Sulfonamide interleukin-1beta converting enzyme inhibitors

Abstract

The present invention relates to compounds that are inhibitors of interleukin-1β converting enzyme that have the Formula (I). This invention also relates to a method of treatment of stroke, reperfusion injury, Alzheimer's disease, shigellosis, inflammatory diseases, and septic shock and to a pharmaceutically acceptable composition that contains a compound that is an inhibitor of interleukin-1β converting enzyme.

1 . A compound of Formula I  
       
         
           
           
               
               
           
         
         R 3  is hydrogen, 
 C 1 -C 6  alkyl,  
 —(CH 2 ) n  aryl, or  
 —(CH 2 ) n  heteroaryl;  
 
         R 4  is C 1 -C 6  alkyl, 
 —(CH 2 ) n  aryl, or  
 —(CH 2 ) n  heteroaryl;  
 
         R 5  and R 6  are each independently hydrogen, 
 C 1 -C 6  alkyl,  
 —(CH 2 ) n  aryl, or  
 —(CH 2 ) n  heteroaryl;  
 
         R 7  is C 1 -C 6  alkyl, 
 —(CH 2 ) n  aryl, or  
 —(CH 2 ) n  heteroaryl;  
 
         each n is independently 0 to 6;  
         each m is independently 0, 1, 2, or 3;  
         A is alanine, leucine, isoleucine, proline, phenylalanine, glycine, tyrosine, serine, threonine, tryptophan, cysteine, methionine, valine, asparagine, glutamine, aspartic acid, lysine, glutamic acid, arginine, or histidine;  
         each R Q  is independently hydrogen or C 1 -C 6  alkyl;  
         R 2  is —(CH 2 ) n —Z; and  
         Z is aryl, heteroaryl, cycloalkyl, C 1 -C 6 alkyl,  
         
           
             
             
                 
                 
             
           
         
          fluorenyl, substituted fluorenyl, substituted aryl, substituted heteroaryl, or substituted cycloalkyl, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.  
       
     
     
         2 . A compound according to  claim 1  wherein R 1  is  
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound according to  claim 1  wherein R 1  is  
       
         
           
           
               
               
           
         
         m is 0, and R 7  is —(CH 2 ) n  aryl.  
       
     
     
         4 . A compound according to  claim 1  wherein R 1  is  
       
         
           
           
               
               
           
         
         m is 0, and R 7  is —CH 2  aryl.  
       
     
     
         5 . A compound according to  claim 1  wherein R 2  is —(CH 2 ) n  aryl.  
     
     
         6 . A compound according to  claim 5  wherein aryl is phenyl or naphthyl.  
     
     
         7 . A compound according to  claim 1  wherein R 2 is —(CH 2 ) n  -cycloalkyl.  
     
     
         8 . A compound according to  claim 1  wherein R 1    
       
         
           
           
               
               
           
         
       
       or —SO 2 -phenyl.  
     
     
         9 . A compound according to  claim 1  wherein R 2  is  
       
         
           
           
               
               
           
         
       
     
     
         10 . A compound according to  claim 1  wherein R 2  is  
       
         
           
           
               
               
           
         
       
     
     
         11 . A compound of the Formula I  
       
         
           
           
               
               
           
         
         wherein R 2  is —CH 2 CH 2 — aryl, —CH 2 — cycloalkyl, —CH 2 CH 2 — cycloalkyl, or —CH 2 CH 2 — heteroaryl;  
         R 1  is  
         
           
             
             
                 
                 
             
           
         
         R a  is —(CH 2 ) n  aryl or —(CH 2 ) n  heteroaryl;  
         R b  is aryl or heteroaryl;  
         R c  is —CH 2  aryl or aryl;  
         R d  is hydrogen or C 1 -C 6  alkyl;  
         R e  is —CH 2  aryl or —CH 2  heteroaryl; and the pharmaceutically acceptable  
         salts, esters, amides, and prodrugs thereof.  
       
