Novel Compounds

Abstract

The present invention relates to substituted indoles useful as pharmaceutical compounds for treating respiratory disorders.

1 . A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
       
       in which:
 R 1  is one or more substituents independently selected from 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 , or heteroaryl, the latter which may be optionally substituted by halogen, CN, OR 7 , C 1-3  alkyl (which may be optionally substituted by halogen atoms); 
 R 2  is hydrogen, halogen, CN, SO 2 R 4  or CONR 5 R 6 , CH 2 OH, CH 2 OR 4  or C 1-7 alkyl, the latter group being optionally substituted by one or more substituents independently selected from halogen atoms, OR 8  and NR 5 R 6 , S(O) x R 7  where x 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, OH, SO 2 R 4 , OR 4 , SR 4 , SOR 4 , SO 2 NR 5 R 6 , CONR 5 R 6 , NR 5 R 6 , NHSO 2 R 4 , NHCOR 4 , NHCO 2 R 4 , NR 7 SO 2 R 4 , NR 7 CO 2 R 4 , NR 7 COR 4 , C 2 -C 6  alkenyl, C z —C 6  alkynyl, C 1-6  alkyl, the latter three groups being optionally substituted by one or more substituents independently selected from halogen atoms, OR 8  and NR 5 R 6 , S(O) x R 7  where x is 0, 1 or 2; 
 R 4  represents aryl, heteroaryl, or C 1-6 alkyl all of which may be optionally substituted by one or more substituents independently selected from halogen atoms, aryl, heteroaryl, OR 10 , OH, NR 11 R 12 , S(O) x R 13  (where x is 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, nitro; 
 R 5  and R 6  independently represent a hydrogen atom, a C 1-6 alkyl group, or an aryl, or a heteroaryl, the latter three of which may be optionally substituted by one or more substituents independently selected from halogen atoms, aryl, OR 8  and NR 14 R 15 , CONR 14 R 15 , NR 14 COR 15 , SO 2 NR 14 R 15 , NR 14 SO 2 R 15 ; CN, nitro, C 1-3  alkyl (which may be optionally substituted by halogen atoms; 
 
       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) x  where x is 0, 1 or 2, NR 16 , and itself optionally substituted by C 1-3  alkyl; 
 R 7  and R 13  independently represent a C 1 -C 6 , alkyl, an aryl or a heteroaryl group, all of which may be optionally substituted by halogen atoms; 
 R 8  represents a hydrogen atom, C(O)R 9 , C 1 -C 6  alkyl (optionally substituted by halogen atoms or aryl) an aryl or a heteroaryl group (optionally substituted by halogen); 
 each of R 9 R 10 , R 11 , R 12 , R 14 , R 15 , independently represents a hydrogen atom, C 1 -C 6  alkyl, an aryl or a heteroaryl group (all of which may be optionally substituted by halogen atoms); and 
 R 16  is hydrogen, C 1-4  alkyl, COC 1 -C 4  alkyl or COYC 1 -C 4 alkyl where Y is O or NR 7 . 
 
     
     
         2 . A compound according to  claim 1  in which R 1  is NHSO 2 R 4  or NH(CO)R 4  or heteroaryl (the latter being optionally substituted by a C 1-3  alkyl group). 
     
     
         3 . A compound according to  claim 1  or  2  in which R 2  is C 1-6 alkyl. 
     
     
         4 . A compound according to  claim 3  in which R 3  is phenyl optionally substituted with halogen or methyl sulfone. 
     
