Pyrazole substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors

Abstract

This invention is in the field of antiinflammatory pharmaceutical agents and specifically relates to compounds, compositions and methods for treating disorders mediated by cyclooxygenase-2 or 5-lipoxygenase, such as inflammation.

What is claimed is:  
     
         1 . A compound of Formula II  
       
         
           
           
               
               
           
         
       
       wherein A is a ring substituent selected from thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, cyclopentenyl, phenyl, and pyridyl; wherein A is optionally substituted with a radical selected from acyl, halo, hydroxyl, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl; wherein Y is selected from lower alkyl, lower alkenyl and lower alkynyl; wherein R 1  is selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R 1  is optionally substituted at a substituable position 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; wherein R 2  is selected from lower alkyl and amino; and wherein R 5  is selected from hydrido, lower alkyl, phenyl, 5- and 6-membered heterocyclo and lower cycloalkyl; provided R 2  is amino when A is pyrazolyl; or a pharmaceutically-acceptable salt thereof.  
     
     
         2 . Compound of  claim 1  wherein A is selected from thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isoxazolyl, pyrazolyl, cyclopenzenyl, phenyl, and pyridyl, wherein A is optionally substituted with a radical selected from formyl, fluoro, chloro, bromo, methyl, trifluoromethyl, oxo, cyano, carboxyl, methoxy, aminocarbonyl, methoxycarbonyl, ethoxycarbonyl, acetyl, carboxypropyl, and hydroxymethyl; wherein Y is a radical selected from methyl, ethyl, isooropyl, propyl, butyl, propenyl, butenyl, propynyl and butynyl; wherein R 1  is selected from thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isoxazolyl, pyrazolyl, pyridyl, and phenyl, where R 1  is optionally substituced at a substitutable position with one or more radicals selected from methyl, trifluoromethyl, hydroxyl, hydroxymethyl, trifluoromethoxy, methoxymethyl, fluoro, chloro, bromo, methoxy and methylthio; wherein R 2  is methyl or amino; and wherein R 5  is selected from hydrido, methyl, and phenyl; or a pharmaceutically-acceptable salt thereof.  
     
     
         3 . A compound according to  claim 1  selected from 
 [1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-yl]-N-hydroxy-N-methyl-ethanamide;  
 4-[[4-aminosulfonyl)phenyl]-5-(3,4-dichlorophenyl)-N-hydroxy-2-oxazolebutanamide; and  
 4-(4-fluorophenyl)-N-hydroxy-N-methyl-5-[(4-methylsulfonyl)phenyl]-2-oxazolpropanamide.  
 
     
     
         4 . A compound of Formula III  
       
         
           
           
               
               
           
         
       
       wherein A is a ring substituent selected from thienyl, oxazolyl furyl, pyrrolyl, thiazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, cyclopentenyl, phenyl, and pyridyl; wherein A is optionally substituted with a radical selected from acyl, halo, hydroxyl, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl; wherein Y is selected from lower alkyl, lower alkenyl and lower alkynyl; wherein R 1  is selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R 1  is optionally substituted at a substitutable position 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; wherein R 2  is selected from lower alkyl and amino; and wherein R 5  is selected from hydrido and alkyl; or a pharmaceutically-acceptable salt thereof.  
     
     
         5 . Compound of  claim 4  wherein A is selected from thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isoxazolyl, pyrazolyl, cyclopentenyl, phenyl, and pyridyl, wherein A is optionally substituted with a radical selected from formyl, fluoro, chloro, bromo, methyl, trifluoromethyl, oxo, cyaro, carboxyl, methoxy, aminocarbonyl, methoxycarbonyl, ethoxycarbonyl, acetyl, carboxypropyl, and hydroxymethyl; wherein Y is selected from methyl, ethyl, isopropyl, propyl, butyl, propenyl, butenyl, propynyl and butynyl; wherein R 1  is selected from thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isoxazolyl, pyrazolyl, pyridyl, and phenyl, where R 1  is optionally substituted at a substitutable position with one or more radicals selected from methyl, trifuoromethyl, hydroxyl, hydroxymethyl, trifluoromethoxy, methoxymethyl, fluoro, chloro, bromo, methoxy and methylthio; wherein R 2  is methyl or amino; and wherein R 5  is selected from hydrido, and methyl; or a pharmaceutically-acceptable salt thereof.  
     
     
         6 . A compound according to  claim 4  which is N′-[[1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-yl]methyl]-N′-hydroxyurea.  
     
     
         7 . A pharmaceutical composition comprising a therapeutically-effective amount of a compound of claim  1 - 6 , or a pharmaceutically-acceptable salt thereof.  
     
     
         8 . Use of a compound of claim  1 - 6 , or a pharmaceutically-acceptable salt thereof for preparing a medica-ment for treating a condition benefited by the in-hibition of 5-lipoxygenase, cyclooxygenase-2 or both 5-lipoxygenase and cyclooxygenase-2.  
     
     
         9 . Use according to  claim 8  wherein the condition is inflammation or an inflammation-associated disorder.  
     
     
         10 . Use according to  claim 9  wherein the condition is inflammation.  
     
     
         11 . The method of  claim 9  wherein the condition is an inflammation-associated disorder.  
     
     
         12 . The method of  claim 11  wherein the inflammation-associated disorder is arthritis.  
     
     
         13 . The method of  claim 11  wherein the inflammation-associated disorder is pain.  
     
     
         14 . The method of  claim 11  wherein the inflammation-associated disorder is fever.