Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-10-02
2000-09-05
Powers, Fiona T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514513, 514602, 548477, 558254, 564 81, A61K 314035, A61K 3118, A61K 3122, C07D20948, C07D32360
Patent
active
061143723
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to a novel class of peptidyl derivatives, to processes for their preparation, and to their use in medicine.
BACKGROUND OF THE INVENTION
Metalloproteinases, including matrix metalloproteinase (MMP), (human fibroblast) collagenase, gelatinase and TNF convertase (TACE), and their modes of action, and also inhibitors thereof and their clinical effects, are described in WO-A-9611209, PCT/GB96/02438 and PCT/GB96/02892, the contents of which are incorporated herein by reference. MMP inhibitors may also be useful in the inhibition of other mammalian metalloproteinases such as the adamalysin family (or ADAMs) whose members include TNF convertase (TACE) and ADAM-10, which can cause the release of TNF.alpha. from cells, and others, which have been demonstrated to be expressed by human articular cartilage cells and also involved in the destruction of myelin basic protein, a phenomenon associated with multiple sclerosis.
Compounds which have the property of inhibiting the action of metalloproteinases involved in connective tissue breakdown, such as collagenase, stromelysin and gelatinase, have been shown to inhibit the release of TNF both in vitro and in vivo. See Gearing et al (1994), Nature 370:555-557; McGeehan et al (1994), Nature 370:558-561; GB-A-2268934; and WO-A-9320047. All of these reported inhibitors contain a hydroxamic acid zinc-binding group, as do the imidazole-substituted compounds disclosed in WO-A-9523790. Other compounds that inhibit MMP and/or TNF are described in WO-A-9513289, WO-A-9611209, WO-A-96035687, WO-A-96035711, WO-A-96035712 and WO-A-96035714.
SUMMARY OF THE INVENTION
The invention encompasses novel mercaptoalkylacyl compounds of formula (I) which are useful inhibitors of matrix metalloproteinases and/or TNF.alpha.-mediated diseases including degenerative diseases (such as defined above) and certain cancers.
Novel compounds according to the invention are of general formula (I): ##STR2## wherein: X is CH or N; alkyl-aryl, heteroaryl, C.sub.1-6 alkyl-heteroaryl, cyclo(C.sub.3-6)alkyl, C.sub.1-6 alkyl-cyclo(C.sub.3-6)alkyl, heterocyclo(C.sub.4-6)alkyl, C.sub.1-6 alkyl-heterocyclo(C.sub.4-6)alkyl, C.sub.1-6 alkyl-COR.sup.2, or C.sub.1-6 alkyl-AR.sup.3 group where A is O, NR.sup.3 or S(O).sub.n where n=0-2 and R.sup.3 is H, C.sub.1-4 alkyl, aryl, heteroaryl, C.sub.1-4 alkyl-aryl or C.sub.1-4 alkyl-heteroaryl; if A=NR.sup.3 the groups R.sup.3 may be the same or different; or different; (optionally substituted with R.sup.6), C.sub.1-4 alkyl-aryl (optionally substituted with R.sup.6), C.sub.1-4 alkyl-heteroaryl (optionally substituted with R.sup.6), C.sub.1-4 alkyl (optionally substituted with R.sup.6), cyclo(C.sub.3-6) alkyl (optionally substituted with R.sup.6), C.sub.1-4 alkyl-cyclo(C.sub.3-6)alkyl (optionally substituted with R.sup.6), heterocyclo(C.sub.4-6)alkyl (optionally substituted with R.sup.6) or C.sub.1-4 alkyl-heterocyclo(C.sub.4-6)alkyl (optionally substituted with R.sup.6); R.sup.7, COR.sup.9, SO.sub.2 N(R.sup.3).sub.2 where each R.sup.3 may be the same or different, CO.sub.2 R.sup.4, CON(R.sup.3).sub.2 where each R.sup.3 may be the same or different, amidine or guanidine; CO(NR.sup.3).sub.2 where each R.sup.3 may be the same or different; C.sub.1-4 alkyl-heteroaryl; alkyl (optionally substituted with R.sup.12), aryl (optionally substituted with R.sup.12), C.sub.1-6 alkyl-aryl (optionally substituted with R.sup.12), heteroaryl (optionally substituted with R.sup.12), C.sub.1-6 alkyl-heteroaryl (optionally substituted with R.sup.12), cyclo(C.sub.3-6) alkyl (optionally substituted with R.sup.12), C.sub.1-6 alkyl-cyclo(C.sub.3-6)alkyl (optionally substituted with R.sup.12), heterocyclo(C.sub.4-6)alkyl (optionally substituted with R.sup.12) or C.sub.1-4 alkyl-heterocyclo(C.sub.4-6)alkyl (optionally substituted with R.sup.12); may be the same or different, SR.sup.8, COR.sup.13, N(R.sup.3).sub.2 where each R.sup.3 may be the same or different, NR.sup.3 R.sup.14, OR.sup.3, phthalimido or the groups: ##STR3## p and q are each 0 or 1 and ma
Baxter Andrew Douglas
Keily John Fraser
Montana John Gary
Owen David Alan
Watson Robert John
Darwin Discovery Limited
Powers Fiona T.
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