Claims for Patent: 5,633,272

Summary for Patent: 5,633,272

Title:	Substituted isoxazoles for the treatment of inflammation
Abstract:	A class of substituted isoxazolyl compounds is described for use in treating inflammation and inflammation-related disorders. Compounds of particular interest are defined by Formula II II wherein R1 is selected from hydroxyl, lower alkyl, carboxyl, lower carboxyalkyl, lower aminocarbonylalkyl, lower alkoxycarbonylalkyl, lower aralkyl, lower alkoxyalkyl, lower aralkoxyalkyl, lower alkylthioalkyl, lower aralkylthioalkyl, lower alkylaminoalkyl, lower aryloxyalkyl, lower arylthioalkyl, lower haloalkyl, lower hydroxylalkyl, cycloalkyl, cycloalkylalkyl, and aralkyl; wherein R3 is selected from cycloalkyl, cycloalkenyl, aryl, and heteroaryl; wherein R3 is optionally substituted at a substitutable position with one or more radicals independently selected from lower alkylsulfinyl, lower alkyl, cyano, carboxyl, lower alkoxycarbonyl, lower haloalkyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, lower arylamino, lower aminoalkyl, nitro, halo, lower alkoxy, aminosulfonyl, and lower alkylthio; and wherein R4 is selected from lower alkyl, hydroxyl and amino; or a pharmaceutically-acceptable salt thereof.
Inventor(s):	John J. Talley, David L. Brown, Srinivasan Nagarajan, Jeffery S. Carter, Richard M. Weier, Michael A. Stealey, Paul W. Collins, Roland S. Rogers, deceased, Karen Seibert
Assignee:	Pharmacia and Upjohn Co LLC
Application Number:	US08/473,884
Patent Claims:	1. A compound of Formula II ##STR32## wherein R1 is selected from alkyl, carboxyalkyl, alkoxycarbonyl, aminocarbonyl, aminocarbonylalkyl, alkoxycarbonylalkyl, carboxyl, alkoxy, haloalkoxy, aralkoxy, cycloalkylalkoxy, alkylthio, aralkylthio, cycloalkylalkylthio, alkoxyalkyl, aralkoxyalkyl, alkylthioalkyl, aralkylthioalkyl, alkylaminoalkyl, aryloxyalkyl, arylthioalkyl, hydroxyl, amino, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, halo, alkylamino, aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-cycloalkylalkylamino, arylcarbonyloxyalkyl, arylcarbonylthio, alkoxycarbonyloxyalkyl, alkylaminocarbonyloxyalkyl, alkoxycarbonylthioalkyl, and alkylaminocarbonylthioalkyl;wherein R3 is selected from cycloalkyl, cycloalkenyl, and aryl; wherein R3 is optionally substituted at a substitutable position with one or more radicals independently selected from alkyl, cyano, carboxyl, alkoxycarbonyl, haloalkyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, aminoalkyl, nitro, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, halo, alkoxy and alkylthio; and wherein R4 is selected from lower alkyl, hydroxyl, and amino; or a pharmaceutically-acceptable salt thereof. 2. A compound of claim 1 wherein R1 is selected from hydroxyl, amino, lower alkyl, lower carboxyalkyl, lower alkoxycarbonyl, aminocarbonyl, carboxyl, lower aminocarbonylalkyl, lower alkoxycarbonylalkyl, lower alkoxy, lower haloalkoxy, lower aralkoxy, lower cycloalkylalkoxy, lower alkylthio, lower aralkylthio, lower cycloalkylalkylthio, lower alkoxyalkyl, lower aralkoxyalkyl, lower alkylthioalkyl, lower aralkylthioalkyl, lower alkylaminoalkyl, lower aryloxyalkyl, lower arylthioalkyl, lower hydroxyalkyl, lower haloalkyl, lower cycloalkyl, lower cycloalkylalkyl, lower aralkyl, halo, lower alkylamino, lower aralkylamino, lower N-alkyl-N-aralkylamino, lower N-alkyl-N-cycloalkylalkylamino, lower arylcarbonyloxyalkyl, lower alkoxycarbonyloxyalkyl, lower alkylaminocarbonyloxyalkyl, lower alkoxycarbonylthioalkyl, and lower alkylaminocarbonylthioalkyl; wherein R3 is selected from cycloalkyl, cycloalkenyl, and aryl; wherein R3 is optionally substituted at a substitutable position with one or more radicals independently selected from lower alkylsulfinyl, lower alkyl, cyano, carboxyl, lower alkoxycarbonyl, lower haloalkyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, lower arylamino, lower aminoalkyl, nitro, halo, lower alkoxy, lower alkylsulfonyl, aminosulfonyl, and lower alkylthio; and wherein R4 is selected from methyl, hydroxyl and amino; or a pharmaceutically-acceptable salt thereof. 