Inhibitors of P38 and Methods of Using the Same

Abstract

In general, the present invention relates to compounds capable of inhibiting p38 in vivo or in vitro, and methods for treating conditions associated with p38 activity or cytokine activity.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein 
         X is O or S(O) m ; 
         Y is OR 4 , or NR 4 R 5 ; 
         m is 0, 1, or 2; 
         n is 1 or 2; 
         R 1  is independently selected from the group consisting of hydrogen, —CN, —COOH, halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy; C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkyloxy, aryl, aminocarbonyl, C 1 -C 6  alkylcarbonyl, and C 1 -C 6  alkoxycarbonyl; 
         Ar is an aryl group; 
         R 3  is independently selected from the group consisting of hydrogen, halogen, amino, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkyloxy, aryl, aminocarbonyl, C 1 -C 6  alkylcarbonyl, and C 1 -C 6  alkoxycarbonyl; 
         R 4  and R 5  are each independently selected from the group consisting of hydrogen, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, aryl, and heterocyclyl; or R 4  and R 5 , taken together with the N atom to which they are attached, form a heterocyclic ring having from 3 to 8 atoms in the ring; 
         or a prodrug, solvate, or salt of the compound of Formula I; 
         with the proviso that when X is S(O) m , m is 0, Ar is phenyl, Y is NR 4 R 5 , R 4  is hydrogen and R 5  is alkyl, then if R 5  is a hydroxyalkyl group, R 5  1) is not —CH 2 (CH 3 ) 2 CH 2 OH, and 2) is not substituted at the carbon atom alpha to the N atom with a phenyl group (that is, the carbon atom of R 5  that is attached to the N atom does not bear a phenyl group). 
       
     
     
         2 . The compound according to  claim 1 , wherein X is O or S. 
     
     
         3 . The compound according to  claim 2 , wherein X is O. 
     
     
         4 . The compound according to  claim 1 , wherein Ar is a phenyl or napthyl group. 
     
     
         5 . The compound according to  claim 1 , wherein Ar is a phenyl group. 
     
     
         6 . The compound according to  claim 5 , wherein said phenyl group is 4-fluorophenyl. 
     
     
         7 . The compound according to  claim 1 , wherein said compound is selected from the group consisting of compounds LXXXVII, LXXXIV, LXXI, CXIX, CCLXXXI, CCLXXVIII, CCLXXIX, and CCLXXX. 
     
     
         8 . The compound according to  claim 1 , wherein said compound is a pharmaceutically acceptable salt. 
     
     
         9 . A compound of Formula II: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of hydrogen, —CN, —COOH, halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy; C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkyloxy, aryl, aminocarbonyl, C 1 -C 6  alkylcarbonyl, and C 1 -C 6  alkoxycarbonyl; 
         and Ar is an aryl group; 
         or a salt thereof. 
       
     
     
         10 . A compound of Formula III: 
       
         
           
           
               
               
           
         
         wherein X is O or S(O) m ; 
         m and n are each independently 0, 1, or 2; 
         p is 1 or 2; 
         R 1  is independently selected from the group consisting of hydrogen, —CN, —COOH, halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy; C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkyloxy, aryl, aminocarbonyl, C 1 -C 6  alkylcarbonyl, and C 1 -C 6  alkoxycarbonyl; Ar is an aryl group; 
         R 3  is independently selected from the group consisting of hydrogen, halogen, amino, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkyloxy, aryl, aminocarbonyl, C 1 -C 6  alkylcarbonyl, and C 1 -C 6  alkoxycarbonyl; 
         and L is a C 1 -C 6  alkyl group or an aryl group; 
         or a salt thereof. 
       
     
     
         11 . A pharmaceutical composition comprising one or more compounds represented by Formula I and a pharmaceutically acceptable carrier. 
     
     
         12 . A method for treating a p38-associated condition comprising identifying a subject in need of treatment and administering to the subject an amount of a compound of Formula I effective to treat said p38-associated condition. 
     