     
         5 . A compound according to  claim 1  selected from:
 4-(acetylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid; 
 3-[(4-chlorophenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-acetic acid; 
 3-[(4-chlorophenyl)thio]-2-methyl-4-(5-pyrimidinyl)-1H-indole-1-acetic acid; 
 3-[(4-chlorophenyl)thio]-2-methyl-4-pyrazinyl-1H-indole-1-acetic acid; 
 3-[(2-chlorophenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-acetic acid; 
 3-[(3-chlorophenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-acetic acid; 
 3-[(4-chlorophenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-acetic acid; 
 3-[(3-methoxyphenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-acetic acid; 
 3-[(4-methoxyphenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-acetic acid; 
 3-[(2-trifluoromethylphenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-acetic acid; 
 3-[(8-Quinolinyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-acetic acid; 
 3-[(2-(methylethyl)phenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-acetic acid; 
 5-(acetylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid; 
 4-(acetylethylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid; 
 3-[(4-chlorophenyl)thio]-4-[cyclopropylcarbonyl)amino]-2-methyl-1H-indole-1-acetic acid; 
 4-(benzoylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid; 
 4-(acetylamino)-3-[(3-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid; 
 3-[(4-chlorophenyl)thio]-4-[[(dimethylamino)sulfonyl]amino]-2-methyl-1H-indole-1-acetic acid; 
 3-[(4-chlorophenyl)thio]-2-methyl-4-[[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino]-1H-indole-1-acetic acid; 
 3-[(4-chlorophenyl)thio]-4-[[(dimethylamino)acetyl]amino]-2-methyl-1H-indole-1-acetic acid; 
 4-(acetylamino)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-acetic acid; 
 4-(acetylamino)-3-[(2-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid; 
 4-(acetylamino)-2-methyl-3-[[4-(ethylsulfonyl)phenyl]thio]-1H-indole-1-acetic acid; 
 3-[(4-chlorophenyl)thio]-4-[[(ethylamino) carbonyl]amino]-2-methyl-1H-indole-1-acetic acid; 
 3-[[4-(methylsulfonyl)phenyl]thio]-4-(5-pyrimidinyl)-1H-indole-1-acetic acid 
 2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-4-(2-thiophenyl)-1H-indole-1-acetic acid 
 4-(3,5-dimethyl-4-isoxazolyl)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-acetic acid 
 4-(3-furanyl)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-acetic acid 
 2-methyl-4-[(methylsulfonyl)amino]-3-[[(4-(methylsulfonyl)phenyl]thio]-1H-indole-1-acetic acid 
 2-methyl-5-[(methylsulfonyl)amino]-3-[[3-(methylsulfonyl)phenyl]thio]-1H-indole-1-acetic acid 
 2-methyl-5-[(methylsulfonyl)amino]-3-[[2-(methylsulfonyl)phenyl]thio]-1H-indole-1-acetic acid 
 2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(5-pyrimidinyl)-1H-indole-1-acetic acid 
 2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(3-thiophenyl)-1H-indole-1-acetic acid 
 5-(3,5-dimethyl-4-isoxazolyl)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-acetic acid 
 2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(3-pyridinyl)-1H-indole-1-acetic acid 
 2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(1H-pyrazol-4-yl)-1H-indole-1-acetic acid 
 4-(acetylamino)-3-[(4-cyanophenyl)thio]-2-methyl-1H-indole-1-acetic acid 
 
       and pharmaceutically acceptable salts and solvates thereof. 
     
     
         6 . A compound of formula (I) according to any one of  claims 1  to  5  for use in therapy. 
     
     
         7 . 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  5 . 
     
     
         8 . A method of treatment according to  claim 7  wherein the disease is asthma or rhinitis. 
     
     
         9 . The use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in the treatment of a disease mediated by CRTh2. 
     
     
         10 . Use according to  claim 9  where the disease is asthma. 
     
     
         11 . A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof which comprises reaction of a compound of formula (II): 
       
         
           
           
               
               
           
         
       
       in which R 1 , R 2  and R 3  are as defined in formula (I) or are protected derivatives thereof, with a compound of formula (IIA):
   L-CH 2 CO 2 R 17   (IIA)
 
 
       where R 17  is an alkyl group and L is a leaving group such as a halogen atom, in the presence of a base, and optionally thereafter in any order:
 removing any protecting group 
 hydrolysing the ester group R 17  to the corresponding acid 
 forming a pharmaceutically acceptable salt or solvate. 
 
     
     
         12 . A compound of formula (II) as defined in  claim 11 .