Benzamide Derivatives As EP4 Receptor Agonists

Abstract

A compound of formula (I) or a pharmaceutically acceptable derivative thereof, wherein, R 1 , R 2 , R 3 , R 4 , R 5 , m, n and X are as defined in the specification; a process for preparing such compounds; a pharmaceutical composition comprising such compounds; and the use of such compounds in medicine.

1 . A compound of formula (I) or a pharmaceutically acceptable derivative thereof, 
       
         
           
           
               
               
           
         
       
       wherein,
 R 1  represents halogen or C 1-4  alkyl; 
 R 2  represents C 1-4  alkyl or chloro; 
 R 3  represents H, C 1-4  alkyl or halogen; 
 R 4  represents H; 
 R 5  independently each represents halogen or C 1-4  alkyl; 
 m represents 0 or 1; 
 n represents 0, 1 or 2; and 
 X represents O or NH; 
 
       with the proviso that when n represents 2 and R 5  represents halogen, the R 5  groups together with the phenyl group to which they are attached do not form a 2,3-difluorophenyl moiety. 
     
     
         2 . A compound according to  claim 1  wherein X represents O. 
     
     
         3 . A compound according to  claim 1  wherein X represents NH. 
     
     
         4 . A compound according to  claim 1  wherein R 1  represents halogen. 
     
     
         5 . A compound according to  claim 4  wherein R 1  represents chloro. 
     
     
         6 . A compound according to  claim 5  wherein R 1  represents chloro in the C(3) position on the phenyl ring. 
     
     
         7 . A compound according to  claim 1  wherein R 2  is methyl. 
     
     
         8 . A compound according to  claim 1  wherein R 3  is H. 
     
     
         9 . A compound according to  claim 1  wherein R 5  represents methyl. 
     
     
         10 . A compound according to  claim 9  wherein R 5  represents methyl in the C(3) position on the phenyl ring. 
     
     
         11 . A compound according to  claim 1  wherein:
 R 1  represents halogen; 
 R 2  is C 1-4  alkyl; 
 R 3  is H; 
 R 5  represents C 1-4  alkyl; 
 m represents 1; and 
 n represents 1. 
 
     
     
         12 . A compound according to  claim 11  wherein:
 R 1  represents chloro; 
 R 2  is methyl; 
 R 3  is H; 
 R 5  represents methyl; 
 m represents 1; and 
 n represents 1. 
 
     
     
         13 . A compound according to  claim 12  wherein:
 R 1  represents chloro in the C(3) position on the phenyl ring; 
 R 2  is methyl; 
 R 3  is H; 
 R 5  represents methyl in the C(3) position on the phenyl ring; 
 m represents 1; and 
 n represents 1. 
 
     
     
         14 . A compound of formula (I) or a pharmaceutically acceptable derivative thereof, 
       
         
           
           
               
               
           
         
         wherein, 
         R 1  represents chloro; 
         R 2  represents methyl; 
         R 3  represents H; 
         R 4  represents H; 
         R 5  represents methyl; 
         m represents 1; 
         n represents 1; and 
         X represents O. 
       
     
     
