Inhibition of p38 kinase using symmetrical and unsymmetrical diphenyl ureas

Abstract

This invention relates to the use of a group of aryl ureas in treating cytokine mediated diseases and proteolytic enzyme mediated diseases, and pharmaceutical compositions for use in such therapy.

1 . A method of treating a disease, other than cancer, mediated by p-38, comprising administering a compound of formula I 
       
         
           
           
               
               
           
         
         wherein
 A is 
 
       
       
         
           
           
               
               
           
         
         B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms with at least one 6-member aromatic structure containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur, wherein if B is substituted, it is substituted by one or more substituents selected from the group consisting of halogen, up to per-halo, and W n , wherein n is 0-3 and each W is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)NR 7 R 7 , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7 , —NR 7 C(O)OR 7 , —NR 7 C(O)R 7 , C 1 -C 10  alkyl, C 1-10 -alkenyl, C 1-10 -alkoxy, C 3 -C 10  cycloalkyl, C 6 -C 14  aryl, C 7 -C 24  alkaryl, C 3 -C 13  heteroaryl, C 4 -C 23  alkheteroaryl, substituted C 1 -C 10  alkyl, substituted C 2-10 -alkenyl, substituted C 1-10 -alkoxy, substituted C 3 -C 10  cycloalkyl, substituted C 4 -C 23  alkheteroaryl and Q-Ar; 
         wherein if W is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)R 7 , 
         —C(O)NR 7 R 7 , —OR 7 , —SR 7 , —NR 7 R 7 , NO 2 , —NR 7 C(O)R 7 , —NR 7 C(O)OR 7  and halogen up to per-halo;
 wherein each R 7  is independently selected from H, C 1 -C 10  alkyl, C 2-10 -alkenyl, C 3 -C 10  cycloalkyl, C 6 -C 14  aryl, C 3 -C 13  hetaryl, C 7 -C 24  alkaryl, C 4 -C 23  alkheteroaryl, up to per-halosubstituted C 1 -C 10  alkyl, up to per-halo substituted C 2-10 -alkenyl, up to per-halo substituted C 3 -C 10  cycloalkyl, up to per-halosubstituted C 6 -C 14  aryl and up to per-halosubstituted C 3 -C 13  hetaryl, wherein Q is —O—, —S—, —N(R 7 )—, —(CH 2 )— m , —C(O)—, —CH(OH)—, —(CH 2 ) m O—, 
 
         —NR 7 C(O)NR 7 R 7′ —, —NR 7 C(O)—, —C(O)NR 7 —, —(CH 2 ) m S—, —(CH 2 ) m N(R 7 )—, —O(CH 2 ) m —, 
         —CHX a , —CX a   2 —, —S—(CH 2 ) m — and —N(R 7 )(CH 2 ) m —, 
         m=1-3, and X a  is halogen; and 
         Ar is a 5-10 member aromatic structure containing 0-2 members of the group consisting of nitrogen, oxygen and sulfur, which is unsubstituted or substituted by halogen up to per-halo and optionally substituted by Z n1 , wherein  n1  is 0 to 3 and each Z is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)NR 7 R 7 , —C(O)—NR 7 , —COR 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7 , —NR 7 C(O)OR 7 , —NR 7 C(O)R 7 , C 1 -C 10  alkyl, C 3 -C 10  cycloalkyl, C 6 -C 14  aryl, C 3 -C 13  hetaryl, C 7 -C 24  alkaryl, C 4 -C 23  alkheteroaryl, substituted C 1 -C 10  alkyl, substituted C 3 -C 10  cycloalkyl, substituted C 7 -C 24  alkaryl and substituted C 4 -C 23  alkheteroaryl; wherein the one or more substituents of Z is selected from the group consisting of —CN, —CO 2 R 7 , —C(O)NR 7 R 7 , —OR 7 , —SR 7 , —NO 2 , —NR 7 R 7 , —NR 7 C(O)R 7 , —NR 7 C(O)OR 7 , 
         R 3′ , R 4′ , R 5′  are each independently H, C 1-10 -alkyl, optionally substituted by halogen, up to perhalo, C 1-10  alkoxy, optionally substituted by halogen, up to perhaloalkoxy, halogen; NO 2  or NH 2 ; 
         R 6  is H, C 1-10 -alkyl, C 1-10  alkoxy, —NHCOR 1 ; —NR 1 COR 1 ; NO 2 ; 
       
