Prodrugs of benzenesulfonamide-containing COX-2 inhibitors

A compound of Formula II ##STR104## wherein A is a ring substituent selected from partially unsaturated heterocyclyl, 5- or 6-membered heteroaryl, lower cycloalkenyl and phenyl;

• wherein A is unsubstituted or substituted with one or more radicals selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, lower hydroxyalkyl, lower alkylcarbonyloxyalkyl, and phenyl;
• wherein R.sup.4 is selected from heterocyclyl, cycloalkyl, cycloalkenyl and phenyl, wherein R.sup.4 is unsubstituted or substituted with one or more radicals selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio;
• and
• wherein R.sup.5 is selected from hydrido, lower alkyl, lower alkoxy, lower alkoxyalkyl, phenyl, lower aralkyl, lower carboxyalkyl, lower alkoxycarbonylalkyl, lower alkoxycarbonyl, lower aminoalkyl, lower alkoxycarbonylaminoalkyl, and lower alkylcarbonylaminoalkyl;
• provided A is not thienyl when R.sup.4 is 4-fluorophenyl and when R.sup.5 is methyl;
• or a pharmaceutically-acceptable salt thereof.

A compound of Formula III ##STR105## wherein R.sup.6 is selected from hydroxyl, lower alkyl, carboxyl, halo, lower carboxyalkyl, lower alkoxycarbonylalkyl, lower aralkyl, lower alkoxyalkyl, lower alkoxyalkyloxyalkyl, lower aralkoxyalkyl, lower haloalkyl, lower hydroxylalkyl, lower aryl(hydroxylalkyl), lower haloalkylsulfonyloxy, lower alkoxyalkyloxyalkyl, lower carboxyalkoxyalkyl, lower cycloalkylalkyl and lower cycloalkyl;

• wherein R.sup.7 is one or more radicals selected from hydrido, lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio;
• and
• wherein R.sup.8 is selected from hydrido, lower alkyl, lower alkoxy, lower alkoxyalkyl, phenyl, lower carboxyalkyl, lower alkoxycarbonylalkyl, lower alkoxycarbonyl, lower aminoalkyl, lower alkoxycarbonylaminoalkyl, and lower alkylcarbonylaminoalkyl;
• or a pharmaceutically-acceptable salt thereof.

A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compound selected from compounds of Formula I ##STR106## wherein A is a ring substituent selected from partially unsaturated heterocyclyl, heteroaryl, cycloalkenyl and aryl, wherein A is unsubstituted or substituted with one or more radicals selected from alkylcarbonyl, formyl, halo, alkyl, haloalkyl, oxo, cyano, nitro, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl, hydroxyalkyl, hydroxyl, alkoxyalkyloxyalkyl, aryl(hydroxylalkyl), 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 R.sup.1 is selected from heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R.sup.1 is unsubstituted or substituted with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;
• wherein R.sup.2 is selected from hydrido and alkoxycarbonylalkyl;
• and
• wherein R.sup.3 is selected from carboxyalkyl, acyl, alkoxycarbonyl, heteroarylcarbonyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylcarbonyl, amino acid residue, and alkylcarbonylaminoalkylcarbonyl;
• provided A is not tetrazolium, or pyridinium;
• and further provided A is not thienyl when R.sup.1 is 4-fluorophenyl, when R.sup.2 is hydrido and when R.sup.3 is acetyl;
• or a pharmaceutically-acceptable salt thereof.

A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compound selected from compounds of Formula II ##STR107## wherein A is a ring substituent selected from partially unsaturated heterocyclyl, 5- or 6-membered heteroaryl, lower cycloalkenyl and phenyl, wherein A is unsubstituted or substituted with one or more radicals selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, lower hydroxyalkyl, lower alkylcarbonyloxyalkyl, and phenyl;

• wherein R.sup.4 is selected from heterocyclyl, cycloalkyl, cycloalkenyl and phenyl, wherein R.sup.4 is unsubstituted or substituted with one or more radicals selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio;
• and
• wherein R.sup.5 is selected from hydrido, lower alkyl, lower alkoxy, lower alkoxyalkyl, phenyl, lower carboxyalkyl, lower alkoxycarbonylalkyl, lower alkoxycarbonyl, lower aminoalkyl, lower alkoxycarbonylaminoalkyl, and lower alkylcarbonylaminoalkyl;
• provided A is not thienyl when R.sup.4 is 4-fluorophenyl and when R.sup.5 is methyl;
• or a pharmaceutically-acceptable salt thereof.

