Triazolopyridazine derivatives as modulators of TNF activity
A series of substituted [1,2,4]triazolo[4,3-b]pyridazine 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 or solvate thereof, or a glucuronide derivative thereof, or a co-crystal 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 is optionally substituted by one, two, or three substituents independently selected from 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 —;
R 12 represents hydrogen, fluoro, chloro, trifluoro-methyl, methyl or ethoxycarbonylethyl;
R 15 represents difluoromethoxy; and
R 16 represents hydrogen, fluoro, chloro, cyano, methyl, trifluoromethyl, difluoromethoxy or amino.
2. The compound as claimed in claim 1 represented by formula (IIC) or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof:
wherein
W represents O, or C(R 32 )(R 33 );
R 32 represents carboxy; and
R 33 represents hydrogen.
3. A compound that is
4-[5-(3-{[2-(Difluoromethoxy)phenyl]methyl}[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-pyrimidin-2-yl]morpholine; or
1-[5-(3-{[2-(Difluoromethoxy)phenyl]methyl}[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-pyrimidin-2-yl]piperidine-4-carboxylic acid.
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 or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof, in association with a pharmaceutically acceptable carrier.
5. A method for inhibiting TNFα in a patient, which comprises administering to the patient an effective amount of a compound of formula (IIB) 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.
6. A method for treating rheumatoid arthritis or Crohn's disease, which method comprises administering to a patient in need of such treatment an effective amount of a compound of formula (JIB) 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.