       
         
           
           
               
               
           
         
         
           one of R 4 , R 5  or R 6  can be —X—Y, 
         
         or 2 adjacent R 4′ -R 6′  can together be an aryl or hetaryl ring with 5-12 atoms, optionally substituted by C 1-10 -alkyl, C 1-10  alkoxy, C 3-10  cycloalkyl, C 2-10  alkenyl, C 1-10  alkanoyl, C 6-12  aryl, C 5-12  hetaryl or C 6-12  aralkyl; 
         R 1  is C 1-10 -alkyl optionally substituted by halogen, up to perhalo; 
         X is —CH 2 —, —S—, —N(CH 3 )—, —NHC(O)—, —CH 2 —S—, —S—CH 2 —, —C(O)—, or —O—; and 
         X is additionally a single bond where Y is pyridyl; 
         Y is phenyl, pyridyl, naphthyl, pyridone, pyrazine, benzodioxane, benzopyridine, pyrimidine or benzothiazole, each optionally substituted by
 C 1-10 -alkyl, C 1-10 -alkoxy, halogen, OH, —SCH 3  or NO 2  or, where Y is phenyl, by 
 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A method according to  claim 1 , comprising administering a compound of formula Ia 
       
         
           
           
               
               
           
         
         wherein 
         R 3 , R 4 , R 5 , and R 6  are each independently H; halogen; C 1-10 -alkyl optionally substituted by halogen up to perhalo; C 1-10 -alkoxy optionally substituted by at least one hydroxy group or halogen up to perhalo, C 6-12  aryl, optionally substituted by C 1-10  alkoxy or halogen, C 5-12  hetaryl, optionally substituted by C 1-10  alkyl, C 1-10  alkoxy or halogen; NO 2 ; SO 2 F; —SO 2 CH p X 3-p ; —COOR 1 ; —OR 1 CONHR 1 ; —NHCOR 1 ; —SR 1 ; NH 2 ; —N(SO 2 R 1 ) 2 ; furyloxy; 
       
       
         
           
           
               
               
           
         
         
           2 adjacent R 3 -R 6  can together form an aryl or hetaryl ring with 5-12 atoms, optionally substituted by C 1-10 -alkyl, C 1-10 -alkoxy, C 3-10 -cycloalkyl, C 2-10 -alkenyl, C 1-10 -alkanoyl, C 6-12 -aryl, C 5-12 -hetaryl, C 6-12 -aralkyl, C 6-12 -alkaryl, halogen; —NR 1 ; —NO 2 ; —CF 3 ; 
         
         —COOR 1 ; —NHCOR 1 ; —CN; —CONR 1 R 1 ; —SO 2 R 2 ; —SOR 2 ; —SR 2 ; in which R 1  is H or C 1-10 -alkyl and R 2  is C 1-10 -alkyl optionally substituted by halogen, up to perhalo, with —SO 2 — optionally incorporated in the aryl or hetaryl ring; 
         p is 0 or 1; 
         one of R 3 , R 4 , R 5  or R 6  can be —X—Y, 
         with the proviso that if R 3  and R 6  are both H, one of R 4  or R 5  is not H, and R 3′ -R 6′  are as defined in  claim 1 . 
       
