Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1997-08-04
1999-01-26
Ramsuer, Robert W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
560 13, 562430, 562623, A61K 31185, C07C31118
Patent
active
058639497
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/US96/02679 filed Mar. 7, 1996 which claims priority from U.S. Ser. No. 08/401,049 filed Mar. 8, 1995 now abandoned.
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 (hereinafter also referred to as 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.
This invention also relates to a method of using such compounds in the treatment of the above diseases in mammals, especially humans, and to the 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. Friers, 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 to 6; and R.sup.2 are each independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkyl, piperidyl, (C.sub.1 -C.sub.6)alkylpiperidyl, (C.sub.6 -C.sub.10)arylpiperidyl, (C.sub.5 -C.sub.9)heteroarylpiperidyl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkylpiperidyl, (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkylpiperidyl, (C.sub.1 -C.sub.6)acylpiperidyl, (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, (C.sub.6 -C.sub.10)aryl(C.sub.6 -C.sub.10)aryl, (C.sub.6 -C.sub.10)aryl(C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.6)cycloalkyl, (C.sub.3 -C.sub.6)cycloalkyl(C.sub.1 -C.sub.6)alkyl, R.sup.5 (C.sub.2 -C.sub.6)alkyl, (C.sub.1 -C.sub.5)alkyl(CHR.sup.5) (C.sub.1 -C.sub.6)alkyl wherein R.sup.5 is hydroxy, (C.sub.1 -C.sub.6)acyloxy, (C.sub.1 -C.sub.6)alkoxy, piperazino, (C.sub.1 -C.sub.6)alkylamino, (C.sub.1 -C.sub.6)alkylthio, (C.sub.6 -C.sub.10)arylthio, (C.sub.1 -C.sub.6)alkylsulfinyl, (C.sub.6 -C.sub.10)arylsulfinyl, (C.sub.1 -C.sub.6)alkylsulfoxyl, (C.sub.6 -C.sub.10)arylsulfoxyl, amino, (C.sub.1 -C.sub.6)alkylamino, ((C.sub.1 -C.sub.6)alkyl).sub.2 amino, (C.sub.1 -C.sub.6)acylpiperazino, (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 or pyrrolidino; R.sup.6 (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.5)alkyl(CHR.sup.6)(C.sub.1 -C.sub.6)alkyl wherein R.sup.6 is piperidyl, (C.sub.1 -C.sub.6)alkylpiperidyl, (C.sub.6 -C.sub.10)arylpiperidyl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkylpiperidyl, (C.sub.5 -C.sub.9)heteroarylpiperidyl or (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkylpiperidyl; and CH(R.sup.7)COR.sup.8 wherein R.sup.7 is hydrogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.6
REFERENCES:
Parker et al,, The Development of 27023A. Poster P73 at the Seventh International Conference of the Inflammation Research Association, Sep. 25-29, 1994.
Rizzi James P.
Robinson Ralph P.
Ginsburg Paul H.
Holtrust Gezina
Pfizer Inc
Ramsuer Robert W.
Richardson Peter C.
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