     
         13 . The method according to  claim 12 , wherein the compound of Formula I is combined with another pharmaceutically-active agent. 
     
     
         14 . The method according to  claim 12 , wherein said subject is a mammal selected from the group consisting of cattle, pigs, sheep, goats, horses, camels, buffalo, cats, dogs, rats, mice, and humans. 
     
     
         15 . The method according to  claim 12 , wherein said subject is a human. 
     
     
         16 . The method according to  claim 12 , wherein said p38-associated condition is associated with a specific isoform of p38. 
     
     
         17 . The method according to  claim 16 , wherein said specific isoform of p38 is selected from the group consisting of p38α, p38β, p38δ, and p38γ. 
     
     
         18 . The method according to  claim 17 , wherein said specific isoform of p38 is p38α. 
     
     
         19 . A method for treating a condition associated with altered activity of one or more cytokines comprising identifying a subject in need of treatment and administering to the subject an amount of a compound of Formula I effective to treat the altered activity of the one or more cytokines. 
     
     
         20 . The method according to  claim 19 , wherein the compound of Formula I is combined with another pharmaceutically-active agent. 
     
     
         21 . The method according to  claim 19 , wherein said subject is a mammal selected from the group consisting of cattle, pigs, sheep, goats, horses, camels, buffalo, cats, dogs, rats, mice, and humans. 
     
     
         22 . The method according to  claim 19 , wherein said subject is a human. 
     
     
         23 . The method according to  claim 19 , wherein at least one of the one or more cytokines is selected from the group consisting of IL-1, IL-6, IL-8, and TNFα. 
     
     
         24 . A method for inhibiting the activity of p38 in a cell in vivo or in vitro comprising contacting the cell with an effective amount of a compound of Formula I effective to inhibit p38 activity in the cell. 
     
     
         25 . A method for determining the presence, location, or quantity or any combination thereof of p38 protein in a cell or tissue comprising a) contacting the cell or tissue with a compound of Formula I under conditions such that the compound of Formula I can bind to p38 protein; and b) determining the presence, location or quantity or any combination thereof of the compound of Formula I in the cell or tissue, thereby determining the presence, location or quantity or any combination thereof of p38 protein in the cell or tissue. 
     
     
         26 . A method for preparing a compound of Formula I or a salt thereof comprising reacting a compound of Formula III in which n is 2 with a nucleophile of the formula HOR 4  or HNR 4 R 5 , in which R 4  and R 5  have the meanings described in Formula I, or a conjugate base thereof, under conditions such that the group —S(O) n  is displaced and a compound of Formula I, or a salt thereof, is formed. 
     
     
         27 . A method for preparing a compound of Formula III comprising reacting a compound of Formula IV: 
       
         
           
           
               
               
           
         
         in which X is O or S(O) m ; 
         m is 0, 1, or 2; 
         n is 1 or 2; 
         R 1  is independently selected from the group consisting of hydrogen, —CN, —COOH, halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy; C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkyloxy, aryl, aminocarbonyl, C 1 -C 6  alkylcarbonyl, and C 1 -C 6  alkoxycarbonyl; and Ar is an aryl group; 
         or a salt of the compound of Formula IV, with a compound represented by Formula V: 
       
       
         
           
           
               
               
           
         
         in which Z is selected from the group consisting of halogen, triflate, or other suitable leaving groups; 
         p is 1 or 2; 
         R 3  is independently selected from the group consisting of hydrogen, halogen, amino, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkyloxy, aryl, aminocarbonyl, C 1 -C 6  alkylcarbonyl, and C 1 -C 6  alkoxycarbonyl; 
         Y is S(O) n L; 
         n is 0, 1, or 2; 
         and L is a C 1 -C 6  alkyl group; 
         or a salt of the compound of Formula V, 
         in the presence of a metal catalyst and under conditions such that the compound of Formula III is formed.