     
     
         3 . A method according to  claim 2 , wherein
 R 3  is H; halogen; C 1-10 -alkyl optionally substituted by halogen, up to perhalo, NO 2 , —SO 2 F or —SO 2 CF 3 ;   R 4  is H, C 1-10 -alkyl, C 1-10 -alkoxy, halogen or NO 2 ;   R 5  is H, C 1-10 -alkyl optionally substituted by halogen, up to perhalo;   R 6  is H, hydroxy, C 1-10 -alkoxy optionally substituted by at least one hydroxy group; —COOR 1 ; —OR 1 CONHR 1 ; —NHCOR 1 ; —SR 1 ; phenyl optionally substituted by halo or C 1-10 -alkoxy; NH 2 ; —N(SO 2 R 1 ) 2 , furyloxy, thiophene, pyrole or methyl substituted pyrole,   
       
         
           
           
               
               
           
         
       
     
     
         4 . A method according to  claim 2 , wherein R 3  is Cl, F, C 4-5 -branched alkyl, —SO 2 F or —SO 2 CF 3 ; and R 6  is hydroxy; C 1-10 -alkoxy optionally substituted by at least one hydroxy group; —COOR 1 ; —OR 1 CONHR 1 ; —NHCOR 1 ; —SR 1 ; phenyl optionally substituted by halo or C 1-10 -alkoxy; NH 2 ; —N(SO 2 R 1 ) 2 , furyloxy, 
       
         
           
           
               
               
           
         
       
     
     
         5 . A method according to  claim 2 , wherein R 4′  is C 1-10 -alkyl or halogen;
 R 5′  is H, C 1-10 -alkyl, halogen, CF 3 , halogen, NO 2  or NH 2 ; and R 6′  is H, C 1-10 -alkyl, halogen, —NHCOCH 3 , —N(CH 3 )COCH 3 , NO 2 , 
 
       
         
           
           
               
               
           
         
       
     
     
         6 . A method according to  claim 2 , wherein R 5′  is C 1-10 -alkyl, halogen, CF 3 , halogen, NO 2  or NH 2 . 
     
     
         7 . A method according to  claim 2 , wherein R 6′  is C 1-10 -alkyl, halogen, —NHCOCH 3 , —N(CH 3 )COCH 3 , NO 2 , 
       
         
           
           
               
               
           
         
       
     
     
         8 . A method according to  claim 4 , wherein R 3  is t-butyl or CF 3  and R 6  is —OCH 3 . 
     
     
         9 . A method according to  claim 2 , wherein the disease is mediated by a cytokine or protease regulated by p38. 
     
     
         10 . A method according to  claim 2 , wherein the disease is mediated by TNFα, MMP-1, MMP-3, IL-1, IL-6 or IL-8. 
     
     
         11 . A method according to  claim 2 , wherein the disease is an inflammatory or immunomodulatory disease. 
     
     
         12 . A method according to  claim 2 , wherein the disease is osteoarthritis, rheumatoid arthritis, osteoporosis, asthma, septic shock, inflammatory bowel disease, or the result of host-versus-graft reactions. 
     