         15 . A compound according to  claim 1  selected from the group consisting of:
 (3-chloro-4-{[(2-chloro-5-{[(3-chlorophenyl)methyl]oxy}phenyl)carbonyl]amino}phenyl)acetic acid; 
 {3-chloro-4-[({2-chloro-5-[(phenylmethyl)oxy]phenyl}carbonyl)amino]phenyl}acetic acid; 
 (4-{[(2-chloro-5-{[(3-chlorophenyl)methyl]oxy}phenyl)carbonyl]amino}phenyl)acetic acid; 
 (4-{[(2-chloro-5-{[(3-chlorophenyl)methyl]oxy}phenyl)carbonyl]amino}-2-fluorophenyl)acetic acid; 
 (4-{[(2-chloro-5-{[(3-chlorophenyl)methyl]oxy}phenyl)carbonyl]amino}-3-fluorophenyl)acetic acid; 
 (4-{[(2-chloro-5-{[(3-chlorophenyl)methyl]oxy}phenyl)carbonyl]amino}-2,5-difluorophenyl)acetic acid; 
 (3-chloro-4-{[(2-chloro-5-{[(3-chlorophenyl)methyl]oxy}phenyl)carbonyl]amino}-2-fluorophenyl)acetic acid; 
 (4-{[(2-chloro-5-{[(3-chlorophenyl)methyl]oxy}phenyl)carbonyl]amino}-3-methylphenyl)acetic acid; 
 {4-[({2-chloro-5-[(phenylmethyl)amino]phenyl}carbonyl)amino]phenyl}acetic acid; 
 (4-{[(2-chloro-5-{[(3-chlorophenyl)methyl]amino}phenyl)carbonyl]amino}phenyl)acetic acid; 
 (4-{[(2-chloro-5-{[(2-chlorophenyl)methyl]amino}phenyl)carbonyl]amino}phenyl)acetic acid; 
 (5-chloro-4-{[(2-chloro-5-{[(3-chlorophenyl)methyl]oxy}phenyl)carbonyl]amino}-2-fluorophenyl)acetic acid; 
 (4-{[(5-{[(3-chlorophenyl)methyl]oxy}-2-methylphenyl)carbonyl]amino}phenyl)acetic acid; 
 {4-[({2-methyl-5-[(phenylmethyl)oxy]phenyl}carbonyl)amino]phenyl}acetic acid; 
 (4-{[(6-Chloro-3-{[(3-chlorophenyl)methyl]oxy}-2-fluorophenyl)carbonyl]amino}phenyl)acetic acid; 
 {4-[({6-chloro-2-fluoro-3-[(phenylmethyl)oxy]phenyl}carbonyl)amino]phenyl}acetic acid; 
 {3-chloro-4-[({2-methyl-5-[(phenylmethyl)oxy]phenyl}carbonyl)amino]phenyl}acetic acid; 
 (3-chloro-4-{[(5-{[(3-chlorophenyl)methyl]oxy}-2-methylphenyl)carbonyl]amino}phenyl)acetic acid; 
 {3-chloro-4-[({6-chloro-2-fluoro-3-[(phenylmethyl)oxy]phenyl}carbonyl)amino]phenyl}acetic acid; 
 (3-chloro-4-{[(6-chloro-3-{[(3-chlorophenyl)methyl]oxy}-2-fluorophenyl)carbonyl]amino}phenyl)acetic acid; 
 (4-{[(2-chloro-5-{[(3-fluorophenyl)methyl]oxy}phenyl)carbonyl]amino}-3-methylphenyl)acetic acid; 
 (4-{[(2-chloro-5-{[(3-fluorophenyl)methyl]oxy}phenyl)carbonyl]amino}-3-fluorophenyl)acetic acid; 
 (4-{[(5-{[(3-chlorophenyl)methyl]oxy}-2-methylphenyl)carbonyl]amino}-3-fluorophenyl)acetic acid; 
 (4-{[(2-chloro-5-{[(3-methylphenyl)methyl]oxy}phenyl)carbonyl]amino}-3-fluorophenyl)acetic acid; 
 (4-{[(2-chloro-5-{[(3-methylphenyl)methyl]oxy}phenyl)carbonyl]amino}-3-methylphenyl)acetic acid; 
 (4-{[(2-chloro-5-{[(2-chlorophenyl)methyl]oxy}phenyl)carbonyl]amino}phenypacetic acid; 
 (3-chloro-4-{[(2-chloro-5-{[(2-chlorophenyl)methyl]oxy}phenyl)carbonyl]amino}phenyl)acetic acid; 
 (3-chloro-4-{[(2-chloro-5-{[(4-chlorophenyl)methyl]oxy}phenyl)carbonyl]amino}phenyl)acetic acid; 
 (3-chloro-4-{[(2-chloro-5-{[(3-fluorophenyl)methyl]oxy}phenyl)carbonyl]amino}phenyl)acetic acid; 
 (3-chloro-4-{[(2-chloro-5-{[(3-methylphenyl)methyl]oxy}phenyl)carbonyl]amino}phenyl)acetic acid; 
 (3-fluoro-4-{[(5-{[(3-fluorophenyl)methyl]oxy}-2-methylphenyl)carbonyl]amino}phenyl)acetic acid; 
 (4-{[(5-{[(3-fluorophenyl)methyl]oxy}-2-methylphenyl)carbonyl]amino}-3-methylphenyl)acetic acid; 
 (3-fluoro-4-{[(2-methyl-5-{[(3-methylphenyl)methyl]oxy}phenyl)carbonyl]amino}phenyl)acetic acid; 
 (3-chloro-4-{[(2-methyl-5-{[(3-methylphenyl)methyl]oxy}phenyl)carbonyl]amino}phenyl)acetic acid; 
 (4-{[(2-chloro-5-{[(3-chlorophenyl)methyl]oxy}phenyl)carbonyl]amino}-3,5-difluorophenyl)acetic acid; 
 (3-methyl-4-{[(2-methyl-5-{[(3-methylphenyl)methyl]oxy}phenyl)carbonyl]amino}phenyl)acetic acid; 
 (3-chloro-4-{[(5-{[(3-fluorophenyl)methyl]oxy}-2-methylphenyl)carbonyl]amino}phenyl)acetic acid; 
 (4-{[(6-chloro-3-{[(3-chlorophenyl)methyl]oxy}-2-fluorophenyl)carbonyl]amino}-3-fluorophenyl)acetic acid; 
 (4-{[(5-{[(3-chlorophenyl)methyl]oxy}-2-methylphenyl)carbonyl]amino}-3,5-difluorophenyl)acetic acid; 
 (4-{[(6-chloro-3-{([(3-chlorophenyl)methyl]oxy}-2-fluorophenyl)carbonyl]amino}-3-methylphenyl)acetic acid; 
 (3-chloro-4-{[(6-chloro-2-fluoro-3-{[(3-fluorophenyl)methyl]oxy}phenyl)carbonyl]amino}phenyl)acetic acid; 
 (4-{[(6-chloro-2-fluoro-3-{[(3-fluorophenyl)methyl]oxy}phenyl)carbonyl]amino}-3-fluorophenyl)acetic acid; 
 (4-{[(6-chloro-2-fluoro-3-{[(3-fluorophenyl)methyl]oxy}phenyl)carbonyl]amino}-3-methylphenyl)acetic acid; 
 (4-{[(6-chloro-2-fluoro-3-{[(3-methylphenyl)methyl]oxy}phenyl)carbonyl]amino}-3-fluorophenyl)acetic acid; 
 
       or a pharmaceutically acceptable derivative thereof. 
     
     
         16 . A method of treating a human or animal subject suffering from a condition which is mediated by the action, or by loss of action, of PGE 2  at EP 4  receptors which comprises administering to said subject an effective amount of a compound of  claim 1 . 
     
     
         17 . A method according to  claim 16  wherein the condition is pain. 
     
     
         18 . A method according to  claim 17  wherein the pain condition is selected from the group consisting of: chronic articular pain; musculoskeletal pain; lower back and neck pain; sprains and strains; neuropathic pain; sympathetically maintained pain; myositis; pain associated with cancer and fibromyalgia; pain associated with migraine; pain associated with influenza or other viral infections; rheumatic fever; pain associated with functional bowel disorders; pain associated with myocardial ischemia; post operative pain; headache; toothache and dysmenorrhea.