Benzo (F) insoindol derivatives and their use as EP4 receptor ligands

Abstract

The present invention relates to compounds of formula (I) and pharmaceutically acceptable derivatives thereof, which bind with high affinity to the EP4 receptor and are of use in the treatment or prevention of conditions such as a pain, inflammatory, immunological, bone, neurodegenerative or renal disorder.

1 . A method of treating a human or animal subject suffering from a condition mediated by action of PGE 2  at EP4 receptors, which comprises administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivatives thereof:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  is selected from the group consisting of H, halogen, C 1-6 alkyl, S-C 1-6 alkyl, C 1-6 alkoxy, OCF 3 , OCH 2 CF 3 , O-cyclopropyl, OCH 2 -cyclopropyl, N H 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , NO 2 , OH, CH 2 OC 1-6 alkyl and CH 2 OH;  
 R 2  each independently is selected from C 1-4 alkyl;  
 R 3 is H or O;  
 R 4  is H or C 1-6 alkyl;  
 R 5  is selected from the group consisting of C 1-6 alkyl, phenyl, phenyl substituted by one or more R 6 , naphthyl, phenylC 1-6 alkyl, pyridyl, oxazolyl, isoxazolyl, isoxazolyl substituted with one or two C 1-6 alkyl, thiophenyl, C 1-6 alkylCO 2 C 1-6 alkyl, pyrrolyl, furanyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, thiadiazolyl, isothiadiazolyl, indolyl, indazolyl and benzothiophenyl;  
 R 6  is selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkyl substituted by one or more fluorine atoms, C 1-6 alkoxy, cyano, CO 2 H, CO 2 C 1-6 alkyl, OH, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , S(O) n C 1-6 alkyl where n=0, 1 or 2, CONH 2 , CON(C 1-6 alkyl) 2 , COC 1-6 alkyl and NHCO(C 1-6 alkyl);  
 R 7  to R 10  are each independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy substituted by one or more fluorine atoms, O-cyclopropyl, OCH 2 -cyclopropyl, S-C 1-6 alkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , halogen, NO 2 , OH, CH 2 OC 1-6 alkyl and CH 2 OH;  
 R 11  is selected from the group consisting of H, OH, halogen, dihalogen, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 dialkyl, C 1-6 alkoxy, NHCO(C 1-6 alkyl), and ═O; and 
 provided that 
    is a single bond, when R 3  is O, a double bond.