Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-06-17
2000-06-20
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546146, 546172, 546196, 546256, 548159, 548204, 548214, 548217, 548235, 548247, 548253, 5483051, 5483114, 5483644, 548464, 548525, 549 58, 549 60, 549459, 549463, A01N 4308, A61K 3134, C07D30700, C07D30793
Patent
active
060778644
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to cyclic sulfone derivatives which are inhibitors a matrix metalloproteinases or the production of tumor necrosis factor (TNF) and as such are useful in the treatment of a condition selected from the group consisting of arthritis, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, scleritis and other diseases characterized by matrix metalloproteinase activity, AIDs, sepsis, septic shock and other diseases involving the production of TNF. In addition, the compounds of the present invention may be used in combination therapy with standard non-steroidal anti-inflammatory drugs (hereinafter NSAID'S) and analgesics for the treatment of arthritis, and in combination with cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and alkaloids, such as vincristine, in the treatment of cancer.
This invention also relates to a method of using such compounds in the treatment of the above diseases in mammals, especially humans, and to pharmaceutical compositions useful therefor.
There are a number of enzymes which effect the breakdown of structural proteins and which are structurally related metalloproteases. Matrix-degrading metalloproteinases, such as gelatinase, stromelysin and collagenase, are involved in tissue matrix degradation (e.g. collagen collapse) and have been implicated in many pathological conditions involving abnormal connective tissue and basement membrane matrix metabolism, such as arthritis (e.g. osteoarthritis and rheumatoid arthritis), tissue ulceration (e.g. corneal, epidermal and gastric ulceration), abnormal wound healing, periodontal disease, bone disease (e.g. Paget's disease and osteoporosis), tumor metastasis or invasion, as well as HIV-infection (J. Leuk. Biol., 52 (2): 244-248, 1992).
Tumor necrosis factor is recognized to be involved in many infectious and auto-immune diseases (W. Fiers, FEBS Letters, 1991, 285, 199). Furthermore, it has been shown that TNF is the prime mediator of the inflammatory response seen in sepsis and septic shock (C. E. Spooner et al., Clinical Immunology and Immunopathology, 1992, 62 S11).
SUMMARY OF THE INVENTION
The present invention relates to a compound of the formula ##STR2## or pharmaceutically acceptable salt thereof, wherein the broken line represents an optional double bond;
n is 0, 1 or 2;
X and Y are each independently CR.sup.1 wherein R.sup.1 is hydrogen, (C.sub.1 -C.sub.6)alkyl optionally substituted by (C.sub.1 -C.sub.6)alkylamino, (C.sub.1 -C.sub.6)alkylthio, (C.sub.1 -C.sub.6)alkoxy, trifluoromethyl, (C.sub.6 -C.sub.10)aryl, (C.sub.5 -C.sub.9)heteroaryl, (C.sub.6 -C.sub.10)arylamino, (C.sub.6 -C.sub.10)arylthio, (C.sub.6 -C.sub.10)aryloxy, (C.sub.5 -C.sub.9)heteroarylamino, (C.sub.5 -C.sub.9)heteroarylthio, (C.sub.5 -C.sub.9)heteroaryloxy, (C.sub.6 -C.sub.10)aryl(C.sub.6 -C.sub.10)aryl, (C.sub.3 -C.sub.6)cycloalkyl, hydroxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl(hydroxymethylene),piperazinyl,(C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkoxy,(C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkoxy, (C.sub.1 -C.sub.6)acylamino, (C.sub.1 -C.sub.6)acylthio, (C.sub.1 -C.sub.6)acyloxy, (C.sub.1 -C.sub.6)alkylsulfinyl, C.sub.6 -C.sub.10)arylsulfinyl, (C.sub.1 -C.sub.6)alkylsulfonyl, (C.sub.6 -C.sub.10)arylsulfonyl, amino, C.sub.1 -C.sub.6)alkylamino or ((C.sub.1 -C.sub.6)alkyl).sub.2 amino; trifluoromethyl, (C.sub.1 -C.sub.6)alkyl (difluoromethylene), (C.sub.1 C.sub.3)alkyl(difluoromethylene)(C.sub.1 -C.sub.3)alkyl, (C.sub.6 -C.sub.10)aryl, (C.sub.5 -C.sub.9)heteroaryl, (C.sub.3 -C.sub.6)cycloalkyl, (C.sub.1 -C.sub.6)alkyl-(hydroxymethylene), R.sup.3 (C.sub.1 -C.sub.6)alkyl wherein R.sup.3 is (C.sub.1 -C.sub.6)acylpiperazino, (C.sub.6 -C.sub.10)arylpiperazino, (C.sub.5 -C.sub.9)heteroarylpiperazino, (C.sub.1 -C.sub.6)alkylpiperazino, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkylpiperazino, (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C.sub.1 -
REFERENCES:
patent: 3268539 (1966-08-01), Levy
Marvin Stolberg et al. .."Vicinally Substituted Hydroxamic Acids" May 20, 1957.
Burgess Laurence Edward
Rizzi James Patrick
Appleman Jolene W.
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
Schroeder T. Benjamin
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