Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-06-29
2000-03-14
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514399, 5462741, 5483111, 5483154, A01N 4340, A01N 4350, C07D40104, C07D23302
Patent
active
060373555
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to novel imidazole lipoxygenase inhibitors. The compounds of the present invention inhibit the biosynthesis of leukotrienes by intervention of the action of the enzyme 5-lipoxygenase on arachidonic acid and are therefore useful in the treatment or alleviation of inflammatory diseases, allergy and cardiovascular diseases in mammals. This invention also relates to pharmaceutical compositions comprising such compounds.
BACKGROUND ART
Arachidonic acid is known to be the biological precursor of several groups of biologically active endogenous metabolites. The first step in the metabolism of arachidonic acid is its release from membrane phospholipids, via the action of phospholipase A.sub.2. Arachidonic acid is then metabolized either by cyclooxygenase to produce prostaglandins including prostacyclin, and thromboxanes or by lipoxygenase to generate hydroperoxy fatty acids which may be further converted to the leukotrienes.
The leukotrienes are extremely potent substances which elicit a wide variety of biological effects, often in the nanomolar to picomolar concentration range. The peptidoleukotrienes (LTC.sub.4, LTD.sub.4, LTE.sub.4) are important bronchoconstrictors and vaso-constrictors, and also cause plasma extravasation by increasing capillary permeability. LTB.sub.4 is a potent chemotactic agent, enhancing the influx of leukocytes and inducing their subsequent degranulation at the site of inflammation. A pathophysiological role for leukotrienes has been implicated in a number of human disease states including asthma and related obstructive airway diseases, allergic rhinitis, rheumatoid arthritis and gout, psoriasis and atopic dermatitis, adult respiratory distress syndrome (ARDS), inflammatory bowel diseases (e.g. Crohn's disease), endotoxin shock, atherosclerosis and cardiovascular disorders (e.g. ischemia-induced myocardial injury) and glomerular nephritis. Any agent that inhibits the action of 5-lipoxygenase is expected to be of considerable therapeutic value for the treatment of acute and chronic inflammatory conditions.
For a review article on lipoxygenase inhibitors, see H. Masamune and L. S. Melvin, Sr.: Annual Reports in Medicinal Chemistry, 1989, 24, pp 71-80 (Academic). More recently, further examples of lipoxygenase inhibitors have been disclosed in WO 95/03309 and WO94/29299.
BRIEF DISCLOSURE OF THE INVENTION
The present invention provides a novel chemical compound of formula I: ##STR2## and a pharmaceutically acceptable salt, wherein Ar is phenylene optionally substituted with halo, hydroxy, cyano, amino, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 halo-substituted alkyl, C.sub.1 -C.sub.4 halo-substituted alkoxy; -C.sub.4 alkylene, and X.sup.1 is oxy, thio, sulfinyl or sulfonyl; halo, hydroxy, cyano, nitro, amino, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 halo-substituted alkyl, C.sub.1 -C.sub.4 halo-substituted alkoxy, C.sub.1 -C.sub.4 alkylamino, di(C.sub.1 -C.sub.4)alkylamino; hydrogen or C.sub.1 -C.sub.4 alkyl; and an oxygen atom.
A preferred group of compounds of this invention includes compounds of the formula I, wherein Ar is phenylene optionally substituted with halo or C.sub.1 -C.sub.4 alkyl; X is oxy or thio; Ar.sup.1 is phenylene optionally substituted with halo or C.sub.1 -C.sub.4 alkyl; Y is CN or CONR.sup.1 R.sup.2 wherein R.sup.1 and R.sup.2 are independently hydrogen or C.sub.1 -C.sub.2 alkyl; R is C.sub.1 -C.sub.3 alkyl; and W is C.sub.2 -C.sub.3 alkylene.
A more preferred group of compounds of this invention includes compounds of the formula I, wherein Ar is 1,4-phenylene optionally substituted with halo or C.sub.1 -C.sub.4 alkyl, more preferably 1,4-phenylene; X is thio; Ar.sub.1 is 1,3-phenylene optionally substituted with halo or C.sub.1 -C.sub.4 alkyl, more preferably 1,3-phenylene; Y is CN or CONH.sub.2 ; R is C.sub.1 -C.sub.2 alkyl, more preferably methyl; and W is C.sub.2 -C.sub.3 alkylene, more preferably ethylene.
Preferr
REFERENCES:
patent: 5753682 (1998-05-01), Stevens et al.
Mano Takashi
Stevens Rodney W.
Ginsburg Paul H.
Jacobs Seth H.
Pfizer Inc
Richardson Peter C.
Shah Mukund J.
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