Indole-3-Sulphur Derivatives

Abstract

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

1 . A compound of formula (I) or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
       in which: 
       n represents 1 or 2; 
       R 1  is one or more substituents independently selected from halogen, CN, nitro, SO 2 R 4 , OR 4 , SR 4 , SOR 4 , SO 2 NR 5 R 6 , CONR 5 R 6 , NR 5 R 6 , NR 9 SO 2 R 4 , NR 9 CO 2 R 4 , NR 9 COR 4 , aryl, heteroaryl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl or C 1-6 alkyl, the latter five groups being optionally substituted by one or more substituents independently selected from halogen, OR 7  and NR 8 R 9 , NR 8 R 9 , S(O) x R 7  where x is 0, 1 or 2; 
       R 2  is hydrogen, halogen, CN, SO 2 R 4  or CONR 5 R 6 , COR 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 a 5-7 membered aromatic ring containing one or more heteroatoms selected from N, S and O, each of which is optionally substituted by one or more substituents independently selected from halogen, CN, nitro, SO 2 R 4 , OH, OR 4 , SR 4 , SOR 4 , SO 2 NR 5 R 6 , CONR 5 R 6 , NR 5 R 6 , NR 9 SO 2 R 4 , NR 9 CO 2 R 4 , NR 9 COR 4 , C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  alkyl, the latter three groups being optionally substituted by one or more substituents independently selected from halogen atoms, OR' and NR 8 R 9 , S(O) x R 7  where x is 0, 1 or 2; 
       R 4  represents aryl, heteroaryl, or C 1 -C 6  alkyl, all of which may be optionally substituted by one or more substituents independently selected from halogen atoms, aryl, heteroaryl, OR 10  and NR 11 R 12 S(O) x R 13  (where x=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 -C 6  alkyl group, 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 13  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; 
       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 the ring itself optionally substituted by C 1 -C 3  alkyl; 
       R 7  and R 13  independently represent a C 1 -C 6  alkyl group, an aryl or 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, aryl or heteraryl groups, both of which may also be optionally substituted by one or more fluorine atoms); an aryl or a heteroaryl group, which may be optionally substituted by one or more halogen atoms; 
       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 one or more halogen atoms); and 
       R 16  is hydrogen, C 1-4  alkyl, —C(O)C 1 -C 4  alkyl, C(O)YC 1 -C 4 alkyl, Y is O or NR 7 . 
       or a pharmaceutically acceptable salt or solvate thereof. 
     
   
   
       2 . A compound according to  claim 1  in which n is 2. 
   
   
       3 . A compound according to  claim 1  in which R 1  is halogen, nitrile, C 1-6 alkyl or SO 2 R 4 , NO 2 , NR 9 COR 4 , NR 9 SO 2 R 4 , aryl, NR 5 R 6 . 
   
   
       4 . A compound according to  claim 1  in which the substituent(s) is/are in the 4- and/or 5-position. 
   
   
       5 . A compound according to  claim 1  in which R 2  is C 1-6 alkyl. 
   
   
       6 . A compound according to  claim 4  in which R 3  is phenyl substituted by halogen. 
   
   
       7 . A compound according to  claim 1  selected from:
 3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid;   5-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic acid;   6-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic acid;   7-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic acid;   5-chloro-3-[(4-chlorophenyl)sulfonyl]-4-cyano-2-methyl-1H-indole-1-acetic acid;   5-chloro-3-[(4-chlorophenyl)sulfonyl]-6-cyano-2-methyl-1H-indole-1-acetic acid;   3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-acetic acid;   3-[(4-chlorophenyl)sulfonyl]-4-(ethylsulfonyl)-7-methoxy-2-methyl-1H-indole-1-acetic acid;   3-[(4-chlorophenyl)sulfonyl]-5-cyano-2-methyl-1H-indole-1-acetic acid;   3-[(4-chlorophenyl)sulfonyl]-5-cyano-2-methyl-1H-indole-1-acetic acid;   5-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic acid,   4-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic acid;   3-[(4-methoxyphenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid;   3-[(3-methoxyphenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid;   3-[(2-Chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid;   3-[(3-Chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid;   3-[(4-Cyanophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-acetic acid;   3-[(2-methylphenyl)sulfonyl]-2,5-Dimethyl-1H-indol-1-acetic acid;   3-[(2-ethylphenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid;   3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-nitro-1H-indole-1-acetic acid;   4-(Acetylamino)-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic acid;   3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-acetic acid;   3-[(4-chlorophenyl)sulfonyl]-4-(ethylamino)-2-methyl-1H-indole-1-acetic acid;   3-[(2,6-Dichlorophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-acetic acid;   3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-phenyl-1H-indole-1-acetic acid   3-[(4-chlorophenyl)sulfonyl]-5-fluoro-2-methyl-1H-indole-1-acetic acid,   3-[(3-chlorophenyl)sulfonyl]-5-fluoro-2-methyl-1H-indole-1-acetic acid,   5-fluoro-2-methyl-3-[[4-(trifluoromethyl)phenyl]sulfonyl]-1H-indole-1-acetic acid,   
     and pharmaceutically acceptable salts thereof. 
   
   
       8 . (canceled) 
   
   
       9 . 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  claim 1 . 
   
   
       10 . A method according to  claim 9  where the disease is asthma or rhinitis. 
   
   
       11 . Use of a compound of a compound of formula (I), or a pharmaceutically acceptable salt as defined in  claim 1 , in the manufacture of a medicament for treating a disease mediated by prostaglandin D2. 
   
   
       12 - 13 . (canceled) 
   
   
       14 . A process for the preparation of a compound of formula (I) of  claim 1  which comprises reaction of a compound of formula (II):
 (a) oxidation of a compound of formula (II):   
     
       
         
         
             
             
         
       
     
     in which R 17  is hydrogen or alkyl and R 1 , R 2  and R 3  are as defined in  claim 1  or are protected derivatives thereof, or
 (b) reaction of a compound of formula (III): 
 
     
       
         
         
             
             
         
       
     
     in which R 1 , R 2  and R 3  are as defined in  claim 1  or are protected derivatives thereof, with a compound of formula (IV):
   R 18 —O(CO)CH 2 -L  (IV) 
 
     where R 18  is an alkyl group and L is a leaving group in the presence of a base, and optionally thereafter (a) or (b) in any order:
 hydrolysing the ester group R 17  or R 18  to the corresponding acid 
 removing any protecting group 
 forming a pharmaceutically acceptable salt.