Imidazole derivatives and their use as cytokine inhibitors

Details Imidazole derivatives and their use as cytokine inhibitors Imidazole derivatives and their use as cytokine inhibitors

1994-11-30

1997-11-11

Higel, Floyd D.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514341, 514397, 514398, 514399, 514400, 514401, 514307, 514394, 514256, 5142358, 514314, 546278, 546167, 546144, 5483134, 5483061, 544333, 544124, A61K 3144, A61K 3147, A61K 31435, A61K 31505, C07D40104, C07D40304

Patent

active

056864558

DESCRIPTION:

BRIEF SUMMARY
This invention relates to a novel group of imidazole compounds, processes for the preparation thereof, the use thereof in treating cytokine mediated diseases and pharmaceutical compositions for use in such therapy.


BACKGROUND OF THE INVENTION

There has been much interest in the past few years in compounds which are cytokine-inhibitors, for use in treating disease states which are associated with the excessive or unregulated production of cytokines. Compounds of the general formula (A): ##STR1## wherein R.sub.a is pyridyl, R.sub.b is optionally substituted phenyl and W is a partially or fully unsaturated fused 5- or 6-membered heterocyclic ring, such as pyrrolyl, pyridyl, dihydropyrrolyl, dihydropyridinyl, dihydrothiazolyl or tetrahydro-triazinyl, are inhibitors of the cytokines IL-1 and TNF (see WO88/01169, WO90/15534, WO91/00092, WO92/10190, WO92/10498 and WO92/12154, published after the filing of this application). In addition, these compounds are also inhibitors of the enzyme 5-lipoxygenase. We have now surprisingly found that if the ring W is replaced by certain substituents at the 2-position, cytokine-inhibitory activity is maintained. Such compounds are generically 2-substituted-4-aryl-5-heteroaryl-imidazoles. Compounds within this class have already been extensively investigated, as anti-inflammatory agents, acting principally as cyclo-oxygenase inhibitors, as described in, for instance, U.S. Pat. Nos. 3,707,405 and 3,929,807. The latter discloses compounds of the general formula (B): ##STR2## wherein one of R.sub.a and R.sub.b is optionally substituted phenyl and the other is a 6-membered heterocyclic ring with 1 or 2 nitrogen atoms and R.sub.c represents lower alkyl, cycloalkyl or phenyl optionally substituted by halogen, lower alkyl or lower alkoxy, in particular the compound 2-(4-chlorophenyl)-4-(4-methoxyphenyl)-5-(4-pyridyl)-imidazole. These compounds are said to have anti-inflammatory, analgesic and antipyretic activity. There is however no mention that these compounds may be cytokine inhibitors.


FULL DESCRIPTION OF THE INVENTION

Accordingly, the present invention provides a compound of formula (I): ##STR3## wherein: R.sub.1 is 4-pyridyl, pyrimidinyl, quinolyl, isoquinolinyl, 1-imidazolyl or 1-benzimidazolyl which is optionally substituted with one or two substituents each of which is independently selected from C.sub.1-4 alkyl, halo, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, NH.sub.2, mono- or di-C.sub.1-6 -alkylamino or N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR.sub.22 ; optionally substituted by C.sub.1-4 alkyl and optionally interrupted by --NR.sub.8 --, --O-- or --S--; halo-substituted C.sub.1-5 alkyl, halogen, --X.sub.a --P(Z)--(X.sub.b R.sub.13).sub.2 or --(CR.sub.10 R.sub.20).sub.n Y.sub.2 ; --S(O).sub.m NR.sub.8, --NR.sub.8 R.sub.9, --O(CR.sub.10 R.sub.20).sub.n NR.sub.8 R.sub.9, --C(O)R.sub.8, --CO.sub.2 R.sub.8, --CO.sub.2 (CR.sub.10 R.sub.20).sub.n 'CONR.sub.8 R.sub.9, --ZC(O)R.sub.8, --CN, --C(Z)NR.sub.8 R.sub.9, --NR.sub.10 C(Z)R.sub.8, --C(Z)NR.sub.8 OR.sub.9, --NR.sub.10 C(Z)NR.sub.8 R.sub.9, --NR.sub.10 S(O).sub.m R.sub.11, --N(OR.sub.21)C(Z)NR.sub.8 R.sub.9, --N(OR.sub.21)C (Z)R.sub.8, --C(.dbd.NOR.sub.21)R.sub.8, --NR.sub.10 C(.dbd.NR.sub.15)SR.sub.11, --NR.sub.10 C(.dbd.NR.sub.15)NR.sub.8 R.sub.9, --NR.sub.10 C(.dbd.CR.sub.14 R.sub.24)SR.sub.11, --NR.sub.10 C(.dbd.CR.sub.14 R.sub.24)NR.sub.8 R.sub.9, --NR.sub.10 C(O)C(O)NR.sub.8 R.sub.9, --NR.sub.10 C(O)C(O)OR.sub.10, --C(.dbd.NR.sub.13)NR.sub.8 R.sub.9, --C(.dbd.NOR.sub.13)NR.sub.8 R.sub.9, --C(.dbd.NR.sub.13)ZR.sub.11, --OC(Z)NR.sub.8 R.sub.9, --NR.sub.10 S(O).sub.m CF.sub.3 , --NR.sub.10 C(Z)OR.sub.10, 5-(R.sub.18)-1,2,4-oxadizaol-3-yl or 4-(R.sub.12)-5-(R.sub.18 R.sub.19)-4, 5-dihydro-1,2,4-oxadiazol-3-yl; substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-1-yl or 5-naphth-2-yl substituent, is halo, cyano, --C(Z)NR.sub.7 R.sub.17, --C(Z)OR.sub.23, --(CR.sub

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