     
     
         12 . A compound according to  claim 11  wherein R 1  is  
       
         
           
           
               
               
           
         
       
     
     
         13 . A compound according to  claim 11  wherein R 1  is  
       
         
           
           
               
               
           
         
       
     
     
         14 . A compound according to  claim 11  wherein R e  is —(CH 2 ) n  aryl.  
     
     
         15 . A compound according to  claim 14  wherein aryl is phenyl or naphthyl.  
     
     
         16 . A compound according to  claim 13  wherein R b  is aryl.  
     
     
         17 . A compound according to  claim 16  wherein is aryl is phenyl.  
     
     
         18 . The compounds: 
 3-Benzyloxycarbonylamino-4-oxo-5-(2-phenylmethanesulfonylamino)-pentanoic acid;    3-Benzyloxycarbonylamino-4-oxo-5-(3-phenyl-propane-1-sulfonylamino)-pentanoic acid;    3-Benzyloxycarbonylamino-4-oxo-5-phenylmethanesulfonyl-amino-pentanoic acid;    5-Benzenesulfonylamino-3-Benzyloxycarbonylamino-4-oxo-pentanoic acid;    3-Benzyloxycarbonylarnino-5-methanesulfonylamino-4-oxo-pentanoic acid;    3-Benzyloxycarbonylamino-5-(naphthalene-1-sulfonylamino)-4-oxo-pentanoic acid;    3-Benzyloxycarbonylamino-5-(2-cyclohexyl-ethanesulfonylamino)-4-oxo-pentanoic acid;    3-Benzyloxycarbonylamino-5-(2-naphthalen-1-yl-ethanesulfonylamino)-4-oxo-pentanoic acid;    3-Benzyloxycarbonylamino-5-(7,7-dimethyl-2-oxo-bicyclo [2.2.1]hept-1-(R)-ylmethanesulfonylamino)-4-oxo-pentanoic acid;    3-Benzyloxycarbonylamino-5-(indan-1-ylmethanesulfonylamino)-4-oxo-pentanoic acid;    3-Benzyloxycarbonylamino-5-(9-fluoro-9H-fluoren-9-ylmethanesulfonylamino)-4-oxo-pentanoic acid;    3-Benzyloxycarbonylamino-5-(7,7-dimethyl-2-oxo-bicyclo [2.2.1]hept-1-(S)-ylmethanesulfonylamino)-4-oxo-pentanoic acid;    3-(2-Acetylamino-3-methyl-butyrylamino)-5-(7,7-dimethyl-2-oxo-bicyclo[2.2.1]hept-1-(S)-ylmethanesulfonylamino)-4-oxo-pentanoic acid;    3-(2-Acetylamino-propylamino)-5-(7,7-dimethyl-2-oxo-bicyclo[2.2.1]hept-1-(S)-ylmethanesulfonylamino)-4-oxo-pentanoic acid;    3-(1,2,3,4-tetrahydro-1-oxo-isoquinoline-2-yl)-acetanino-5-benzenesulfonylamino-4-oxo-pentanoic acid;    (S)-5-(Bicyclo[2.2.1]hept-1-ylmethanesulfonylamino)-4-oxo-3-[2-(1-oxo-3,4-dihydro-1 H-isoquinolin-2-yl)-acetylamino]-pentanoic acid;    (S)-4-Oxo-3-[2-(1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-acetylamino ]-5-(2-phenyl-ethanesulfonylamino)-pentanoic acid; and    4-Oxo-3-[2-(1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-acetylamino]-5-phenylmethanesulfonylamino-pentanoic acid.    
     
     
         19 . A method of inhibiting interleukin-1β converting enzyme, the method comprising administering to a patient in need of inhibition of interleukin-1β converting enzyme a therapeutically effective amount of a compound of  claim 1 .  
     
