Tetrahydrobenzimidazole derivatives as modulators of TNF activity
A series of substituted 4,5,6,7-tetrahydrobenzimidazole derivatives, being potent modulators of human TNFα activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.
1. A compound represented by formula (IIA) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a glucuronide derivative thereof:
wherein
E represents —CH 2 —;
Q represents —CH 2 — or —CH(OH)—;
Z represents hydrogen, methyl, phenyl, methylsulfonylphenyl, pyridinyl, methyl sulfonylpyridinyl, oxopyrrolidinylphenyl, (hydroxy)(oxo)pyrrolidinylphenyl or (oxo)oxazolidinylphenyl;
R 11 represents hydrogen or halogen;
R 12 represents hydrogen, fluoro, chloro, trifluoro-methyl, methyl or ethoxycarbonylethyl;
R 15 represents hydrogen, halogen, C 1-6 alkyl, trifluoro-methyl, C 1-6 alkoxy, difluoromethoxy or trifluoromethoxy; and
R 16 represents hydrogen, halogen, cyano, C 1-6 alkyl, trifluoromethyl, difluoromethoxy or amino.
2. A compound that is {1-[(2,5-Dimethylphenyl)methyl]-4,5,6,7-tetrahydrobenzimidazol-2-yl}(pyridin-4-yl)methanol.
3. A pharmaceutical composition comprising a compound of formula (IIA) as defined in claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a glucuronide derivative thereof, in association with a pharmaceutically acceptable carrier.
4. The pharmaceutical composition as claimed in claim 3 further comprising an additional pharmaceutically active ingredient.
5. A method for the treatment of Crohn's disease or rheumatoid arthritis, which method comprises administering to a patient in need of such treatment an effective amount of a compound of formula (IIA) as defined in claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a glucuronide derivative thereof.