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Claims for Patent: 5,633,272

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Claims 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 ##STR1## wherein R.sup.1 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 R.sup.3 is selected from cycloalkyl, cycloalkenyl, aryl, and heteroaryl; wherein R.sup.3 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 R.sup.4 is selected from lower alkyl, hydroxyl and amino; or a pharmaceutically-acceptable salt thereof.
Inventor(s): Talley; John J. (Brentwood, MO), Brown; David L. (Chesterfield, MO), Nagarajan; Srinivasan (Chesterfield, MO), Carter; Jeffery S. (Chesterfield, MO), Weier; Richard M. (Lake Bluff, IL), Stealey; Michael A. (Libertyville, IL), Collins; Paul W. (Deerfield, IL), Rogers, deceased; Roland S. (late of Richmond Heights, MO), Seibert; Karen (St. Louis, MO)
Assignee:
Application Number:08/473,884
Patent Claims: 1. A compound of Formula II ##STR32## wherein R.sup.1 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 R.sup.3 is selected from cycloalkyl, cycloalkenyl, and aryl; wherein R.sup.3 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 R.sup.4 is selected from lower alkyl, hydroxyl, and amino;

or a pharmaceutically-acceptable salt thereof.

2. A compound of claim 1 wherein R.sup.1 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 R.sup.3 is selected from cycloalkyl, cycloalkenyl, and aryl; wherein R.sup.3 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 R.sup.4 is selected from methyl, hydroxyl and amino; or a pharmaceutically-acceptable salt thereof.

3. A compound of claim 2 wherein R.sup.1 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 R.sup.3 is selected from cycloalkyl, cycloalkenyl, and aryl; wherein R.sup.3 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 R.sup.4 is selected from methyl, hydroxyl and amino; or a pharmaceutically-acceptable salt thereof.

4. A compound of claim 3 wherein R.sup.1 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 R.sup.3 is selected from phenyl, naphthyl, biphenyl, cyclohexyl, cyclopentyl, cycloheptyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 4-cyclohexenyl, and 1-cyclopentenyl; wherein R.sup.3 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 R.sup.4 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 R.sup.1 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; and

wherein R.sup.3 is selected from cycloalkyl, cycloalkenyl, and aryl; wherein R.sup.3 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 R.sup.1 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 R.sup.3 is selected from cycloalkyl, cycloalkenyl, and aryl; and wherein R.sup.3 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 R.sup.1 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 R.sup.3 is selected from phenyl, naphthyl, biphenyl, cyclohexyl, cyclopentyl, cycloheptyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 4-cyclohexenyl, and 1-cyclopentenyl; wherein R.sup.3 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 R.sup.1 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 R.sup.3 is selected from cycloalkyl, cycloalkenyl, and aryl; wherein R.sup.3 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 R.sup.4 is selected from lower alkyl, hydroxyl, and amino;

or a pharmaceutically-acceptable salt thereof.

10. A pharmaceutical composition of claim 9 wherein R.sup.1 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 R.sup.3 is selected from cycloalkyl, cycloalkenyl, and aryl; wherein R.sup.3 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 R.sup.4 is selected from methyl, hydroxyl and amino; or a pharmaceutically-acceptable salt thereof.

11. A pharmaceutical composition of claim 10 wherein R.sup.1 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 R.sup.3 is selected from phenyl, naphthyl, biphenyl, cyclohexyl, cyclopentyl, cycloheptyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 4-cyclohexenyl, and 1-cyclopentenyl; wherein R.sup.3 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 R.sup.4 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 R.sup.1 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; and

wherein R.sup.3 is selected from cycloalkyl, cycloalkenyl, and aryl; wherein R.sup.3 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 R.sup.1 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 R.sup.3 is selected from cycloalkyl, cycloalkenyl, and aryl; wherein R.sup.3 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 R.sup.4 is selected from lower alkyl, hydroxyl, and amino;

or a pharmaceutically-acceptable salt thereof.

15. A method of claim 14 wherein R.sup.1 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 R.sup.3 is selected from cycloalkyl, cycloalkenyl, and aryl; wherein R.sup.3 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 R.sup.4 is selected from methyl, hydroxyl and amino; or a pharmaceutically-acceptable salt thereof.

16. A method of claim 15 wherein R.sup.1 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 R.sup.3 is selected from phenyl, naphthyl, biphenyl, cyclohexyl, cyclopentyl, cycloheptyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 4-cyclohexenyl, and 1-cyclopentenyl; wherein R.sup.3 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 R.sup.4 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 R.sup.1 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; and

wherein R.sup.3 is selected from cycloalkyl, cycloalkenyl, and aryl; wherein R.sup.3 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 of

4-[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]benzenesulfona mide;

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]ace tic 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]ace tic acid; and

[4-[4-(aminosulfonyl)phenyl]-3-(3-fluoro-4-methoxyphenyl)isoxazol-5-yl]prop anoic 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 of

4-[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]benzenesulfona mide;

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]ace tic 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]ace tic acid; and

[4-[4-(aminosulfonyl)phenyl]-3-(3-fluoro-4-methoxyphenyl)isoxazol-5-yl]prop anoic 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 of

4-[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]benzenesulfon amide;

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]ace tic 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]ace tic acid; and

[4-[4-(aminosulfonyl)phenyl]-3-(3-fluoro-4-methoxyphenyl)isoxazol-5-yl]prop anoic 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.
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