     
         20 . A method of inhibiting Caspase-4, the method comprising administering to a patient in need of Caspase-4 inhibition a Caspase-4 inhibiting amount of a compound of  claim 1 .  
     
     
         21 . A method of treating or preventing stroke, the method comprising administering to a patient having a stroke or having had a stroke a therapeutically effective amount of a compound of  claim 1 .  
     
     
         22 . A method of treating inflammatory diseases, the method comprising administering to a patient having an inflammatory disease a therapeutically effective amount of a compound of  claim 1 .  
     
     
         23 . The method of  claim 22  wherein the inflammatory disease is arthritis.  
     
     
         24 . The method of  claim 22  wherein the inflammatory disease inflammatory bowel disease.  
     
     
         25 . A pharmaceutically acceptable composition that contains a compound of  claim 1 .  
     
     
         26 . A method of inhibiting interleukin-1β converting enzyme, the method comprising administering to a patient in need of inhibition of interleukin-1β converting enzyme a therapeutically effective amount of a compound of  claim 11 .  
     
     
         27 . A method of inhibiting Caspase-4, the method comprising administering to a patient in need of Caspase-4 inhibition a Caspase-4 inhibiting amount of a compound of  claim 11 .  
     
     
         28 . A method of treating or preventing stroke, the method comprising administering to a patient having a stroke or having had a stroke a therapeutically effective amount of a compound of  claim 11 .  
     
     
         29 . A method of treating inflammatory diseases, the method comprising administering to a patient having an inflammatory disease a therapeutically effective amount of a compound of  claim 11 .  
     
     
         30 . The method of  claim 29  wherein the inflammatory disease is arthritis.  
     
     
         31 . The method of  claim 29  wherein the inflammatory disease is inflammatory bowel disease.  
     
     
         32 . A pharmaceutically acceptable composition that contains a compound of  claim 11 .  
     
     
         33 . A method of treating septic shock, the method comprising administering to a patient having septic shock a therapeutically effective amount of a compound of  claim 1 .  
     
     
         34 . A method of treating septic shock, the method comprising administering to a patient having septic shock a therapeutically effective amount of a compound of  claim 11 .  
     
     
         35 . A method of treating reperfusion injury, the method of comprising administering to a patient having reperfusion injury a therapeutically effective amount of a compound of  claim 1 .  
     
     
         36 . A method of treating reperfusion injury, the method of comprising administering to a patient having reperfusion injury a therapeutically effective amount of a compound of  claim 11 .  
     
     
         37 . A method of treating Alzheimer's disease, the method comprising administering to a patient having Alzheimer's disease a therapeutically effective amount of a compound of  claim 1 .  
     
     
         38 . A method of treating Alzheimer's disease, the method comprising administering to a patient having Alzheimer's disease a therapeutically effective amount of a compound of  claim 11 .  
     
     
         39 . A method of treating shigellosis, the method comprising administering to a patient having shigellosis a therapeutically effective amount of a compound of  claim 1 .  
     
     
         40 . A method of treating shigellosis, the method comprising administering to a patient having shigellosis a therapeutically effective amount of a compound of  claim 11 .  
     
     
         41 . A compound of the Formula II  
       
         
           
           
               
               
           
         
         R a  is —(CH 2 ) n — aryl or —(CH 2 ) n  heteroaryl;  
         R b  is aryl or heteroaryl;  
         R c  is —CH 2  aryl or aryl;  
         R d  is hydrogen or C 1 -C 6  alkyl;  
         R e  is —CH 2  aryl or —CH 2  heteroaryl; and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.  
       
     
     
         42 . A compound according to  claim 41  wherein R 1  is  
       
         
           
           
               
               
           
         
       
     
     
         43 . A compound according to  claim 41  wherein R 1  is  
       
         
           
           
               
               
           
         
       
     
     
         44 . A compound according to  claim 41  wherein R e  is —(CH 2 ) n  aryl.  
     
     
         45 . A compound according to  claim 41  wherein aryl is phenyl or naphthyl.  
     
