Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-03-24
1996-07-30
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548491, C07D20908, A61K 3140
Patent
active
055412181
DESCRIPTION:
BRIEF SUMMARY
This invention relates to novel N-hydroxyurea and hydroxamic acid compounds. The compounds of the present invention inhibit the action of lipoxygenase enzyme and are useful in the treatment or alleviation of inflammatory diseases, allergy and cardiovascular diseases in mammals, especially human subjects. This invention also relates to pharmaceutical compositions comprising such compounds.
BACKGROUND OF THE INVENTION
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 the arachidonic acid metabolism is the release of arachidonic acid and related unsaturated fatty acids from membrane phospholipids, via the action of phospholipase A2. Free fatty acids are then metabolized either by cyclooxygenase to produce the prostaglandins and thromboxanes or by lipoxygenase to generate hydroperoxy fatty acids which maybe further converted to the leukotrienes. Leukotrienes have been implicated in the pathophysiology of inflammatory diseases, including rheumatoid arthritis, gout, asthma, ischemia reperfusion injury, psoriasis and inflammatory bowel diseases. 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 H. Masamune and L. S. Melvin, Sr.: Annual Reports in Medicinal Chemistry, 24 (1989) pp 71-80 (Academic), and B. J. Fitzsimmons and J. Rokach: Leukotrienes and Lipoxygenases (1989) pp 427-502 (Elsevier).
Compounds of similar structure to the object compounds of the present invention are disclosed in EP 279263 A2, WO 89/04299 and WO 91/16298.
The present inventors have worked to prepare compounds capable of inhibiting the action of lipoxygenase and after extensive research they have succeeded in synthesizing a series of compounds as disclosed in detail herein.
SUMMARY OF THE INVENTION
The present invention provides novel N-hydroxyurea and hydroxamic acid derivatives of the following chemical formula (I) and pharmaceutically acceptable salts thereof; ##STR2## wherein R.sub.1 is C.sub.1 -C.sub.4 alkyl or --NR.sub.2 R.sub.3 ; R.sub.2 and R.sub.3 are each, independently, hydrogen or C.sub.1 -C.sub.4 alkyl; R.sub.4 is C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.7 cycloalkylalkyl, aryloxy C.sub.2 -C.sub.4 alkyl, arylthio C.sub.2 C.sub.4 alkyl, arylamino C.sub.2 -C.sub.4 alkyl, arylsulfinyl C.sub.2 -C.sub.4 alkyl, aryl, aryl C.sub.1 -C.sub.6 alkyl, aryloxyaryl C.sub.1 -C.sub.6 alkyl or arylthioaryl C.sub.1 -C.sub.6 alkyl, and the aryl groups in the said aryloxyalkyl, arylthioalkyl, arylaminoalkyl, arylsulfinylalkyl, aryl, arylalkyl, aryloxyarylalkyl and arylthioarylalkyl may be substituted up to the maximal number of substituents and the substituents are each, independently, selected from the group consisting of halo, cyano, C.sub.1 -C.sub.5 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.5 alkoxy, C.sub.2 -C.sub.6 alkenyloxy, C.sub.2 -C.sub.6 alkoxyalkyl, halosubstituted C.sub.1 -C.sub.4 alkyl, halosubstituted C.sub.1 C.sub.4 alkoxy, C.sub.2 -C.sub.5 alkoxycarbonyl, aminocarbonyl and C.sub.1 -C.sub.4 alkylthio; --O--(CH.sub.2).sub.m --; C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.6 alkoxy or C.sub.3 -C.sub.8 alkenyloxy; are attached to the aromatic ring.
DETAILED DESCRIPTION OF THE INVENTION
In this application, chain radicals including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, and the like; including, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy and the like; including, but not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio and the like; chain radicals having one double bond including, but not limited to, ethenyl, 1- and 2-propenyl, 2-methyl-1-propenyl, 1- and 2-butenyl and the like; alkenyl) including, but not limited to, ethenyloxy, 1- and 2-propenyloxy, 2-methyl-1-propenyloxy, 1- and 2-butenyloxy and the like; hydrocarb
REFERENCES:
patent: 5132319 (1992-07-01), Girand et al.
patent: 5187192 (1993-02-01), Brooks et al.
Ikeda Takafumi
Stevens Rodney W.
Bekelnitzky Seymour G.
Ginsburg Paul H.
Grumbling Matthew V.
Pfizer Inc.
Richardson Peter C.
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