3. A compound of claim 2 wherein R1 is selected from hydroxyl, lower alkyl, carboxyl, lower carboxyalkyl, lower aminocarbonylalkyl, lower alkoxycarbonylalkyl, lower aralkyl, lower alkoxyalkyl, lower aralkoxyalkyl, lower alkylthioalkyl, lower aralkylthioalkyl, lower alkylaminoalkyl, lower aryloxyalkyl, lower arylthioalkyl, lower haloalkyl, lower hydroxylalkyl, cycloalkyl, cycloalkylalkyl, and aralkyl; wherein R3 is selected from cycloalkyl, cycloalkenyl, and aryl; wherein R3 is optionally substituted at a substitutable position with one or more radicals independently selected from lower alkylsulfinyl, lower alkyl, cyano, carboxyl, lower alkoxycarbonyl, lower haloalkyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, lower arylamino, lower aminoalkyl, nitro, halo, lower alkoxy, aminosulfonyl, and lower alkylthio; and wherein R4 is selected from methyl, hydroxyl and amino; or a pharmaceutically-acceptable salt thereof. 4. A compound of claim 3 wherein R1 is selected from hydroxyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, neopentyl, hexyl, carboxyl, carboxypropyl, carboxymethyl, carboxyethyl, benzyl, phenethyl, aminocarbonylmethyl, methoxycarbonylmethyl, methoxycarbonylethyl, methoxymethyl, benzyloxymethyl, phenylethoxymethyl, methylthiomethyl, benzylthiomethyl, N-methylaminomethyl, N,N-dimethylaminomethyl, phenyloxymethyl, phenylthiomethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, fluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, hydroxylmethyl, hydroxylpropyl, hydroxylethyl, cyclohexyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclohexylmethyl, cyclohexylethyl, cyclobutylethyl, cyclopentylmethyl, cycloheptylpropyl, and lower aralkyl selected form benzyl and phenylethyl, wherein the phenyl ring is optionally substituted at a substitutable position with fluoro, chloro, bromo, iodo, methyl, and methoxy; wherein R3 is selected from phenyl, naphthyl, biphenyl, cyclohexyl, cyclopentyl, cycloheptyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 4-cyclohexenyl, and 1-cyclopentenyl; wherein R3 is optionally substituted at a substitutable position with one or more radicals independently selected from trifluoromethoxy, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-dipropylamino, N-butylamino, N-methyl-N-ethylamino, phenylamino, N-methyl-N-phenylamino, methylsulfinyl, ethylsulfinyl, methyl, ethyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, cyano, carboxyl, methoxycarbonyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, fluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, hydroxyl, hydroxymethyl, amino, nitro, fluoro, chloro, bromo, iodo, methoxy, ethoxy, propoxy, n-butoxy, pentoxy, hexyloxy, methylenedioxy, aminosulfonyl, methylthio, ethylthio, butylthio, and hexylthio; and wherein R4 is selected from methyl, hydroxyl and amino; or a pharmaceutically-acceptable salt thereof. 5. The compound of claim 4 which is 4-[5-methyl-3-phenyl-isoxazol-4-yl]benzenesulfonamide, or a pharmaceutically-acceptable salt thereof. 6. A compound of Formula III ##STR33## wherein R1 is selected from hydroxyl, alkyl, carboxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, carboxyl, alkoxy, haloalkoxy, aralkoxy, cycloalkylalkoxy, alkylthio, aralkylthio, cycloalkylalkylthio, alkoxyalkyl, aralkoxyalkyl, alkylthioalkyl, aralkylthioalkyl, alkylaminoalkyl, aryloxyalkyl, arylthioalkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, halo, alkylamino, aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-cycloalkylalkylamino, arylcarbonyloxyalkyl, arylcarbonylthio, alkoxycarbonyloxyalkyl, alkylaminocarbonyloxyalkyl, alkoxycarbonylthioalkyl, and alkylaminocarbonylthioalkyl; andwherein R3 is selected from cycloalkyl, cycloalkenyl, and aryl; wherein R3 is optionally substituted at a substitutable position with one or more radicals independently selected from alkyl, cyano, carboxyl, alkoxycarbonyl, haloalkyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, aminoalkyl, nitro, alkoxyalkyl, alkylsulfinyl, aminosulfonyl, halo, alkoxy and alkylthio; or a pharmaceutically-acceptable salt thereof. 