other proliferative diseases such as psoriasis and restenosis.

1 . The compounds are defined by Formula I  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is hydrogen, hydroxy, C 1 -C 8  alkyl, C 1 -C 8  alkoxy, halo, trifluoromethyl, or CN;  
 R 2  is hydrogen;  
 R 3 , R 4 , and R 5  independently are hydrogen, hydroxy, halo, trifluoromethyl, C 1 -C 8  alkyl, C 1 -C 8  alkoxy, nitro, CN, or (O or NH) m —(CH 2 ) n —R 9 , where R 9  is hydrogen, hydroxy, CO 2 H or NR 10 R 11 ;  
 n is 0 to 4;  
 m is 0 or 1;  
 R 10  and R 11  independently are hydrogen or C 1 -C 8  alkyl, or taken together with the nitrogen to which they are attached can complete a 3- to 10-member cyclic ring optionally containing one, two, or three additional heteroatoms selected from O, S, NH, or N—C 1 -C 8  alkyl;  
 R 6  is hydrogen, C 1 -C 8  alkyl,  
                     
 aryl, aralkyl, or C 3 -C 10  cycloalkyl;  
 R 7  is C 3 -C 10  cycloalkyl;  
 and wherein any of the foregoing alkyl groups can be unsubstituted or substituted by cycloalkyl (or cycloalkyl optionally containing a heteroatom selected from O, S, or NR 9 ), aryl, aryloxy, heteroaryl, or heteroaryloxy.  
 
     
     
         2 . A compound according to  claim 1  wherein R 1  is C 1 -C 8  alkyl or halo.  
     
     
         3 . A compound according to  claim 2  wherein R 6  is hydrogen.  
     
     
         4 . A compound according to  claim 3  wherein R 1  is methyl.  
     
     
         5 . A compound according to  claim 4  having the formula  
       
         
           
           
               
               
           
         
       
     
     
         6 . A compound of  claim 5  wherein R 4  is fluoro, and R 3  and R 5  are hydrogen.  
     
     
         7 . A compound of  claim 6  which is: 
 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopropylmethoxy)-benzamide; or    4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopentoxy)-benzamide.    
     
     
         8 . A compound of  claim 5  wherein R 3  and R 4  are fluoro, and R 5  is hydrogen.  
     
     
         9 . A compound of  claim 8  which is: 
 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopropyl-methoxy)-benzamide;    3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclobutyloxy)-benzamide;    3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopentyloxy)-benzamide;    3,4-Difluoro-2-(2-chloro-4-iodo-phenylamino)-N-cyclobutylmethoxy-benzamide; or    3,4-Difluoro-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-benzamide.    
     
     
         10 . A compound of  claim 5  wherein R 3  and R 4  are fluoro, and R 5  is bromo.  
     
     
         11 . A compound according to  claim 10  which is: 
 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopropylmethoxy)-benzamide;    5-Bromo-N-cyclohexylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;    5-Bromo-N-cyclopentylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; or    5-Bromo-N-cyclobutylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide.    
     
     
         12 . A compound of  claim 5  wherein R 3  and R 4  are hydrogen, and R 5  is halo.  
     
     
         13 . A compound of  claim 4  having the formula  
       
         
           
           
               
               
           
         
       
     
     
         14 . A compound of  claim 13  wherein R 3  and R 4  are fluoro, and R 5  is hydrogen.  
     
     
         15 . A compound according to  claim 14  which is: 
 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(cyclobutoxy)-benzamide;    3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(cyclopropyl-methoxy)-benzamide; or    3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(cyclopentoxy)-benzamide.    
     
     
         16 . A compound according to  claim 1  which is: 
 N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;    5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;    5-Bromo-N-cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;    N-Cyclopropylmethoxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro-benzamide;    N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;    5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;    5-Bromo-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide;    N-Cyclopropylmethoxy-2-(2-fluoro-4-iodo-phenylamino)-4-nitro-benzamide;    2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4,5-trifluoro-benzamide;    5-Chloro-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide;    2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4,5-trifluoro-benzamide;    2-(2-Bromo-4-iodo-phenylamino)-5-chloro-N-cyclopropylmethoxy-3,4-difluoro-benzamide    2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-nitro-benzamide;    N-Cyclopropylmethoxy-4-fluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;    N-Cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;    2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-fluoro-benzamide;    2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide;    2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-fluoro-benzamide;    2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide;    N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;    2-(2-Chloro-4-iodo-phenylamino)-N-cyclobutylmethoxy-3,4-difluoro-benzamide;    2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide; or    5-Bromo-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide.    
     
     
         17 . A pharmaceutical formulation comprising a compound of  claim 1  admixed with a pharmaceutically acceptable excipient, diluent, or carrier.  
     
     
         18 . A formulation of  claim 17  comprising a compound of the formula  
       
         
           
           
               
               
           
         
       
     
     
         19 . A formulation of  claim 17  comprising a compound of the formula  
       
         
           
           
               
               
           
         
       
     
     
         20 . A method for inhibiting MEK enzymes in a mammal comprising administering an MEK inhibiting amount of a compound of  claim 1 .  
     
     
         21 . A method of treating a mammal suffering from a proliferative disease and in need of treatment comprising administering an antiproliferative amount of a compound of  claim 1 .  
     
     
         22 . A method according to  claim 21  wherein the proliferative disease is psoriasis, restenosis, autoimmune disease, or atherosclerosis.  
     
     
         23 . A method according to  claim 21  wherein the proliferative disease is cancer.  
     
     
         24 . A method for treating a mammal suffering from stroke and in need of treatment comprising administering an effective amount of a Compound of  claim 1 .  
     
     
         25 . A method for treating a mammal suffering from heart failure and in need of treatment comprising administering an effective amount of a Compound of  claim 1 .  
     
     
         26 . A method for treating a mammal suffering from hepatomegaly and in need of treatment comprising administering an effective amount of a Compound of  claim 1 .  
     
     
         27 . A method for treating a mammal suffering from cardiomegaly and in need of treatment comprising administering an effective amount of a Compound of  claim 1 .  
     
     
         28 . A method for treating a mammal suffering from diabetes and in need of treatment comprising administering an effective amount of a Compound of  claim 1 .  
     
     
         29 . A method for treating a mammal suffering from Alzheimer's disease and in need of treatment comprising administering an effective amount of a Compound of  claim 1 .  
     
     
         30 . A method for treating a mammal suffering from cancer comprising administering an effective amount of a compound of  claim 1  in conjunction with conventional radiation therapy.  
     
     
         31 . A method for treating a mammal suffering from cystic fibrosis and in need of treatment comprising administering an effective amount of a compound of  claim 1.