Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-09-05
1997-12-09
Criares, Theodore J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514379, 514380, A61K 3142
Patent
active
056961413
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to a method of inhibiting 5-lipoxygenase (5-LO) in a mammal in need thereof which comprises administering to said mammal a 5-lipoxygenase inhibiting amount of a compound of the formula (I), shown below, or a pharmaceutically acceptable salt thereof, 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 is 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, Sr., in Annual Reports in Medicinal Chemistry, 24, 71-80 (Academic Press, 1989) and B. J. Fitzsimmons and J. Rokach in Leukotrienes and Upoxygenases, 427-502 (Elsevier, 1989).
The compounds utilized in the present invention are disclosed and claimed in copending U.S. application Ser. No. 08/157,248 filed Nov. 26, 1993 and Ser. No. 08/157,241 filed Nov. 26, 1993, wherein said compounds are disclosed as having phosphodiesterase type IV (PDE.sub.IV) inhibiting activity. The disclosures thereof are incorporated herein by reference.
SUMMARY OF THE INVENTION
This invention is concerned with a method of inhibiting production of 5-lipoxygenase (5-LO) in a mammal in need thereof which method comprises administering to said mammal an effective amount of a compound selected from the group consisting of compounds of the formula (I) ##STR2## the racemic, racemic-diastereomeric mixtures and optical isomers of said compounds, and the pharmaceutically acceptable salts thereof, wherein phenyl portion is optionally substituted with (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, halogen or CF.sub.3, or --O(CH.sub.2).sub.n quinoline where the quinoline is optionally substituted with (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, halogen or CF.sub.3 ; -C.sub.7)cycloalkyl or --O(CH.sub.2).sub.n phenyl where the phenyl portion is optionally substituted with (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, halogen or CF.sub.3 ; 3-O-cyclopentyl; R.sup.1 is not 4-O-cyclopentyl; and R.sup.2 is not 3-O-(CH.sub.2).sub.5 phenyl.
A preferred method of inhibiting production of 5-lipoxygenase (5-LO) in a mammal in need thereof which method comprises administering to said mammal an effective amount of a compound selected from the group consisting of compounds of the formula (I) ##STR3## the racemic, racemic-diastereomeric mixtures and optical isomers of said compounds, and the pharmaceutically acceptable salts thereof, wherein R.sup.2 is not 3-O-(CH.sub.2).sub.5 phenyl.
Further, this invention is directed to a method of treating or alleviating an inflammatory disease or condition, allergy or cardiovascular disease in a mammal in need thereof which method comprises administering to said mammal an effective amount of a compound selected from the group consisting of compounds
REFERENCES:
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H. Masamune and L. S. Melvin, Jr., Annual Reports in Medicinal Chemistry, 24, 71-80, Academic Press, 1989.
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Cohan Victoria Lee
Kleinman Edward Fox
Benson Gregg C.
Criares Theodore J.
Olson A. Dean
Pfizer Inc.
Richardson Peter C.
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