Substituted pyrazolyl benzenesulfonamides for the treatment of inflamation

Abstract

A class of pyrazolyl benzenesulfonamide compounds is described for use in treating inflammation and inflammation-related disorders. Compounds of particular interest are defined by Formula II: wherein R 2 is selected from hydrido, alkyl, haloalkyl, alkoxycaronyl, cyano, cyanoalkyl, carboxyl, aminocaronyl, alkylaminocarbonyl, cycloalklaminocarbonyl, arylaminocarbonyl, carboxyalkylaminocarbonyl, carboxyalkyl, aralkoxycarbonylalkylaminocarbonyl, amioncarbonylalkyl, alkoxycarbonylcyanoalkenyl and hydroxyalkyl; wherein R 3 is selected from hydrido, alkyl, cyano, hydroxyalkyl, cycloalkyl, alkylsulfonyl and halo; and wherein R 4 is selected from aralkenyl, aryl, cycloalkyl, cycloalkenyl and heterocyclic; wherein R 4 is optionally substituted at a substitutable position with one or more radicals selected from halo alkylthio, alkylsulfonyl, cyano, nitro, haloalkyl, alkyl, hydroxyl, alkenyl, hydroxyalkyl, carboxyl, cycloalkyl, alkylamino, dialkylamino, alkoxycarbonyl, aminocarbonyl, alkoxy, haloalkoxy, sulfamyl, heterocyclic and amino; provided R 2 and R 3 are not both hydrido; further provided that R 2 is not carboxyl or methyl when R 3 is hydrido and when R 4 is phenyl; further provided that R 4 is not triazolyl when R 2 is methyl; further provided that R 4 is not arakenyl when R 2 is carboxyl, aminocarbonyl or ethoxycarbonyl; further provided that R 4 is not phenyl when R 2 is methyl and R 3 is carboxyl; and further provided that R 4 is not unsubstituted thienyl when R 2 is trifluoromethyl; or a pharmaceutically-acceptable salt thereof.

1 - 21 . (canceled)  
     
     
         22 . A method for the preparation of 4-[5-(4-fluorophenyl)-3-trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide wherein the method comprises: 
 mixing ethyl trifluoroacetate with a base,    contacting the ethyl trifluoroacetate and base mixture with 4′-fluoroacetophenone to form 4,4-trifluoro-1-[4-fluorophenyl]-butane-1,3-dione; and    contacting the 4,4-trifluoro-1-[4-(fluoro)phenyl]-butane-1,3-dione with 4-sulphonamidophenyl hydrazine to produce 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.    
     
     
         23 . The method according to  claim 22  wherein the base comprises an alkoxide.  
     
     
         24 . The method according to  claim 23  wherein the alkoxide comprises sodium methoxide.  
     
     
         25 . The method according to  claim 22  wherein the ethyl trifluoroacetate and the base are mixed in the presence of a first solvent.  
     
     
         26 . The method according to  claim 25  wherein the first solvent comprises at least one compound selected from the group consisting of an alcohol and an ether.  
     
     
         27 . The method according to  claim 26  wherein the first solvent comprises an alcohol.  
     
     
         28 . The method according to  claim 26  wherein the alcohol is a C 1  to about C 10  alcohol.  
     
     
         29 . The method according to  claim 25  wherein the first solvent comprises an ether.  
     
     
         30 . The method according to  claim 29  wherein the ether is methyl tert-butyl ether.  
     
     
         31 . The method according to  claim 22  wherein the 4,4-trifluoro-1-[4-(fluoro)phenyl]-butane-1,3-dione and the 4-sulfonamidophenyl hydrazine are contacted in the presence of a second solvent.  
     
     
         32 . The method according to  claim 31  wherein the second solvent comprises an alcohol.  
     
     
         33 . The method according to  claim 31  wherein the alcohol is ethanol.  
     
     
         34 . The method according to  claim 22  wherein the method comprises: 
 mixing ethyl trifluoroacetate with sodium methoxide and methanol,    contacting the ethyl trifluoroacetate, sodium methoxide, and methanol mixture with 4′-fluoroacetophenone to form 4,4-trifluoro-1-[4-fluorophenyl]-butane-1,3-dione; and    contacting the 4,4-trifluoro-1-[4-fluorophenyl]-butane-1,3-dione with 4-sulphonamidophenyl hydrazine in the presence of ethanol under reflux to produce 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.