| abstract |
This invention relates to compounds of general formula (I) :n nwherein n R 1 and R 3 may be the same or different and each independently represents a group -L 1 -R 5 [where L 1 is a direct bond, a straight or branched C 1-6 alkylene chain, a straight or branched C 2-6 alkenylene chain, a straight or branched C 2-6 alkynylene chain or a straight or branched C 1-6 alkylene chain containing an oxygen or sulfur atom, a phenylene, imino (-NH-) or alkylimino linkage, or a sulfinyl or sulfonyl group, in which each of the alkylene, alkenylene and alkynylene chains may be optionally substituted, the substituents chosen from alkoxy, aryl, carboxy, cyano, cycloalkyl, halogen, heteroaryl, hydroxyl, or oxo; and R 5 represents hydrogen, aryl, aroyl, carboxy or an acid bioisostere, cyano, cycloalkyl, cycloalkenyl, heterocycloalkyl, heteroaryl, arylalkoxycarbonyl, -NH-C(=O)-NH 2 , -C=N-O-C(=O)-NH 2 , -C(=O)-NY 1 Y 2 , -NY 1 SO 2 aryl, -NHR 6 , -SR 6 , or -OR 6 ]; n R 2 and R 4 may be the same or different and are each independently hydrogen or alkyl; or n R 2 and R 4 together form a bond; or R 1 and R 2 , or R 1 and R 3 , or R 3 and R 4 together with the carbon atom(s) to which they are attached form a 3 to 8 membered cycloalkyl or cycloalkenyl ring, optionally substituted by alkyl, arylalkyl, or heteroarylalkyl, and which may optionally contain a heteroatom selected from O, S or NR 6 ; or R 1 and R 3 together with the carbon atoms to which they are attached form a heteroaryl ring; n Y represents tetrazolyl, 3,5-dioxo-1,2,4-oxadiazolidinyl, 3-hydroxyisoxazolyl or 3-hydroxy-1-methylpyrazolyl; n A 1 represents a direct bond, a straight or branched C 1-4 alkylene chain or a NR 6 group; n Ar is a group chosen from :n nandn nand n n is 0, 1 or 2; n and N-oxides thereof, and their prodrugs, pharmaceutically acceptable salts, and solvates (e.g. hydrates), thereof. n Such compounds inhibit the production or physiological effects of TNF and inhibit cyclic AMP phosphodiesterase. The invention is also directed to pharmaceutical compositions comprising compounds of formula (I), their pharmaceutical use and methods for their preparation. |