Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-09-03
1997-09-09
Richter, Johann
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514396, 5483027, 5483044, 5483351, 5483381, 5483435, A01N 4352, A61K 31415, C07D23364, C07D23504
Patent
active
056657536
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to novel compounds for both pharmaceutical and veterinary treatment of matrix-degrading metalloproteinase related disease states.
BACKGROUND OF THE INVENTION
Many different metalloproteinase enzymes are involved in connective tissue degradation or breakdown, such as collagenase, stromelysin and gelatinase. Inhibitors of matrix degrading metalloproteinases (MMP's) are known to be useful in the treatment or prophylaxis of conditions involving such tissue degradation. Such diseases include rheumatoid arthritis, osteoarthritis, arthropathy, dermatological conditions, bone resorption, inflammatory diseases, tumor invasion or metastasis, in the promotion of wound healing, osteoporosis, rheumatoid arthritis, periodonititis, gingivitis, and corneal ulceration, gastric ulceration.
A number of hydroxamic acid derivatives have been suggested as being useful as collagenase inhibitors, or for promoting tumor regression, such as those in the following patents and patent applications: U.S. Pat. No. 4,599,361; EP 236872; WO 90/05716; WO 91/02716; WO 90/05719; WO 93/20047; EPO 0 498 665 A1; and WO 93/21942.
These compounds, however, have generally poor pharmacokinetic properties and or poor water solubility. Therefor a need still exists to identify novel compounds which overcome these deficiencies.
SUMMARY OF THE INVENTION
The present invention relates to a series of novel imidazole substituted hydroxamic acid derivatives, and compositions useful thereof as inhibitors of matrix-degrading metalloproteinase. By inhibiting the action of metalloproteinases the compounds of Formula (I) may be used in the treatment of disease states mediated thereby.
This invention relates to the novel compounds of Formula (I) and pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable diluent or carrier.
This invention also relates to a method of inhibiting cytokines and the treatment of a cytokine mediated disease, in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I).
Compounds of Formula (I) have the following structure: ##STR1## wherein
R.sub.1 is hydrogen, hydroxy, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.1-6 alkenyl, phenyl, optionally substituted phenyl C.sub.1-6 alkyl-, R.sub.7 --S(O).sub.n C.sub.1-6 -alkyl-;
n is 0 or an integer having a value of 1 or 2;
R.sub.7 is C.sub.1-6 alkyl, phenyl, phenyl C.sub.1-6 alkyl, heterocyclic, heterocyclic C.sub.1-6 alkyl, heteroaryl, heteroaryl C.sub.1-6 alkyl, C.sub.1-6 alkyl carbonyl, or phenacyl, all of which may be optionally substituted one to four time independently from C1-6 alkyl, C.sub.1-6 alkoxy, hydroxy, thio C.sub.1-6 alkyl, amino, halogen, CF.sub.3 or nitro;
R.sub.2 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkenyl, phenyl C.sub.1-6 alkyl, cycloalkyl C.sub.1-6 alkyl, or cycloalkenyl C.sub.1-6 alkyl;
R.sub.3 is hydrogen or methyl;
R.sub.4 is hydrogen, C.sub.1-6 alkyl, cyclopropyl, an amino acid residue, optionally substituted phenyl, optionally substituted phenyl C.sub.1-6 alkyl-, optionally substituted --C.sub.1-6 -alkyl-oxy C.sub.1-6 alkyl, optionally substituted --C.sub.1-6 alkyl oxy C.sub.1-6 alkyl phenyl, or an optionally substituted --C.sub.1-6 alkyl oxy phenyl; four times by halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxy, thiol, C.sub.1-6 alkylthio-, --NR.sub.12 R.sub.13, --NHR.sup.a, --NO.sub.2, --C(O).sub.2 R.sub.14, --C(O).sub.2 NR.sub.12 R.sub.13, cyanoamino, R.sub.14 C(O)--O--, C.sub.1-6 alkyl OH, C.sub.1-6 alkyl-C(O).sub.2 R.sub.14, C.sub.1-6 alkyl-oxy-C.sub.1-6 alkyl, C(O)C.sub.1-6 alkylNR.sub.12 R.sub.13, or C.sub.1-6 alkyl-(O).sub.2 C--R.sub.14 ;
R.sup.a is hydrogen, C.sub.1-6 alkyl, or the side chain of an amino acid,
R.sub.14 is hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl C.sub.1-6 alkyl, aryl C.sub.1-6 alkyl, heteroarylC.sub.1-6 alkyl, or heterocyclic C.sub.1-6 alkyl;
R.sub.5 is hydrogen or C.sub.1-6 alkyl;
R.sub.6 and R.sub.7 are independently hydrogen
REFERENCES:
patent: 4996358 (1991-02-01), Handa et al.
patent: 5240958 (1993-08-01), Campion et al.
patent: 5300674 (1994-04-01), Crimmin et al.
patent: 5304604 (1994-04-01), Davidson et al.
Frazee James Simpson
Gleason John Gerald
Metcalf Brian Walter
Dinner Dara L.
Lentz Edward T.
Oswecki Jane C.
Richter Johann
SmithKline Beecham Corporation
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