Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-02-16
2000-11-28
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
5142375, 51425501, 514315, 514330, 514412, 514423, 514539, 514542, 514550, 544 584, 544159, 544386, 544391, 546226, 546245, 548953, 548540, 560 13, 560150, A61K 3118, A61K 31445, A61K 31495, C07C31129, C07D21158
Patent
active
061536091
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to arylsulfonylamino hydroxamic acid derivatives which are inhibitors of 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 matalloproteinases, 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 the pharmaceutically acceptable salts thereof, wherein n is 1 or 6; pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, piperazinyl or a bridged diazabicycloalkyl ring selected from the group consisting of ##STR3## wherein r is 1, 2 or 3; groups selected from hydroxy, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, (C.sub.1 -C.sub.10)acyl, (C.sub.1 -C.sub.10)acyloxy, (C.sub.6 -C.sub.10)aryl, (C.sub.5 -C.sub.9)heteroaryl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl, (C.sub.5 -C.sub.9)heteroaryl (C.sub.1 -C.sub.6)alkyl, hydroxy (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)acyloxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylthio, (C.sub.1 -C.sub.6)alkylthio (C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)arylthio, (C.sub.6 -C.sub.10) arylthio(C.sub.1 -C.sub.6)alkyl, R.sup.9 R.sup.10 N, R.sup.9 R.sup.10 NSO.sub.2, R.sup.9 R.sup.10 NCO, R.sup.9 R.sup.10 NCO(C.sub.1 -C.sub.6)alkyl wherein R.sup.9 and R.sup.10 are each independently hydrogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl, (C.sub.5 -C.sub.9)heteroaryl, (C.sub.6 -C.sub.10)aryl (C.sub.1 -C.sub.6)alkyl or (C.sub.5 -C.sub.9)heteroaryl (C.sub.1 -C.sub.6)alkyl or R.sup.9 and R.sup.10 may be taken together with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or thiomorpolinyl ring; R.sup.12 SO.sub.2, R.sup.12 SO.sub.2 NH wherein R.sup.12 is trifluoromethyl, (C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl, (C.sub.5 -C.sub.9)heteroaryl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl or (C.sub.5 -C.sub.9)heteroaryl (C.sub.1 -C.sub.6)alkyl; R.sup.13 CONR.sup.9 wherein R.sup.9 is as defined above and R.sup
REFERENCES:
patent: 5863949 (1999-01-01), Robinson et al.
patent: 5994351 (1999-11-01), Robinson et al.
Parker et al., The Development of CGS27023A, A Novel, Potent and Orally Active Matrix Metalloprotease Inhibitor, Poster P73 at the Seventh International Conference of the Inflammation Research Association, Sep. 25-29, 1994.
Blumenkopf Todd A.
Robinson Ralph P.
Ginsburg Paul H.
Looney Adrian G.
Pfizer Inc
Raymond Richard L.
Richardson Peter C.
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