7. A compound of claim 6 wherein R1 is selected from hydroxyl, lower alkyl, carboxyl, lower carboxyalkyl, lower aminocarbonylalkyl, lower alkoxycarbonylalkyl, lower aralkyl, lower alkoxyalkyl, lower aralkoxyalkyl, lower alkylthioalkyl, lower aralkylthioalkyl, lower alkylaminoalkyl, lower aryloxyalkyl, lower arylthioalkyl, lower haloalkyl, lower hydroxylalkyl, lower cycloalkyl, lower cycloalkylalkyl, and aralkyl; wherein R3 is selected from cycloalkyl, cycloalkenyl, and aryl; and wherein R3 is optionally substituted at a substitutable position with one or more radicals independently selected from lower alkylsulfinyl, aminosulfonyl, lower alkyl, cyano, carboxyl, lower alkoxycarbonyl, lower haloalkyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, lower arylamino, lower aminoalkyl, nitro, halo, lower alkoxy and lower alkylthio; or a pharmaceutically-acceptable salt thereof. 8. A compound of claim 7 wherein R1 is selected from hydroxyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, neopentyl, hexyl, carboxyl, carboxypropyl, carboxymethyl, carboxyethyl, benzyl, phenethyl, aminocarbonylmethyl, methoxycarbonylmethyl, methoxycarbonylethyl, methoxymethyl, benzyloxymethyl, phenylethoxymethyl, methylthiomethyl, benzylthiomethyl, N-methylaminomethyl, N,N-dimethylaminomethyl, phenyloxymethyl, phenylthiomethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, fluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, hydroxylmethyl, hydroxylpropyl, hydroxylethyl, cyclohexyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclohexylmethyl, cyclohexylethyl, cyclobutylethyl, cyclopentylmethyl, cycloheptylpropyl, and lower aralkyl selected from phenylethyl and benzyl optionally substituted at a substitutable position with fluoro, chloro, bromo, iodo, methyl, and methoxy; and wherein R3 is selected from phenyl, naphthyl, biphenyl, cyclohexyl, cyclopentyl, cycloheptyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 4-cyclohexenyl, and 1-cyclopentenyl; wherein R3 is optionally substituted at a substitutable position with one or more radicals independently selected from trifluoromethoxy, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-dipropylamino, N-butylamino, N-methyl-N-ethylamino, phenylamino, N-methyl-N-phenylamino, methylsulfinyl, ethylsulfinyl, methyl, ethyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, cyano, carboxyl, methoxycarbonyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, fluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, hydroxyl, hydroxymethyl, amino, aminomethyl, nitro, fluoro, chloro, bromo, iodo, methoxy, ethoxy, propoxy, n-butoxy, pentoxy, hexyloxy, methylenedioxy, methylthio, aminosulfonyl, ethylthio, butylthio, and hexylthio; or a pharmaceutically-acceptable salt thereof. 9. A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compound selected from a family of compounds of Formula II ##STR34## wherein R1 is selected from alkyl, carboxyalkyl, alkoxycarbonyl, aminocarbonyl, aminocarbonylalkyl, alkoxycarbonylalkyl, carboxyl, alkoxy, haloalkoxy, aralkoxy, cycloalkylalkoxy, alkylthio, aralkylthio, cycloalkylalkylthio, alkoxyalkyl, aralkoxyalkyl, alkylthioalkyl, aralkylthioalkyl, alkylaminoalkyl, aryloxyalkyl, arylthioalkyl, hydroxyl, amino, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, halo, alkylamino, aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-cycloalkylalkylamino, arylcarbonyloxyalkyl, arylcarbonylthio, alkoxycarbonyloxyalkyl, alkylaminocarbonyloxyalkyl, alkoxycarbonylthioalkyl, and alkylaminocarbonylthioalkyl;wherein R3 is selected from cycloalkyl, cycloalkenyl, and aryl; wherein R3 is optionally substituted at a substitutable position with one or more radicals independently selected from alkyl, cyano, carboxyl, alkoxycarbonyl, haloalkyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, aminoalkyl, nitro, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, halo, alkoxy and alkylthio; and wherein R4 is selected from lower alkyl, hydroxyl, and amino; or a pharmaceutically-acceptable salt thereof. 