Inhibition of p38 kinase activity by aryl ureas

Abstract

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

1 . A method for the treatment of a disease, other than cancer, mediated by p38, comprising administering a compound of Formula I 
     
       
         
         
             
             
         
       
     
     wherein
 A is optionally substituted C 6-12 -aryl or C 5-12 -heteroaryl; 
 B is 
 
     
       
         
         
             
             
         
       
       R 1  is H or C 1-4 -alkyl; 
       R 2  and R 3  are each independently halogen, —COOR 1 , —CN, —CONR 7 R 8 , or —CH 2 NHR 9 ; 
       R 5  is C 3-5 -alkyl; 
       R 6  is C 1-6 -alkyl; 
       R 7  is hydrogen; 
       R 8  is methyl; 
       R 9  is hydrogen, methyl or —CO—R 10 ; and 
       R 10  is hydrogen or methyl optionally substituted by NR 6   2  or COOR 6 . 
     
   
   
       2 . A method according to  claim 1 , wherein the disease is mediated by a cytokine or protease regulated by p38. 
   
   
       3 . A method according to  claim 1 , wherein A is C 6-12 -aryl or C 5-12 -heteroaryl optionally substituted by C 1-4 -alkyl, C 3-6 -cycloalkyl, halogen, —OH, —OR 1 , or —NR 1   2 . 
   
   
       4 . A method according to  claim 1 , wherein R 5  is isopropyl or tert-butyl. 
   
   
       5 . A method according to  claim 1 , wherein A is phenyl, 1,3,4-thiadiazol-2- or -5-yl, 7-indolyl, or 8-quinolinyl, each optionally substituted by C 1-4 -alkyl, C 3-6 -cycloalkyl, halogen, —OH, —OR 1 , or —N 1   2 . 
   
   
       6 . A method according to  claim 1 , wherein A is 4-methylphenyl, 4-fluorophenyl, 5-methyl-2-thienyl, 4-methyl-2-thienyl, or 5-cyclopropyl-1,3,4-thiadiazol-2-yl. 
   
   
       7 . A method according to  claim 1 , wherein R 2  or R 3  is —COOR 1  or CH 2 NHR 9 , and R 1  is C 1-4 -alkyl, R 7  is H, and R 8  is C 1-10 -alkyl. 
   
   
       8 . A method according to  claim 1 , comprising administering an amount of a compound of Formula I effective to inhibit p38. 
   
   
       9 . A method according to  claim 2 , wherein the disease is mediated by TNFα, MMP-1, MMP-3, IL-1, IL-6, or IL-8. 
   
   
       10 . A method according to  claim 1 , wherein the disease is an inflammatory or immunomodulatory disease. 
   
   
       11 . A method according to  claim 1 , wherein the disease is rheumatoid arthritis, osteoperosis, asthma, septic shock, inflammatory bowel disease, or the result of host-versus-graft reactions. 
   
   
       12 . A method according to  claim 1 , wherein the compound is N-(2-carbomethoxy-5-isopropyl-3-thienyl)-N′-(phenyl)urea; N-(2-carbomethoxy-5-tert-butyl-3-thienyl)-N′-(4-methylphenyl)urea; N-(2-carbomethoxy-5-tert-butyl-3-thienyl)-N′-(4-fluorophenyl)urea; N-(2-carbomethoxy-5-tert-butyl-3-thienyl)-N′-(3-methylphenyl)urea; N-(2-carbomethoxy-5-tert-butyl-3-thienyl)-N′-(5-cyclopropyl-2-thiadiazolyl)urea; N-(2-carbomethoxy-5-tert-butyl-3-thienyl)-N′-(2-aminophenyl)urea; N-(2-carboethoxy-5-tert-butyl-3-thienyl)-N′-(4-methylphenyl)urea; N-(2-(carbo-1-prop-2-enyloxy)-5-tert-butyl-3-thienyl)-N′-(4-methylphenyl)urea; N-(2-(carbo-2-propyloxy)-5-tert-butyl-3-thienyl)-N-(4-methylphenyl)urea; N-(2-(carbo-1-propyloxy)-5-tert-butyl-3-thienyl)-N′-(4-methylphenyl)urea; N-(2-methylcarbamoyl-5-tert-butyl-3-thienyl)-N′-(4-methylphenyl)urea; N-(2-methylcarbamoyl-5-tert-butyl-3-thienyl)-N′-(4-fluorophenyl)urea; N-(2-methylcarbamoyl)-5-tert-butyl-3-thienyl)-N′-(4-ethylphenyl)urea; N-(2-methylcarbamoyl)-5-tert-butyl-3-thienyl)-N′-(4-isopropylphenyl)urea; N-(2-methylcarbamoyl)-5-tert-butyl-3-thienyl)-N′-(2,4-dimethylphenyl)urea; N-(2-methylcarbamoyl)-5-tert-butyl-3-thienyl)-N′-(3-chloro-4-methylphenyl)urea; N-(2-methylcarbamoyl)-5-tert-butyl-3-thienyl)-N′-(3-fluoro-4-methylphenyl)urea; N-(2-methylcarbamoyl)-5-tert-butyl-3-thienyl)-N′-(3-chloro-4-fluorophenyl)urea; N-(2-carboxy-5-tert-butyl-3-thienyl)-N′-(4-methylphenyl)urea; N-(2-(N-glycylaminomethyl)-5-tert-butyl-3-thienyl)-N′-(4-methylphenyl)urea; N-(2-(N—(N-carbo-tert-butoxyglycyl)aminomethyl)-5-tert-butyl-3-thienyl)-N′-(4-methylphenyl)urea; N-(2-(N-acetylaminomethyl)-5-tert-butyl-3-thienyl)-N′-(4-methylphenyl)urea; N-(2-carbomethoxy-5-tert-butyl-3-thienyl)-N′-(4-methyl-2-thienyl)urea; or N-(2-carbomethoxy-5-tert-butyl-3-thienyl)-N′-(5-methyl-2-thienyl)urea. 
   
