Tetrahydroimidazopyridine derivatives as modulators of TNF activity
A series of substituted 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine derivatives of formula (I), being potent modulators of human TNFa 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:
wherein
E represents —CH 2 —;
Q represents —CH 2 —, —CH 2 O— or —CH 2 OCH 2 —;
Z represents hydrogen or methyl;
R 1 represents —SO 2 R a , —COR d or —CO 2 R d ; or R 1 represents C 1-6 alkyl, which group may be optionally substituted by one or more substituents independently selected from halogen and C 2-6 alkoxycarbonyl;
R a represents C 1-6 alkyl;
R d represents trifluoromethyl or C 1-6 alkyl;
R 12 represents hydrogen or halogen;
R 15 represents halogen or difluoromethoxy; and
R 16 represents hydrogen or halogen.
2. A compound that is
1-{3-[(2,5-Dichlorophenyl)methyl]-2-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl}ethanone,
Methyl 3-[(2,5-dichlorophenyl)methyl]-2-methyl-6,7-dihydro-4H-imidazo[4,5-c]-pyridine-5-carboxylate,
Ethyl 3-{3-[(2,5-dichlorophenyl)methyl]-2-methyl-6,7-dihydro-4H-imidazo[4,5-c]-pyridin-5-yl}propanoate,
3-[(2,5-Dichlorophenyl)methyl]-2-methyl-5-(2,2,2-trifluoroethyl)-6,7-dihydro-4H-imidazo[4,5-c]pyridine,
1-{3-[(2,5-Dichlorophenyl)methyl]-2-(methoxymethyl)-6,7-dihydro-4H-imidazo[4,5-c]-pyridin-5-yl}ethanone,
3-[(2,5-Dichlorophenyl)methyl]-2-(methoxymethyl)-5-(methylsulfonyl)-6,7-dihydro-4H-imidazo[4,5-c]pyridine,
Methyl 3-[(2,5-dichlorophenyl)methyl]-2-(methoxymethyl)-6,7-dihydro-4H-imidazo[4,5-c]pyridine-5-carboxylate,
1-{3-[(2,5-Dichlorophenyl)methyl]-2-(methoxymethyl)-6,7-dihydro-4H-imidazo[4,5-c]-pyridin-5-yl}-2,2,2-trifluoroethanone, or
Ethyl 3-{3-[(2,5-dichlorophenyl)methyl]-2-(methoxymethyl)-6,7-dihydro-4H-imidazo-[4, 5-c]pyridin-5-yl}propanoate.
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, 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 disorders for which the administration of a modulator of TNFα function is indicated which 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, wherein the disorder is an inflammatory or autoimmune disorder.