10. A pharmaceutical composition of claim 9 wherein R1 is selected from hydroxyl, amino, lower alkyl, lower carboxyalkyl, lower alkoxycarbonyl, aminocarbonyl, carboxyl, lower aminocarbonylalkyl, lower alkoxycarbonylalkyl, lower alkoxy, lower haloalkoxy, lower aralkoxy, lower cycloalkylalkoxy, lower alkylthio, lower aralkylthio, lower cycloalkylalkylthio, lower alkoxyalkyl, lower aralkoxyalkyl, lower alkylthioalkyl, lower aralkylthioalkyl, lower alkylaminoalkyl, lower aryloxyalkyl, lower arylthioalkyl, lower hydroxyalkyl, lower haloalkyl, lower cycloalkyl, lower cycloalkylalkyl, lower aralkyl, halo, lower alkylamino, lower aralkylamino, lower N-alkyl-N-aralkylamino, lower N-alkyl-N-cycloalkylalkylamino, lower arylcarbonyloxyalkyl, lower alkoxycarbonyloxyalkyl, lower alkylaminocarbonyloxyalkyl, lower alkoxycarbonylthioalkyl, and lower alkylaminocarbonylthioalkyl; wherein R3 is selected from cycloalkyl, cycloalkenyl, and aryl; wherein R3 is optionally substituted at a substitutable position with one or more radicals independently selected from lower alkylsulfinyl, lower alkyl, cyano, carboxyl, lower alkoxycarbonyl, lower haloalkyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, lower arylamino, lower aminoalkyl, nitro, halo, lower alkoxy, lower alkylsulfonyl, aminosulfonyl, and lower alkylthio; and wherein R4 is selected from methyl, hydroxyl and amino; or a pharmaceutically-acceptable salt thereof. 11. A pharmaceutical composition of claim 10 wherein R1 is selected from hydroxyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, neopentyl, hexyl, carboxyl, carboxypropyl, carboxymethyl, carboxyethyl, benzyl, phenethyl, aminocarbonylmethyl, methoxycarbonylmethyl, methoxycarbonylethyl, methoxymethyl, benzyloxymethyl, phenylethoxymethyl, methylthiomethyl, benzylthiomethyl, N-methylaminomethyl, N,N-dimethylaminomethyl, phenyloxymethyl, phenylthiomethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, fluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, hydroxylmethyl, hydroxylpropyl, hydroxylethyl, cyclohexyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclohexylmethyl, cyclohexylethyl, cyclobutylethyl, cyclopentylmethyl, cycloheptylpropyl, and lower aralkyl selected form benzyl and phenylethyl, wherein the phenyl ring is optionally substituted at a substitutable position with fluoro, chloro, bromo, iodo, methyl, and methoxy; wherein R3 is selected from phenyl, naphthyl, biphenyl, cyclohexyl, cyclopentyl, cycloheptyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 4-cyclohexenyl, and 1-cyclopentenyl; wherein R3 is optionally substituted at a substitutable position with one or more radicals independently selected from trifluoromethoxy, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-dipropylamino, N-butylamino, N-methyl-N-ethylamino, phenylamino, N-methyl-N-phenylamino, methylsulfinyl, ethylsulfinyl, methyl, ethyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, cyano, carboxyl, methoxycarbonyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, fluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, hydroxyl, hydroxymethyl, amino, nitro, fluoro, chloro, bromo, iodo, methoxy, ethoxy, propoxy, n-butoxy, pentoxy, hexyloxy, methylenedioxy, aminosulfonyl, methylthio, ethylthio, butylthio, and hexylthio; and wherein R4 is selected from methyl, hydroxyl and amino; or a pharmaceutically-acceptable salt thereof. 12. A pharmaceutical composition of claim 11 wherein said compound is 4-[5-methyl-3-phenyl-isoxazol-4-yl]benzenesulfonamide, or a pharmaceutically-acceptable salt thereof. 