Prodrugs of cox-2 inhibitors

Abstract

A compound of Formula (I), or a pharmaceutically-acceptable salt thereof, suitable for use in the treatment of a cyclooxygenase-2 mediated disease is provided. Also provided is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically-acceptable salt thereof, and a method for treatment of a cyclooxygenase-2 mediated disease by administering to a subject in need thereof a therapeutically-effective amount of the pharmaceutical composition.

1 - 26 . (canceled).  
     
     
         27 . A compound of Formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt thereof, wherein: 
 A is an isoxazole group optionally substituted at a substitutable position with one or more radicals independently selected at each occurrence from the group consisting of alkylcarbonyl, formyl, halo, alkyl, haloalkyl, oxo, cyano, nitro, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl, hydroxyalkyl, haloalkylsulfonyloxy, alkoxyalkyloxyalkyl, carboxyalkoxyalkyl, cycloalkylalkyl, alkenyl, alkenyl heterocyclyloxy, alkylthio, cycloalkyl, aryl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, alkylthioalkyl, arylcarbonyl, aralkylcarbonyl aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl and N-alkyl-N-arylaminosulfonyl;  
 R 1  is selected from the group consisting of heteroaryl, heterocyclyl, cycloalkyl, and cycloalkenyl, wherein R 1  is optionally substituted at a substitutable position with one or more radicals independently selected at each occurrence from the group consisting of alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;  
 R 2  and R 3  are independently selected from the group consisting of hydrido, alkyl, alkylcarbonyl, hydroxyalkyl, heterocyclyl, heteroaryl, monosaccharide, disaccharide, polysaccharide, alkylphosphate, acyloxyalkyl, alkylaminocarbonyl, alkoxyaralkyl and carboxyalkyl, wherein R 3  is optionally substituted at a substitutable position with one or more radicals independently selected at each occurrence from the group consisting of alkylcarbonyl, formyl, halo, alkyl, haloalkyl, oxo, cyano, nitro, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl, hydroxyalkyl, haloalkylsulfonyloxy, alkoxyalkyloxyalkyl, carboxyalkoxyalkyl, cycloalkylalkyl, alkenyl, alkynyl, heterocyclyloxy, alkylthio, cycloalkyl, aryl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, and N-alkyl-N-arylaminosulfonyl;  
 wherein at least one of R 2  and R 3  is other than hydrido;  
 wherein R 2  is other than alkyl, carboxyalkyl or alkylcarbonyl when R 3  is hydrido; and  
 wherein R 3  is other than alkyl, carboxyalkyl or alkylcarbonyl when R 2  is hydrido;  
 or, R 2  and R 3  are taken together along with the nitrogen to which they are attached to form a three to seven membered saturated, partially unsaturated or unsaturated heterocyclic ring and may optionally be substituted at a substitutable position with one or more R 5  radicals, wherein the R 5  radicals are independently selected at each occurrence from the group consisting of alkylcarbonyl, formyl, halo, alkyl, haloalkyl, alkylphosphate, phosphate, oxo, cyano, nitro, alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl, hydroxyalkyl, haloalkylsulfonyloxy, alkoxyalkyloxyalkyl, carboxyalkoxyalkyl, cycloalkylalkyl, alkenyl, alkynyl, heterocyclyloxy, alkylthio, cycloalkyl, aryl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl and N-alkyl-N-arylaminosulfonyl; and  
 R 4  is selected from hydrido and fluoro.  
 
     
     
         28 . A compound according to  claim 27  wherein R 1  is selected from the group consisting of 5- or 6-membered heteroaryl and heterocyclyl, lower cycloalkyl, and lower cycloalkenyl, where R 1  is optionally substituted at a substitutable position with one or more radicals independently selected at each occurrence from the group consisting of lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylmino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio.  
     
     
         29 . A compound according to  claim 27  wherein R 1  is selected from the group consisting of thienyl, oxazolyl, isoxazolyl, furyl, thiazolyl, pyridyl, pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, morpholinyl, thiazolidinyl, dihydrothiophenyl, dihydropyranyi, dihydrofuranyl, dihydrothiazole, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl, where R 1  is optionally substituted at a substitutable position with one or more radicals independently selected at each occurrence from the group consisting of methyl, trifluoromethyl, hydroxyl, hydroxymethyl, trifluoromethoxy, nitro, methoxymethyl, fluoro, chloro, bromo, methoxy and methylthio.  
     
     
         30 . A compound according to  claim 27  that is a pharmaceutically-acceptable metal salt.  
     
     
         31 . A compound according to  claim 30  wherein the metal salt is an alkali metal salt or an alkaline earth metal salt.  
     
     
         32 . A compound according to  claim 31  wherein the metal salt is selected from the group consisting of sodium and potassium salts.  
     
     
         33 . A pharmaceutical composition comprising a compound according to  claim 27  or pharmaceutically-acceptable salt thereof, and at least one pharmaceutically-acceptable carrier, adjuvant or diluent.  
     
     
         34 . A compound according to  claim 27  represented by Formula II:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt thereof wherein: 
 R 1  is selected from heteroaryl, heterocyclyl, cycloalkyl, and cycloalkenyl, wherein R 1  is optionally substituted at a substitutable position with one or more radicals indepedently selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;  
 R 2  and R 3  are independently selected from the group consisting of hydrido, alkyl, alkylcarbonyl, hydroxyalkyl, heterocyclyl, heteroaryl, monosaccharide, disaccharide, polysaccharide, alkylphosphate, acyloxyalkyl, alkylaminocarbonyl, alkoxyaralkyl and carboxyalkyl, wherein R 3  is optionally substituted at a substitutable position with one or more radicals independently selected at each occurrence from the group consisting of alkylcarbonyl, formyl, halo, alkyl, haloalkyl, oxo, cyano, nitro, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl, hydroxyalkyl, haloalkylsulfonyloxy, alkoxyalkyloxyalkyl, carboxyalkoxyalkyl, cycloalkylalkyl, alkenyl, alkynyl, heterocyclyloxy, alkylthio, cycloalkyl, aryl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, and N-alkyl-N-arylaminosulfonyl; and  
 R 4  is selected from hydrido and fluoro;  
 wherein at least one of R 2  and R 3  is other than hydrido;  
 wherein R 2  is other than alkyl, carboxyalkyl or alkylcarbonyl when R 3  is hydrido; and  
 wherein R 3  is other than alkyl, carboxyalkyl or alkylcarbonyl when R 2  is hydrido.  
 
     
     
         35 . A compound according to  claim 34  that is a pharmaceutically-acceptable metal salt.  
     
     
         36 . A compound according to  claim 35  wherein the metal salt is an alkali metal salt or an alkaline earth metal salt.  
     
     
         37 . A compound according to  claim 36  wherein the metal salt is selected from the group consisting of sodium and potassium salts.  
     
     
         38 . A pharmaceutical composition comprising a compound according to  claim 34  or pharmaceutically-acceptable salt thereof, and at least one pharmaceutically-acceptable carrier, adjuvant or diluent.