Imidazopyrimidine derivatives as modulators of TNF activity
A series of substituted imidazo[1,2-a]pyrimidine 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 21 represents hydroxy(C 1-6 )alkyl; or R 21 represents (C 3-7 )heterocycloalkyl, which group may be optionally substitututed by one, two or three substituents independently selected from C 1-6 alkylsulphonyl, oxo and carboxy;
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 ;
Q represents —CH 2 ;
Z represents hydrogen or methyl;
R 12 represents hydrogen, fluoro, chloro, trifluoro-methyl, methyl or ethoxycarbonylethyl;
R 15 represents difluoromethoxy; and
R 16 represents hydrogen or halogen.
2. The compound as claimed in claim 1 represented by formula (IIC) or (IIE), or an N-oxide thereof or a pharmaceutically acceptable salt thereof:
wherein
T represents —CH 2 — or —CH 2 CH 2 —;
U represents C(O) or S(O) 2 ;
W represents O, N(R 31 ) or C(R 32 )(R 33 );
R 31 represents C 1-6 alkylsulphonyl;
R 32 represents carboxy; and
R 33 represents hydrogen.
3. A compound that is
4-[5 -(3-{[2-(Difluoromethoxy)phenyl]methyl}-2-methylimidazo[1,2-a]pyrimidin-6-yl)-pyrimidin-2-yl]morpholine,
1-[5-(3-{[2-(Difluoromethoxy)phenyl]methyl}-2-methylimidazo[1,2-a]pyrimidin-6-yl)-pyrimidin-2-yl]piperidine-4-carboxylic acid,
4-[5-(3-{[2-(Difluoromethoxy)phenyl]methyl}-2-methylimidazo[1,2-a]pyrimidin-6-yl)-pyrimidin-2-yl]piperazin-2-one, or
3-{[2-(Difluoromethoxy)phenyl]methyl}-2-methyl-6-{2-[4-(methylsulfonyl)piperazin-1-yl]pyrimidin-5-yl}imidazo[1,2-a]pyrimidine.
4. 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.
5. The pharmaceutical composition as claimed in claim 4 further comprising an additional pharmaceutically active ingredient.
6. 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 an N-oxide thereof, or a pharmaceutically acceptable salt thereof.