13. A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compound selected from a family of compounds of Formula III ##STR35## wherein R1 is selected from hydroxyl, alkyl, carboxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, carboxyl, alkoxy, haloalkoxy, aralkoxy, cycloalkylalkoxy, alkylthio, aralkylthio, cycloalkylalkylthio, alkoxyalkyl, aralkoxyalkyl, alkylthioalkyl, aralkylthioalkyl, alkylaminoalkyl, aryloxyalkyl, arylthioalkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, halo, alkylamino, aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-cycloalkylalkylamino, arylcarbonyloxyalkyl, arylcarbonylthio, alkoxycarbonyloxyalkyl, alkylaminocarbonyloxyalkyl, alkoxycarbonylthioalkyl, and alkylaminocarbonylthioalkyl; andwherein R3 is selected from cycloalkyl, cycloalkenyl, and aryl; wherein R3 is optionally substituted at a substitutable position with one or more radicals independently selected from alkyl, cyano, carboxyl, alkoxycarbonyl, haloalkyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, aminoalkyl, nitro, alkoxyalkyl, alkylsulfinyl, aminosulfonyl, halo, alkoxy and alkylthio; or a pharmaceutically-acceptable salt thereof. 14. A method of treating inflammation or an inflammation-associated disorder in a subject, said method comprising administering to the subject having or susceptible to said inflammation or inflammation-associated disorder, a therapeutically-effective amount of a compound of Formula II ##STR36## wherein R1 is selected from alkyl, carboxyalkyl, alkoxycarbonyl, aminocarbonyl, aminocarbonylalkyl, alkoxycarbonylalkyl, carboxyl, alkoxy, haloalkoxy, aralkoxy, cycloalkylalkoxy, alkylthio, aralkylthio, cycloalkylalkylthio, alkoxyalkyl, aralkoxyalkyl, alkylthioalkyl, aralkylthioalkyl, alkylaminoalkyl, aryloxyalkyl, arylthioalkyl, hydroxyl, amino, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, halo, alkylamino, aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-cycloalkylalkylamino, arylcarbonyloxyalkyl, arylcarbonylthio, alkoxycarbonyloxyalkyl, alkylaminocarbonyloxyalkyl, alkoxycarbonylthioalkyl, and alkylaminocarbonylthioalkyl;wherein R3 is selected from cycloalkyl, cycloalkenyl, and aryl; wherein R3 is optionally substituted at a substitutable position with one or more radicals independently selected from alkyl, cyano, carboxyl, alkoxycarbonyl, haloalkyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, aminoalkyl, nitro, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, halo, alkoxy and alkylthio; and wherein R4 is selected from lower alkyl, hydroxyl, and amino; or a pharmaceutically-acceptable salt thereof. 15. A method of claim 14 wherein R1 is selected from hydroxyl, amino, lower alkyl, lower carboxyalkyl, lower alkoxycarbonyl, aminocarbonyl, carboxyl, lower aminocarbonylalkyl, lower alkoxycarbonylalkyl, lower alkoxy, lower haloalkoxy, lower aralkoxy, lower cycloalkylalkoxy, lower alkylthio, lower aralkylthio, lower cycloalkylalkylthio, lower alkoxyalkyl, lower aralkoxyalkyl, lower alkylthioalkyl, lower aralkylthioalkyl, lower alkylaminoalkyl, lower aryloxyalkyl, lower arylthioalkyl, lower hydroxyalkyl, lower haloalkyl, lower cycloalkyl, lower cycloalkylalkyl, lower aralkyl, halo, lower alkylamino, lower aralkylamino, lower N-alkyl-N-aralkylamino, lower N-alkyl-N-cycloalkylalkylamino, lower arylcarbonyloxyalkyl, lower alkoxycarbonyloxyalkyl, lower alkylaminocarbonyloxyalkyl, lower alkoxycarbonylthioalkyl, and lower alkylaminocarbonylthioalkyl; wherein R3 is selected from cycloalkyl, cycloalkenyl, and aryl; wherein R3 is optionally substituted at a substitutable position with one or more radicals independently selected from lower alkylsulfinyl, lower alkyl, cyano, carboxyl, lower alkoxycarbonyl, lower haloalkyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, lower arylamino, lower aminoalkyl, nitro, halo, lower alkoxy, lower alkylsulfonyl, aminosulfonyl, and lower alkylthio; and wherein R4 is selected from methyl, hydroxyl and amino; or a pharmaceutically-acceptable salt thereof. 