     
         13 . A method according to  claim 1 , wherein the compound of formula I is
 N-(5-tert-Butyl-2-methoxyphenyl)-N-(4-phenyloxyphenyl)urea;   N-(5-tert-Butyl-2-methoxyphenyl)-N-(4-(4-methoxyphenyloxy)phenyl)urea;   N-(5-tert-Butyl-2-methoxyphenyl)-N-(4-(4-pyridinyloxy)phenyl)urea;   N-(5-tert-Butyl-2-methoxyphenyl)-N-(4-(4-pyridinylmethyl)phenyl)urea;   N-(5-tert-Butyl-2-methoxyphenyl)-N-(4-(4-pyridinylthio)phenyl)urea;   N-(5-tert-Butyl-2-methoxyphenyl)-N-(4-(4-(4,7-methano-1H-isoindole-1,3(2H)-dionyl)methyl)phenyl)urea;   N-(5-tert-Butyl-2-phenylphenyl)-N-(2,3-dichlorophenyl)urea;   N-(5-tert-Butyl-2-(3-thienyl)phenyl)-N-(2,3-dichlorophenyl)urea;   N-(5-tert-Butyl-2-(N-methylaminocarbonyl)methoxyphenyl)-N-(2,3-dichlorophenyl)urea;   N-(5-tert-Butyl-2-(N-methylaminocarbonyl)methoxyphenyl)-N-(1-naphthyl)urea;   N-(5-tert-Butyl-2-(N-morpholinocarbonyl)methoxyphenyl)-N-(2,3-dichlorophenyl)urea;   N-(5-tert-Butyl-2-(N-morpholinocarbonyl)methoxyphenyl)-N-(1-naphthyl)urea;   N-(5-tert-Butyl-2-methoxyphenyl)-N′-(4-(3-pyridinyl)methylphenyl)urea;   N-(5-tert-Butyl-2-(3-tetrahydrofuranyloxy)phenyl)-N-(2,3-dichlorophenyl)urea;   N-(5-Trifluoromethyl-2-methoxyphenyl)-N-(4-methylphenyl)urea;   N-(5-Trifluoromethyl-2-methoxyphenyl)-N-(4-methyl-2-fluorophenyl)urea;   N-(5-Trifluoromethyl-2-methoxyphenyl)-N-(4-fluoro-3-chlorophenyl)urea;   N-(5-Trifluoromethyl-2-methoxyphenyl)-N-(4-methyl-3-chlorophenyl)urea;   N-(5-Trifluoromethyl-2-methoxyphenyl)-N-(4-methyl-3-fluorophenyl)urea;   N-(5-Trifluoromethyl-2-methoxyphenyl)-N-(2,4-difluorophenyl)urea;   N-(5-Trifluoromethyl-2-methoxyphenyl)-N-(4-phenyloxy-3,5-dichlorophenyl)urea;   N-(5-Trifluoromethyl-2-methoxyphenyl)-N-(4-(4-pyridinylmethyl)phenyl)urea;   N-(5-Trifluoromethyl-2-methoxyphenyl)-N-(4-(4-pyridinylthio)phenyl)urea;   N-(5-Trifluoromethyl-2-methoxyphenyl)-N-(4-(4-pyridinyloxy)phenyl)urea;   N-(5-Trifluoromethyl-2-methoxyphenyl)-N-(3-(4-pyridinylthio)phenyl)urea;   N-(5-Trifluoromethyl-2-methoxyphenyl)-N-(4-(3-(N-methylaminocarbonyl)-phenyloxy)phenyl)-urea;   N-(5-Fluorosulfonyl)-2-methoxyphenyl)-N-(4-methylphenyl)urea;   N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N-(4-methylphenyl)urea;   N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N-(4-fluorophenyl)urea;   N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N-(4-methyl-2-fluorophenyl)urea;   N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N-(4-methyl-3-fluorophenyl)urea;   N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N-(4-methyl-3-chlorophenyl)urea;   N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N-(4-fluoro-3-chlorophenyl)urea;   N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N-(4-fluoro-3-methylphenyl)urea;   N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N-(2,3-dimethylphenyl)urea;   N-(5-(Trifluoromethanesulfonyl)-2-methoxyphenyl)-N-(4-methylphenyl)urea;   N-(3-methoxy-2-naphthyl)-N′-(2-fluorophenyl)urea);   N-(3-Methoxy-2-naphthyl)-N-(4-methylphenyl)urea;   N-(3-Methoxy-2-naphthyl)-N-(3-fluorophenyl)urea;   N-(3-Methoxy-2-naphthyl)-N-(4-methyl-3-fluorophenyl)urea;   N-(3-Methoxy-2-naphthyl)-N-(2,3-dimethylphenyl)urea;   N-(3-Methoxy-2-naphthyl)-N-(1-naphthyl)urea;   N-(3-Methoxy-2-naphthyl)-N-(4-(4-pyridinylmethyl)phenyl)urea;   N-(3-Methoxy-2-naphthyl)-N-(4-(4-pyridinylthio)phenyl)urea;   N-(3-Methoxy-2-naphthyl)-N-(4-(4-methoxyphenyloxy)phenyl)urea; and   N-(3-Methoxy-2-naphthyl)-N-(4-(4-(4,7-methano-1H-isoindole-1,3(2H)-dionyl)methyl)phenyl)urea.   N-(2-Hydroxy-4-nitro-5-chlorophenyl)-N-(phenyl)urea; or   N-(2-Hydroxy-4-nitro-5-chlorophenyl)-N-(4-(4-pyridinylmethly)phenyl)urea.   
     
     
         14 .- 22 . (canceled)