A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compound selected from compounds of Formula III ##STR108## wherein R.sup.6 is selected from hydroxyl, lower alkyl, carboxyl, halo, lower carboxyalkyl, lower alkoxycarbonylalkyl, lower aralkyl, lower alkoxyalkyl, lower alkoxyalkyloxyalkyl, lower aralkoxyalkyl, lower haloalkyl, lower hydroxylalkyl, lower aryl(hydroxylalkyl), lower haloalkylsulfonyloxy, lower alkoxyalkyloxyalkyl, lower carboxyalkoxyalkyl, lower cycloalkylalkyl and lower cycloalkyl;

• wherein R.sup.7 is one or more radicals selected from hydrido, lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio;
• and
• wherein R.sup.8 is selected from hydrido, lower alkyl, lower alkoxy, lower alkoxyalkyl, phenyl, lower carboxyalkyl, lower alkoxycarbonylalkyl, lower alkoxycarbonyl, lower aminoalkyl, lower alkoxycarbonylaminoalkyl, and lower alkylcarbonylaminoalkyl;
• or a pharmaceutically-acceptable salt thereof.

A method of treating inflammation, said method comprising administering to the subject having or susceptible to such inflammation or inflammation-associated disorder, a therapeutically-effective amount of a compound of Formula I' ##STR109## wherein A is a ring substituent selected from partially unsaturated heterocyclyl, heteroaryl, cycloalkenyl and aryl, wherein A is unsubstituted or substituted with one or more radicals selected from alkylcarbonyl, formyl, halo, alkyl, haloalkyl, oxo, cyano, nitro, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl, hydroxyalkyl, hydroxyl, alkoxyalkyloxyalkyl, aryl(hydroxylalkyl), 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 R.sup.1 is selected from heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R.sup.1 is unsubstituted or substituted with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;
• wherein R.sup.2 is selected from hydrido and alkoxycarbonylalkyl;
• and
• wherein R.sup.3 is selected from carboxyalkyl, acyl, alkoxycarbonyl, heteroarylcarbonyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylcarbonyl, amino acid residue, and alkylcarbonylaminoalkylcarbonyl;
• provided A is not thienyl when R.sup.1 is 4-fluorophenyl, when R.sup.2 is hydrido and when R.sup.3 is acetyl;
• or a pharmaceutically-acceptable salt thereof.

A method of treating inflammation, said method comprising administering to the subject having or susceptible to such inflammation or inflammation-associated disorder, a therapeutically-effective amount of a compound of Formula II ##STR110## wherein A is a ring substituent selected from partially unsaturated heterocyclyl, 5- or 6-membered heteroaryl, lower cycloalkenyl and phenyl, wherein A is unsubstituted or substituted with one or more radicals selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, lower hydroxyalkyl, lower alkylcarbonyloxyalkyl, and phenyl;

• wherein R.sup.4 is selected from heterocyclyl, cycloalkyl, cycloalkenyl and phenyl, wherein R.sup.4 is unsubstituted or substituted with one or more radicals selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio;
• and
• wherein R.sup.5 is selected from hydrido, lower alkyl, lower alkoxy, lower alkoxyalkyl, phenyl, lower carboxyalkyl, lower alkoxycarbonylalkyl, lower alkoxycarbonyl, lower aminoalkyl, lower alkoxycarbonylaminoalkyl, and lower alkylcarbonylaminoalkyl;
• provided A is not thienyl when R.sup.4 is 4-fluorophenyl and when R.sup.5 is methyl;
• or a pharmaceutically-acceptable salt thereof.

A method of treating inflammation, said method comprising administering to the subject having or susceptible to such inflammation or inflammation-associated disorder, a therapeutically-effective amount of a compound of Formula III ##STR111## wherein R.sup.6 is selected from hydroxyl, lower alkyl, carboxyl, halo, lower carboxyalkyl, lower alkoxycarbonylalkyl, lower aralkyl, lower alkoxyalkyl, lower alkoxyalkyloxyalkyl, lower aralkoxyalkyl, lower haloalkyl, lower hydroxylalkyl, lower aryl(hydroxylalkyl), lower haloalkylsulfonyloxy, lower alkoxyalkyloxyalkyl, lower carboxyalkoxyalkyl, lower cycloalkylalkyl and lower cycloalkyl;

• wherein R.sup.7 is one or more radicals selected from hydrido, lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio;
• and
• wherein R.sup.8 is selected from hydrido, lower alkyl, lower alkoxy, lower alkoxyalkyl, phenyl, lower carboxyalkyl, lower alkoxycarbonylalkyl, lower alkoxycarbonyl, lower aminoalkyl, lower alkoxycarbonylaminoalkyl, and lower alkylcarbonylaminoalkyl;
• or a pharmaceutically-acceptable salt thereof.