16. A method of claim 15 wherein R1 is selected from hydroxyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, neopentyl, hexyl, carboxyl, carboxypropyl, carboxymethyl, carboxyethyl, benzyl, phenethyl, aminocarbonylmethyl, methoxycarbonylmethyl, methoxycarbonylethyl, methoxymethyl, benzyloxymethyl, phenylethoxymethyl, methylthiomethyl, benzylthiomethyl, N-methylaminomethyl, N,N-dimethylaminomethyl, phenyloxymethyl, phenylthiomethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, fluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, hydroxylmethyl, hydroxylpropyl, hydroxylethyl, cyclohexyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclohexylmethyl, cyclohexylethyl, cyclobutylethyl, cyclopentylmethyl, cycloheptylpropyl, and lower aralkyl selected form benzyl and phenylethyl, wherein the phenyl ring is optionally substituted at a substitutable position with fluoro, chloro, bromo, iodo, methyl, and methoxy; wherein R3 is selected from phenyl, naphthyl, biphenyl, cyclohexyl, cyclopentyl, cycloheptyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 4-cyclohexenyl, and 1-cyclopentenyl; wherein R3 is optionally substituted at a substitutable position with one or more radicals independently selected from trifluoromethoxy, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-dipropylamino, N-butylamino, N-methyl-N-ethylamino, phenylamino, N-methyl-N-phenylamino, methylsulfinyl, ethylsulfinyl, methyl, ethyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, cyano, carboxyl, methoxycarbonyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, fluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, hydroxyl, hydroxymethyl, amino, nitro, fluoro, chloro, bromo, iodo, methoxy, ethoxy, propoxy, n-butoxy, pentoxy, hexyloxy, methylenedioxy, aminosulfonyl, methylthio, ethylthio, butylthio, and hexylthio; and wherein R4 is selected from methyl, hydroxyl and amino; or a pharmaceutically-acceptable salt thereof. 17. A method of claim 16 wherein said compound is 4-[5-methyl-3-phenyl-isoxazol-4-yl]benzenesulfonamide, or a pharmaceutically-acceptable salt thereof. 18. A method of treating inflammation or an inflammation-associated disorder in a subject, said method comprising administering to the subject having or susceptible to said inflammation or inflammation-associated disorder, a therapeutically-effective amount of a compound of Formula III ##STR37## wherein R1 is selected from hydroxyl, alkyl, carboxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, carboxyl, alkoxy, haloalkoxy, aralkoxy, cycloalkylalkoxy, alkylthio, aralkylthio, cycloalkylalkylthio, alkoxyalkyl, aralkoxyalkyl, alkylthioalkyl, aralkylthioalkyl, alkylaminoalkyl, aryloxyalkyl, arylthioalkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, halo, alkylamino, aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-cycloalkylalkylamino, arylcarbonyloxyalkyl, arylcarbonylthio, alkoxycarbonyloxyalkyl, alkylaminocarbonyloxyalkyl, alkoxycarbonylthioalkyl, and alkylaminocarbonylthioalkyl; andwherein R3 is selected from cycloalkyl, cycloalkenyl, and aryl; wherein R3 is optionally substituted at a substitutable position with one or more radicals independently selected from alkyl, cyano, carboxyl, alkoxycarbonyl, haloalkyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, aminoalkyl, nitro, alkoxyalkyl, alkylsulfinyl, aminosulfonyl, halo, alkoxy and alkylthio; or a pharmaceutically-acceptable salt thereof. 19. A method of claim 14 for use in treatment of inflammation. 20. A method of claim 14 for use in treatment of an inflammation-associated disorder. 21. A method of claim 20 wherein the inflammation-associated disorder is arthritis. 22. A method of claim 20 wherein the inflammation-associated disorder is pain. 23. A method of claim 20 wherein the inflammation-associated disorder is fever. 