Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-09-30
1997-09-09
Gerstl, Robert
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548210, C07D41712, A01K 31425
Patent
active
056657498
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to a series of substituted 1,1-dioxo[d]isothiazol-3-one compounds which are inhibitors of 5-lipoxygenase (5-LO) per se and as such are useful in the treatment or alleviation of inflammatory diseases or conditions, allergy and cardiovascular diseases in mammals wherein the inflammatory disease or condition includes but is not limited to asthma, arthritis, bronchitis, chronic obstructive pulmonary disease, psoriasis, allergic rhinitis, dermatitis, shock, atopic dermatitis, rheumatoid arthritis or osteoarthritis; and this invention also relates to pharmaceutical compositions useful therefor.
Arachidonic acid is known to be the biological precursor of several groups of endogenous metabolites, prostaglandins including prostacyclins, thromboxanes and leukotrienes. The first step of arachidonic acid metabolism is the release of esterified arachidonic acid and related unsaturated fatty acids from membrane phospholipids via the action of phospholipase. Free fatty acids are then metabolized either by cycloxygenase to produce the prostaglandins and thromboxanes or by lipoxygenase to generate hydroperoxy fatty acids which may be further converted to leukotrienes. Leukotrienes have been implicated in the pathophysiology of inflammatory diseases, including rheumatoid arthritis, gout, asthma, ischemia, reperfusion injury, psoriasis and inflammatory bowel disease. Any drug that inhibits lipoxygenase is expected to provide significant new therapy for both acute and chronic inflammatory conditions.
Recently, several review articles on lipoxygenase inhibitors have been reported. See, for example, H. Masamune and L. S. Melvin, Jr., in Annual Reports in Medicinal Chemistry, 24, 71-80 (Academic Press, 1989) and B. J. Fitzsimmons and J. Rokach in Leukotrienes and Lipoxygenases, 427-502 (Elsevier, 1989).
SUMMARY OF THE INVENTION
This invention is concerned with a series of substituted 1,1-dioxo[d]isothiazol-3-one compounds. These new compounds inhibit the production of 5-lipoxygenase (5-LO) in a mammal and as such are useful in the treatment or alleviation of inflammatory disease or condition, allergy and cardiovascular diseases in mammals wherein the inflammatory disease or condition includes but is not limited to asthma, arthritis, bronchitis, chronic obstructive pulmonary disease, psoriasis, allergic rhinitis, dermatitis, shock, atopic dermatitis, rheumatoid arthritis or osteoarthritis.
The compounds of the present invention are of the formula ##STR1## wherein R.sup.1 is (C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.10)cycloalkyl, (C.sub.3 -C.sub.6)alkenyl, (C.sub.3 -C.sub.6)alkynyl or (C.sub.1 -C.sub.6)alkyl-phenyl wherein the alkyl portion is optionally substituted by methyl or ethyl and the phenyl portion is optionally substituted by (C.sub.1 -C.sub.4)alkoxy, (C.sub.1 -C.sub.4)alkyl, F, Cl, Br or CF3; CF.sub.3.
A preferred group of compounds are those compounds of the formula (I) or (II) wherein R.sup.1 is (C.sub.1 -C.sub.6)alkyl; R.sup.2 is hydrogen or fluoro; and R.sup.3 is hydrogen or methyl.
A particularly preferred group of compounds of the present invention are those compounds of formula (I) or (II) wherein R.sup.1 is methyl or t-butyl; R.sup.2 is fluoro; and R.sup.3 is methyl.
A more particularly preferred group of compounds of the present invention are those compounds of formula (I) wherein R.sup.1 is methyl or t-butyl; R.sup.2 is fluoro; and R.sup.3 is methyl.
Another more particularly preferred group of compounds of the present invention are those compounds of formula (II) wherein R.sup.1 is methyl or t-butyl; R.sup.2 is fluoro; and R.sup.3 is methyl.
In a further aspect this invention provides pharmaceutical compositions comprising a compound of the formula (I) or (II) together with a pharmaceutically acceptable diluent or carrier which are useful in the inhibition of 5-LO per se and in the treatment or alleviation of inflammatory disease or condition, allergy or cardiovascular diseases in mammals wherein the inflammatory disease or condition include but are not l
REFERENCES:
patent: 5134148 (1992-07-01), Crawley et al.
patent: 5196419 (1993-03-01), Crawley et al.
H. Masamune and L.S. Melvin, Jr., Annual Reports in Medicinal Chemistry, 24, pp. 71-80 (Academic Press, 1989).
B. J. Fitzsimmons and J. Rokach, Leukotrienes and Lipoxygenases, pp. 427-502 (Elsevier, 1989).
Benson Gregg C.
Conway John D.
Gerstl Robert
Pfizer Inc.
Richardson P. C.
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