Tetrahydroimidazopyridine derivatives as modulators of TNF activity
A series of substituted 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine derivatives, being potent 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 or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof:
wherein
R 11 represents hydrogen; and
R 15 represents hydrogen or difluoromethoxy
R 16 represents hydrogen or halogen;
E represents —CH 2 —;
Q represents —CH 2 — or —CH 2 O—;
Z represents hydrogen; or Z represents C 1-6 alkyl, aryl or heteroaryl, either of which groups may be optionally substituted by one, two or three substituents independently selected from halogen, cyano, nitro, C 1-6 alkyl, trifluoro-methyl, oxo, hydroxy, hydroxy(C 1-6 )alkyl, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C 1-3 alkylenedioxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, di(C 1-6 )alkylamino-(C 1-6 )alkyl, C 2-6 alkylcarbonylamino, C 1-6 alkylsulfonyl-amino, formyl, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, aminosulfonyl, C 1-6 alkyl-aminosulfonyl, di(C 1-6 )alkylaminosulfonyl, amino-carbonylamino and hydrazinocarbonyl;
R 3 represents —CONR b R c ; or R 3 represents heteroaryl, which group may be optionally substituted by one or two substituents independently selected from di(C 1-6 )alkyl-amino; and
R b and R c , when taken together with the nitrogen atom to which they are both attached, represent azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl or homopiperazin-1-yl.
2. The compound as claimed in claim 1 wherein R 15 represents difluoromethoxy.
3. A compound that is
4-{1-[(2,5-Dichlorophenyl)methyl]-2-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl}-N,N-dimethylpyridin-2-amine, or
{1-[(2,5-Dichlorophenyl)methyl]-2-(pyridin-3-yloxymethyl)-6,7-dihydro-4H-imidazo-[4,5-c]pyridin-5-yl}(morpholin-4-yl)methanone.
4. A pharmaceutical composition comprising a compound of formula (IIA) as defined in claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof, in association with a pharmaceutically acceptable carrier.
5. The pharmaceutical composition as claimed in claim 4 further comprising an additional pharmaceutically active ingredient.