     
         46 . A compound according to  claim 41  wherein R b  is aryl.  
     
     
         47 . A compound according to  claim 46  wherein is aryl is phenyl.  
     
     
         48 . A method of inhibiting interleukin-1β converting enzyme, the method comprising administering to a patient in need of inhibition of interleukin-1β converting enzyme a therapeutically effective amount of a compound of  claim 41 .  
     
     
         49 . A method of inhibiting Caspase-4, the method comprising administering to a patient in need of Caspase-4 inhibition a Caspase-4 inhibiting amount of a compound of  claim 41 .  
     
     
         50 . A method of treating or preventing stroke, the method comprising administering to a patient having a stroke or having had a stroke a therapeutically effective amount of a compound of  claim 41 .  
     
     
         51 . A method of treating inflammatory diseases, the method comprising administering to a patient having an inflammatory disease a therapeutically effective amount of a compound of  claim 41 .  
     
     
         52 . The method of  claim 51  wherein the inflammatory disease is arthritis.  
     
     
         53 . The method of  claim 51  wherein the inflammatory disease inflammatory bowel disease.  
     
     
         54 . A method of treating septic shock, the method comprising administering to a patient having septic shock a therapeutically effective amount of a compound of  claim 41 .  
     
     
         55 . A method of treating reperfusion injury, the method of comprising administering to a patient having reperfusion injury a therapeutically effective amount of a compound of  claim 41 .  
     
     
         56 . A method of treating Alzheimer's disease, the method comprising administering to a patient having Alzheimer's disease a therapeutically effective amount of a compound of  claim 41 .  
     
     
         57 . A method of treating shigellosis, the method comprising administering to a patient having shigellosis a therapeutically effective amount of a compound of  claim 41 .  
     
     
         58 . The compounds: 
 3-[2-(2-Benzyloxycarbonylamino-3-methyl-butyrylamino)-propionylamino ]4-oxo-5-(2-phenyl-ethanesulfonylamino)-pentanoic acid;    3-[2-(2-Benzyloxycarbonylamino-4-carboxy-butyrylamino)-3-methyl-butyrylamino]-4-oxo-5-(2-phenyl-ethanesulfonylamino)-pentanoic acid;    3-{2-[4-Carboxy-2-(3-phenyl-propionylamino)-butyrylamino]-3-methyl-butyrylamino}-4-oxo-5-(2-phenyl-ethanesulfonylamino)-pentanoic acid;    3-[2-(2-Benzyloxycarbonylamino-3-methyl-butyrylamino) propionylamino]-5-(7,7-dimethyl-2-oxo-bicyclo[2.2.1]hept-1-ylmethanesulfonylamino)-4-oxo-pentanoic acid;    3-[2-(2-Benzyloxycarbonylamino-4-carboxy-butyrylamino)-3-methyl-butyrylamino]-5-(7,7dimethyl-2-oxo-bicyclo[2.2.1]hept-1-ylmethanesulfonylamino)-4-oxo-pentanoic acid;    3-{2-[4-Carboxy-2-(3-phenyl-propionylamino)-butyrylamino]-3-methyl-butyrylamino}-5-(7,7-dimethyl-2-oxo-bicyclo[2.2.1]hept-1-ylmethanesulfonylamino)-4-oxo-pentanoic acid;    3-(2-{2-[2-Acetylamino-3-(4-hydroxy-phenyl)-propionylamino]-4-carboxy-butyrylamino}-3-methyl-butyrylamino)-5-(7,7-dimethyl-2-oxo-bicyclo[2.2.1]hept-1-ylmethanesulfonylamino)-4-oxo-pentanoic acid; and    3-(2-{2-[2-Acetylamino-3-(4-hydroxy-phenyl)-propionylamino]-4-carboxy-butyrylamino}-3-methyl-butyrylamino)-4-oxo-5-(2-phenyl-ethanesulfonylamino)-pentanoic acid.