   
       13 . A method according to  claim 1 , wherein the compound is N-(2-carbomethoxy-5-tert-butyl-3-furyl)-N′-(4-methylphenyl)urea; N-(2-carbomethoxy-5-tert-butyl-3-furyl)-N′-(4-fluorophenyl)urea; N-(2-carbomethoxy-5-tert-butyl-3-furyl)-N′-(2,3-dichlorophenyl)urea; N-(2-methylcarbamoyl-5-tert-butyl-3-furyl)-N′-(4-fluorophenyl)urea; or N-(2-methylcarbamoyl-5-tert-butylfuryl)-N′-(4-methylphenyl)urea. 
   
   
       14 . A method according to  claim 1 , wherein the compound is N-(2-carbomethoxy-5-tert-butyl-3-pyrrolyl)-N′-(4-methylphenyl)urea; N-(2-carbomethoxy-5-tert-butyl-3-pyrrolyl)-N′-(phenyl)urea; N-(2-carbomethoxy-5-tert-butyl-3-pyrrolyl)-N′-(2,3-dichlorophenyl)urea; or N—(N-methyl-2-carbomethoxy-5-tert-butyl-3-pyrrolyl)-N′-(5-methyl-2-thienyl)urea. 
   
   
       15 . A method according to  claim 1 , wherein the compound is N-(3-carbomethoxy-5-tert-butyl-2-thienyl)-N′-(4-methylphenyl)urea; N-(3-carbomethoxy-5-tert-butyl-2-thienyl)-N′-(phenyl)urea; N-(3-carbomethoxy-5-isopropyl-2-thienyl)-N′-(4-methylphenyl)urea; or N-(3-carbomethoxy-5-isopropyl-2-thienyl)-N′-(phenyl)urea. 
   
   
       16 . A method according to  claim 1 , wherein the compound is N-(2-methylcarbamoyl-5-tert-butyl-3-furyl)-N′-(3,4-dichlorophenyl)urea; N-(2-carbomethoxy-5-tert-butyl-3-pyrrolyl)-N′-(2,3-dichlorophenyl)urea; N-(2-carbomethoxy-5-tert-butyl-3-pyrrolyl)-N′-(3,4-dichlorophenyl)urea; N-(2-carbomethoxy-5-tert-butyl-3-pyrrolyl)-N′-(1-naphthyl)urea; N-(2-carbomethoxy-5-tert-butyl-3-pyrrolyl)-N′-(2-naphthyl)urea; N-(2-carbomethoxy-5-tert-butyl-3-pyrrolyl)-N′-(3-chloro-4-fluorophenyl)urea; N-(2-carbomethoxy-5-tert-butyl-3-pyrrolyl)-N′-(3-chloro-4-methylphenyl)urea; N-(2-methylcarbamoyl-5-tert-butyl-3-pyrrolyl)-N′-(2,3-dichlorophenyl)urea; N-(2-methylcarbamoyl-5-tert-butyl-3-pyrrolyl)-N′-(1-naphthyl)urea; N—(N-methyl-2-carbomethoxy-5-tert-butyl-3-pyrrolyl)-N′-(1-naphthyl)urea; N—(N-methyl-2-carbomethoxy-5-tert-butyl-3-pyrrolyl)-N′-(2,3-dichlorophenyl)urea; N—(N-methyl-2-carbomethoxy-5-tert-butyl-3-pyrrolyl)-N′-(4-methylphenyl)urea; N—(N-methyl-2-carbomethoxy-5-tert-butyl-3-pyrrolyl)-N′-(phenyl)urea; N-(3-carbomethoxy-5-tert-butyl-2-thienyl)-N′-(3-methylphenyl)urea; N-(3-carbomethoxy-5-tert-butyl-2-thienyl)-N′-(2,3-dichlorophenyl)urea; N-(3-carbomethoxy-5-tert-butyl-2-thienyl)-N′-(2,3-dichloro-4-hydroxyphenyl)urea; N-(3-carbomethoxy-5-tert-butyl-2-thienyl)-N′-(3-methoxyphenyl)urea; or N-(3-carbamoyl-5-tert-butyl-2-thienyl)-N′-(4-methylphenyl)urea.