Imidazopyridine derivatives as modulators of TNF activity
A series of substituted 3H imidazo[4,5-b]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 (IIB) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof:
wherein
V represents C—R 22 or N;
R 12 represents hydrogen, fluoro, chloro, trifluoro-methyl, methyl or ethoxycarbonylethyl;
R 15 represents hydrogen, halogen, C 1-6 alkyl or difluoromethoxy;
R 16 represents hydrogen, halogen or C 1-6 alkyl;
R 21 represents hydroxy(C 1-6 )alkyl or (C 1-6 )alkyl-sulphoximinyl; or R 21 represents (C 3-7 )cycloalkyl, which group may be optionally substituted by one, two or three substituents independently selected from C 1-6 alkyl and hydroxy;
R 22 represents hydrogen, halogen or C 1-6 alkyl;
R 23 represents hydrogen, C 1-6 alkyl, trifluoromethyl or C 1-6 alkoxy;
E represents —CH 2 —or —CH(CH 3 )—;
Q represents —CH 2 —, —CH(OH)— or —CH 2 O—;
Z represents hydrogen, methyl, phenyl, amino-carbonylphenyl or aminocarbonylpyridinyl.
2. The compound as claimed in claim 1 wherein R 21 represents hydroxy(C 1-6 )alkyl.
3. The compound as claimed in claim 1 represented by formula (IIF), (IIG), (IIH), or (IIJ), or an N-oxide thereof, or a pharmaceutically acceptable salt thereof:
wherein
W represents C(R 32 )(R 33 );
R 32 represents hydroxy;
R 33 represents hydrogen or C 1-6 alkyl;
R 34 represents hydrogen or hydroxy.
4. A compound as claimed in claim 1 wherein R 15 represents difluoromethoxy.
5. A compound that is
2-(5-{3-[2-(Difluoromethoxy)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl}-pyrimidin-2-yl)propan-2-ol,
2-(5-{3-[2-Bromo-6-(difluoromethoxy)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl}pyrimidin-2-yl)propan-2-ol,
2-(5-{3-[2-(Difluoromethoxy)-6-fluorobenzyl]-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl}pyrimidin-2-yl)propan-2-ol,
cis-1-(5-{3-[2-(Difluoromethoxy)-6-fluorobenzyl]-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl}pyrimidin-2-yl)-3-methylcyclobutane-1,3-diol, or
3-[2-(Difluoromethoxy)-6-fluorobenzyl]-2-methyl-5-{6-[S-(methyl)sulfonimidoyl]-pyridin-3 -yl}-3H-imidazo[4, 5-b]pyridine.
6. A pharmaceutical composition comprising a compound of formula(IIB) as defined in claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
7. The pharmaceutical composition as claimed in claim 6 further comprising an additional pharmaceutically active ingredient.
8. A method of inhibiting TNFα in a subject comprising administering to said subject an effective amount of compound of formula (IIB) as defined in claim 1 or N-oxide thereof, or a pharmaceutically acceptable salt thereof.