24. The compound of claim 4 selected from compounds, or their pharmaceutically acceptable salts, of the group consisting of4-[5-ethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-propyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-isopropyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-butyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-isobutyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-cyclohexyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-neopentyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-cyclohexylmethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-(4-chlorophenyl)methyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-trifluoromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-difluoromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-chloromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonic acid; 4-[5-propyl-3-phenylisoxazol-4-yl]benzenesulfonic acid; 4-[5-methoxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-3-hydroxypropyl)-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[3-4-chlorophenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 4-[3-4-fluorophenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 4-[3-3-fluoro-4-methylphenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 4-[3-3-aminosulfonyl-4-methoxyphenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 4-[3-3-chloro-4-methylphenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 4-[3-3-fluorophenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; [4-[4-(aminosulfonyl)phenyl]-3-phenylisoxazol-5-yl]carboxylic acid; 4-[5-hydroxy-3-phenyl-4-isoxazolyl]benzenesulfonamide; 4-[3-methyl-5-phenyl-isoxazol-4-yl]benzenesulfonamide; 4-[5-methyl-3-phenyl-isoxazol-4-yl]benzenesulfonamide; 4-[3-(3-fluoro-4-methoxyphenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; [3-(3-chloro-4-methoxyphenyl)-4-[4-(methylsulfonyl)phenyl]isoxazol-5-yl]acetic acid; 5-methyl-4-[4-(methylsulfonyl)phenyl]-3-phenyl-isoxazole; 3-(3-chloro-4-methoxyphenyl)-5-methyl-4-[4-(methylsulfonyl)phenyl]isoxazole [4-[4-(aminosulfonyl)phenyl]-3-phenyl-isoxazol-5-yl]acetic acid; [4-[4-(aminosulfonyl)phenyl]-3-phenyl-isoxazol-5-yl]propanoic acid; ethyl [4-[4-(aminosulfonyl)phenyl]-3-phenyl-isoxazol-5-yl]propanoate; [3-(3-fluoro-4-methoxyphenyl)-4-[4-(methylsulfonyl)phenyl]isoxazol-5-yl]acetic acid; and [4-[4-(aminosulfonyl)phenyl]-3-(3-fluoro-4-methoxyphenyl)isoxazol-5-yl]propanoic acid. 25. The compound of claim 4 which is 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide, or a pharmaceutically-acceptable salt thereof. 26. A pharmaceutical composition of claim 11 wherein said compound is selected from compounds, or their pharmaceutically-acceptable salts, of the group consisting of4-[5-ethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-propyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-isopropyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-butyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-isobutyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-cyclohexyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-neopentyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-cyclohexylmethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-(4-chlorophenyl)methyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-trifluoromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-difluoromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-chloromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonic acid; 4-[5-propyl-3-phenylisoxazol-4-yl]benzenesulfonic acid; 4-[5-methoxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-3-hydroxypropyl)-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[3-4-chlorophenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 4-[3-4-fluorophenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 4-[3-3-fluoro-4-methylphenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 