Anti-inflammatory indole derivatives

Abstract

Therapeutic compounds of formula (I) wherein X is CH 2 or SO 2 ; R 1 is an optionally substituted aryl or heteroaryl ring; R 2 and R 3 are various specified groups, R 4 is a group NHCOR 15 , NHSO 2 R 15 or OCONR 16 R 17 where R 15 is optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl and R 16 and R 17 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl and optionally substituted heteroaryl, with the proviso that at least one of R 16 or R 17 is other than hydrogen, or R 16 and R 17 together with the nitrogen atom to which they are attached from an optionally substituted heterocyclic ring which optionally contains further heteroatoms; and R 5 , R 6 and R 7 are independently selected from hydrogen, a functional group or an optionally substituted hydrocarbyl groups or optionally substituted heterocyclic groups; and further provided that when R 4 is a group NHCOR 15 , R 15 is substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl; as well as pharmaceutical compositions containing them are described and claimed. These compounds and compositions are useful in the treatment of disease mediated by monocyte chemoattractant protein-1 or RANTES (Regulated Upon Activation, Normal T-cell Expressed and Secreted), such as inflammatory disease.

1 . A compound of formula (I)  
       
         
           
           
               
               
           
         
         X is CH 2  or SO 2    
         R 1  is an optionally substituted aryl or heteroaryl ring;  
         R 2  is carboxy, cyano, —C(O)CH 2 OH, —CONHR 8 , —SO 2 NHR 9 , tetrazol-5-yl, SO 3 H, or a group of formula (VI)  
         
           
             
             
                 
                 
             
           
         
         where R 8  is selected from hydrogen, alkyl, aryl, cyano, hydroxy, —SO 2 R 12  where R 12  is alkyl, aryl, heteroaryl, or haloalkyl, or R 8  is a group —(CHR 13 ) r —COOH where r is an integer of 1-3 and each R 13  group is independently selected from hydrogen or alkyl; R 9  is hydrogen, alkyl, optionally substituted aryl such as optionally substituted phenyl or optionally subtituted heteroaryl such as 5 or 6 membered heteroaryl groups, or a group COR 14  where R 14  is alkyl, aryl, heteroaryl or haloalkyl; R 10  and R 11  are independently selected from hydrogen or alkyl, particularly C 1-4 alkyl;  
         R 3  is hydrogen a functional group, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aralkyl, optionally substituted aralkyloxy, optionally substituted cycloalkyl;  
         R 4  is a group NHCOR 15 , NHSO 2 R 15  or OCONR 16 R 17  where R 15  is optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl and R 16  and R 17  are independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl and optionally substituted heteroaryl, with the proviso that at least one of R 16  or R 17  is other than hydrogen, or R 16  and R 17  together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring which optionally contains further heteroatoms; and  
         R 5 , R 6  and R 7  are independently selected from hydrogen, a functional group or an optionally substituted hydrocarbyl groups or optionally substituted heterocyclic groups; and further provided that when R 4  is a group NHCOR 15 , R 15  is substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl.  
       
     
     
         2 . A compound according to  claim 1  wherein a group R 15 , R 16  and R 17  as they appear in the definition of R 4 , is substituted by at least one functional group, or an aryl or heterocyclyl groups, either of which may themselves be substituted by one or more functional groups or further aryl or heterocyclyl groups.  
     
     
         3 . A compound according to any one of the preceding claims wherein R 4  is a group NHCOR 15  or NHSO 2 R 15  and R 15  is a substituted alkyl group or an optionally subsituted hetercyclyl or optionally substituted phenyl group.  
     
     
         4 . A compound according to  claim 3  wherein R 15  is alkyl substituted by a group of formula NR 19 R 20  where R 19  and R 20  are independently selected from hydrogen or optionally substituted hydrocarbyl, or R 19  and R 20  together form an optionally substituted ring which optionally contains further heteroatoms such as S(O) m , oxygen and nitrogen, n is an integer of 1 or 2, m is 1 or 2.  
     
     
         5 . A compound according to any one of the preceding claims where R 2  is carboxy.  
     
     
         6 . A compound according to any one of the preceding claims wherein R 1  is 3,4-dichlorophenyl, 3-fluoro-4-chlorophenyl, 3-chloro-4-fluorophenyl or 2,3-dichloropyrid-5-yl.  
     
     
         7 . A compound according to any one of the preceding claims where X is CH 2 .  
     
     
         8 . A process for preparing a compound according to  claim 1  which process comprises either 
 (a) where R 4  is NHCOR 15 or NHSO 2 R 15 , reacting a compound of formula (VII)                          where X, R 1 , R 3 , R 5 , R 6  and R 7  are as defined in  claim 1 , and R 2  is a group R 2  as defined in relation to formula (I) or a protected form thereof, with a compound of formula (VIII)      Z-R 22   (VIII)    where Z is a leaving group and R 22  is a group COR 15′  or SO 2 R 15′  where R 15′  is group R 15  as defined in relation to formula (I) or a precursor thereof;    or (b) where R 4  is a group OCONR 16 R 17 , reacting a compound of formula (VIIA)                          where X, R 2′ , R1, R 3 , R 5 , R 6  and R 7  are as defined  claim 1  and R 2  is a group R 2  as defined in  claim 1  or a protected form thereof, with a compound of formula (VIIIA)      Z-CONR 16 R 17   (VIIIA)    where Z, R 16  and R 17  are as defined above;    and thereafter if desired or necessary:    (i) converting a precursor group R 15′  to a group R 15  and/or converting a group R 15  to a different such group;    (ii) deprotecting a group R 2′  to a group R 2 .    
     
     
         9 . A pharmaceutical composition comprising a compound according to any one of  claims 1  to  7  in combination with a pharmaceutically acceptable carrier.  
     
     
         10 . A compound according to any one of  claims 1  to  7  for use in the preparation of a medicament for use in the treatment of disease mediated by monocyte chemoattractant protein-1 or RANTES  R egulated upon  A ctivation,  N ormal  T -cell  E xpressed and  S ecreted), such as inflammatory disease.