Substituted tetrahydrocarbazole and cyclopentanoindole derivatives
View Patent ↗The present invention provides substituted tetrahydrocarbazole and cyclopentanoindole derivatives as antagonists of DP receptor, and as such are useful for the treatment of prostaglandin D2 mediated diseases such as rhinitis, asthma and nasal congestion.
1. A compound of the formula I:
and pharmaceutically acceptable salts thereof, wherein n is 0 or 1; R 1 is hydrogen or halogen; R 2 is halogen, cyano, C 1-3 alkylsulfonyl or trifluoromethyl; and R 3 is C 1-3 alkyl optionally substituted with 1–5 halogen atoms; and R 4a and R 4b are each hydrogen or one is hydrogen and the other is hydroxy, or both together represent oxo; with the proviso that when R 1 is hydrogen, R 2 is not 4-chloro.
2. A compound of claim 1 wherein R 4a and R 4b are each hydrogen.
3. A compound of claim 1 wherein R 1 is hydrogen and R 2 is CF 3 .
4. A compound of claim 1 wherein R 3 is CH 3 .
5. A compound of claim 1 wherein R 1 and R 2 are independently a halogen atom.
6. A compound of claim 1 wherein n is 1.
7. A compound of claim 1 wherein n is 1, R 3 is CH 3 , and R 4a and R 4b are each hydrogen.
8. A compound of claim 7 wherein R 1 is hydrogen and R 2 is CF 3 .
9. A compound of claim 1 selected from:
((1R)-6-fluoro-8-(methylsulfonyl)-9-{(1S)-1-[4-(trifluoromethyl)phenyl]ethyl}-2,3,4,9-tetrahydro-1H-carbazol-1-yl)acetic acid;
[(1R)-9-[(1S)-1-(3,4-dichlorophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetic acid;
{(1R)-6-fluoro-8-(methylsulfonyl)-9-[(1S)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-1-yl}acid;
[(1R)-6-fluoro-9-[(1S)-1-(4-fluorophenyl)ethyl]-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetic acid;
[(1R)-9-[(1S)-1(4-chloro-3-fluorophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetic acid;
[(1R)-9-[(1S)-1-(3-chlorophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetic acid;
[(1R)-9-[(1S)-1-(4-chloro-2-fluorophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetic acid;
[(1R)-9-[(1S)-1-(4-bromophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetic acid;
[(1R)-9-[(1S)-1-(4-cyanophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetic acid; and
((1R)-6-fluoro-8-(methylsulfonyl)-9-{(1S)-1-[4-(methylsulfonyl)phenyl]ethyl}-2,3,4,9-tetrahydro-1H-carbazol-1-yl)acetic acid; and
pharmaceutically acceptable salts therof.
10. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
11. A method for the treatment rhinitis, asthma, or nasal congestion which comprises administering to a patient a therapeutically effective amount of a compound of claim 1 .