4-[3-3-aminosulfonyl-4-methoxyphenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 4-[3-3-chloro-4-methylphenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 4-[3-3-fluorophenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; [4-[4-(aminosulfonyl)phenyl]-3-phenylisoxazol-5-yl]carboxylic acid; 4-[5-hydroxy-3-phenyl-4-isoxazolyl]benzenesulfonamide; 4-[3-methyl-5-phenyl-isoxazol-4-yl]benzenesulfonamide; 4-[5-methyl-3-phenyl-isoxazol-4-yl]benzenesulfonamide; 4-[3-(3-fluoro-4-methoxyphenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; [3-(3-chloro-4-methoxyphenyl)-4-[4-(methylsulfonyl)phenyl]isoxazol-5-yl]acetic acid; 5-methyl-4-[4-(methylsulfonyl)phenyl]-3-phenyl-isoxazole; 3-(3-chloro-4-methoxyphenyl)-5-methyl-4-[4-(methylsulfonyl)phenyl]isoxazole; [4-[4-(aminosulfonyl)phenyl]-3-phenyl-isoxazol-5-yl]acetic acid; [4-[4-(aminosulfonyl)phenyl]-3-phenyl-isoxazol-5-yl]propanoic acid; ethyl [4-[4-(aminosulfonyl)phenyl]-3-phenyl-isoxazol-5-yl]propanoate; [3-(3-fluoro-4-methoxyphenyl)-4-[4-(methylsulfonyl)phenyl]isoxazol-5-yl]acetic acid; and [4-[4-(aminosulfonyl)phenyl]-3-(3-fluoro-4-methoxyphenyl)isoxazol-5-yl]propanoic acid. 27. A pharmaceutical composition of claim 11 wherein said compound is 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide, or a pharmaceutically-acceptable salt thereof. 28. A method of claim 16 wherein said compound is selected from compounds, or their pharmaceutically-acceptable salts, of the group consisting of4-[5-ethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-propyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5isopropyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-butyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-isobutyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-cyclohexyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-neopentyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-cyclohexylmethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-(4-chlorophenyl)methyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-trifluoromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-difluoromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-chloromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonic acid; 4-[5-propyl-3-phenylisoxazol-4-yl]benzenesulfonic acid; 4-[5-methoxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-(3-hydroxypropyl)-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[3-(4-chlorophenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 4-[3-(4-fluorophenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 4-[3-(3-fluoro-4-methylphenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 4-[3-(3-aminosulfonyl-4-methoxyphenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 4-[3-(3-chloro-4-methylphenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 4-[3-(3-fluorophenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; [4-[4-(aminosulfonyl)phenyl]-3-phenylisoxazol-5-yl]carboxylic acid; 4-[5-hydroxy-3-phenyl-4-isoxazolyl]benzenesulfonamide; 4-[3-methyl-5-phenyl-isoxazol-4-yl]benzenesulfonamide; 4-[5-methyl-3-phenyl-isoxazol-4-yl]benzenesulfonamide; 4-[3-(3-fluoro-4-methoxyphenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; [3-(3-chloro-4-methoxyphenyl)-4-[4-(methylsulfonyl)phenyl]isoxazol-5-yl]acetic acid; 5-methyl-4-[4-(methylsulfonyl)phenyl]-3-phenyl-isoxazole; 3-(3-chloro-4-methoxyphenyl)-5-methyl-4-[4-(methylsulfonyl)phenyl]isoxazole; [4-[4-(aminosulfonyl)phenyl]-3-phenyl-isoxazol-5-yl]acetic acid; [4-[4-(aminosulfonyl)phenyl]-3-phenyl-isoxazol-5-yl]propanoic acid; ethyl [4-[4-(aminosulfonyl)phenyl]-3-phenyl-isoxazol-5-yl]propanoate; [3-(3-fluoro-4-methoxyphenyl)-4-[4-(methylsulfonyl)phenyl]isoxazol-5-yl]acetic acid; and [4-[4-(aminosulfonyl)phenyl]-3-(3-fluoro-4-methoxyphenyl)isoxazol-5-yl]propanoic acid. 29. A method of claim 16 wherein said compound is 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide, or a pharmaceutically-acceptable salt thereof.