Novel Compounds

Abstract

The present invention relates to substituted indoles of formula (I), useful as pharmaceutical compounds for treating respiratory disorders.

1 . A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
       
       in which
 X is O or S(O) n  where n is 0, 1 or 2; 
 R 1  is hydrogen, halogen, CN, nitro, S(O) n R 4 , OH, OR 4 , OS(O) n R 4 , S(O) n R 4 , SO 2 NR 5 R 6 , CONR 5 R 6 , NR 5 R 6 , NR 4 SO 2 R 5 , NR 4 CO 2 R 6 , NR 4 COR 6 , NR 4 SO 2 NR 5 R 6 , NHSO 2 R 5 , NHCO 2 R 6 , NHCOR 6 , NHCONR 4 , NHSO 2 NR 5 R 6 , aryl, heteroaryl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8 cycloalkyl or C 1-6  alkyl, the latter four groups being optionally substituted by one or more substituents independently selected from halogen, OR 8 , NR 5 R 6  and S(O) n R 7  where n is 0, 1 or 2; 
 R 2  is hydrogen, halogen, CN, SO 2 R 4 , CONR 5 R 6 , CH 2 OH, CH 2 OR 4 , C 3-8 cycloalkyl or C 1-7 alkyl, the latter two groups being optionally substituted by one or more substituents independently selected from halogen, OR 8 , NR 5 R 6  or S(O) n R 7  where n is 0, 1 or 2; 
 R 3  is aryl or heteroaryl each of which is optionally substituted by one or more substituents independently selected from hydrogen, halogen, CN, nitro, S(O) n R 4 , OH, OR 4 , OS(O) n R 4 , S(O) n R 4 , SO 2 NR 5 R 6 , CONR 5 R 6 , NR 5 R 6 , NR 4 SO 2 R 5 , NR 4 CO 2 R 6 , NR 4 COR 6 , NR 4 SO 2 NR 5 R 6 , NHSO 2 R 5 , NHCO 2 R 6 , NHCOR 6 , NHCONR 4 , NHSO 2 NR 5 R 6 , aryl, heteroaryl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8 cycloalkyl or C 1-6  alkyl, the latter four groups being optionally substituted by one or more substituents independently selected from halogen atoms, aryl, heteroaryl, OR 8 , NR 5 R 6  or S(O) n R 7  where n=0, 1 or 2; 
 R 4  represents aryl, heteroaryl, C 3-8 cycloalkyl or C 1-6 alkyl all of which may be optionally substituted by one or more substituents independently selected from hydrogen, halogen atoms, aryl, heteroaryl, OR 10 , NR 11 R 12 , S(O) n R 13  (where n=0, 1 or 2), CONR 14 R 15 , NR 14 COR 15 , SO 2 NR 14 R 15 , NR 14 SO 2 R 15 , CN or nitro; 
 R 5  and R 6  independently represent a hydrogen atom, aryl, heteroaryl, C 3-8 cycloalkyl or C 1-6 alkyl, the latter two of which may be optionally substituted by one or more substituents independently selected from halogen atoms, aryl, heteroaryl, OR 10 , NR 11 R 12 , S(O) n R 13  (where n=0, 1 or 2), CONR 14 R 15 , NR 14 COR 15 , SO 2 NR 14 R 15 , NR 14 SO 2 R 15 , tc. CN or nitro; or 
 R 5  and R 6  together with the nitrogen atom to which they are attached can form a 3-8 membered saturated heterocylic ring optionally containing one or more atoms selected from O, S(O) n  where n=0, 1 or 2, or NR 16 , and itself optionally substituted by C 1-6  alkyl or C 3-8 cycloalkyl; 
 R 7  and R 13  independently represent aryl, heteroaryl, C 1- cycloalkyl and C 1-6 alkyl, all of which may be optionally substituted by one or more halogen atoms, aryl, heteroaryl, OR 10 , NR 11 R 12 , S(O) n R 13  (where n=0, 1 or 2), CONR 14 R 15 , NR 14 COR 15 , SO 2 NR 14 R 15 , NR 14 SO 2 R 15 , CN or nitro; 
 R 8  represents a hydrogen atom, C(O)R 9 , aryl, heteroaryl or C 1 -C 6  alkyl (optionally substituted by one or more halogen atoms, aryl or heteroaryl); 
 each of R 9 R 10 , R 12 , R 14  and R 15  independently represents a hydrogen atom, C 3-8 cycloalkyl, C 1 -C 6  alkyl, an aryl or a heteroaryl group (all of which may be optionally substituted by one or more halogen atoms); and 
 R 16  is hydrogen, C 1-4  allyl, —COC 1 -C 4  alkyl, COYC 1 -C 4 alkyl where Y is O, S(O) n R 13  (where n=0, 1 or 2) or NR 7 . 
 Provided that:
 One or more of the substituents on R 3  must be aryl, heteroaryl or C 1-6 alkyl (the latter group being substituted by aryl or heteroaryl); 
 When R 3  is biphenyl X must be O or S; 
 When R 3  is aryl substituted by C 1-6 alkyl X must be O or S; 
 R 3  cannot be 4-phenyl-1,3-thiazol-2-yl. 
 
 
     
     
         2 . A compound according to  claim 1  where X is S(O) n  where n is 0, 1 or 2. 
     
     
         3 . A compound according to  claim 1  where X is S. 
     
     
         4 . A compound according to  claims 1  to  3  where R 1  is halogen. 
     
     
         5 . A compound according to  claims 1  to  3  where R 1  is NHCOR 6 . 
     
     
         6 . A compound according to  claims 1  to  5  where R 2  is C 1-7 alkyl. 
     
     
         7 . A compound according to  claims 1  to  5  where R 2  is methyl. 
     
     
         8 . A compound according to  claims 1  to  7  where R 3  is phenyl optionally substituted by one or more substituents independently selected from hydrogen, halogen, CN, nitro, S(O) n R 4 , OH, OR 4 , OS(O) n R 4 , S(O) n R 4 , SO 2 NR 5 R 6 , CONR 5 R 6 , NR 5 R 6 , NR 4 SO 2 R 5 , NR 4 CO 2 R 6 , NR 4 COR 6 , NR 4 SO 2 NR 5 R 6 , NHSO 2 R 5 , NHCO 2 R 6 , NHCOR 6 , NHCONR 4 , NHSO 2 NR 5 R 6 , aryl, heteroaryl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8 cycloalkyl or C 1-6  alkyl, the latter four groups being optionally substituted by one or more substituents independently selected from halogen atoms, aryl, heteroaryl, OR 8 , NR 5 R 6  or S(O) n R 7  where n=0, 1 or 2. 
     
     
         9 . A compound according to  claim 1  selected from:
 [3-(Biphenyl-4-ylsulfanyl)-5-fluoro-2-methyl-indol-1-yl]-acetic acid;   [5-Fluoro-2-methyl-3-(4-oxazol-5-yl-phenylsulfanyl)-indol-1-yl]acetic acid;   [4-Acetylamino-3-(biphenyl-4-ylsulfanyl)-2-methyl-indol-1-yl]-acetic acid;   [4-Acetylamino-2-methyl-3-(4-oxazol-5-yl-phenylsulfanyl)-indol-1-yl]-acetic acid and pharmaceutically acceptable salts thereof.   
     
     
         10 . A compound of formula (I) according to any one of  claims 1  to  9  for use in therapy. 
     
     
         11 . A method of treating a disease mediated by prostaglandin D2, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt as defined in  claims 1  to  9 . 
     
     
         12 . A method of treating a respiratory disease, such as asthma and rhinitis, in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined in  claims 1  to  9 .