Aryloxycycloalkenyl and aryloxyiminocycloalkenylhydroxyureas

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – N-c doai

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Details

562623, 560251, 560187, 560106, A01N 4728, C07C 6702, C07C 6966, C07C 6976

Patent

active

057983836

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to novel aryloxycycloalkenyl- and aryloxyimino-cycloalkenylhydroxyurea compounds. The compounds of the present invention inhibit the action of 5-lipoxygenase enzyme and are useful in the prevention, treatment or alleviation of inflammatory diseases such as inflammatory bowel disease and rheumatoid arthritis, allergy and cardiovascular diseases in a mammalian subject, e.g., human subject. This invention also relates to pharmaceutical compositions comprising these compounds.


BACKGROUND ART

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 A.sub.2. Free fatty acids are then metabolized either by cyclooxygenase to produce the prostaglandins and thromboxanes or by lipoxygenase to generate hydroperoxy fatty acids which may be further metabolized 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.
For a review article on 5-lipoxygenase inhibitors, see H. Masamune and L. S. Melvin, Sr., Annual Reports in Medicinal Chemistry, 24 (1989) pp71-80 (Academic Press). More recently, further examples of 5-lipoxygenase inhibitors have been disclosed in International Patent Publication Nos. WO 94/14762 and WO 92/9566.


BRIEF DISCLOSURE OF THE INVENTION

The invention provides a compound of formula (I): ##STR2## wherein Ar is selected from the group consisting of: three substituents selected from alkoxy, C.sub.1-4 haloalkoxy, C.sub.2-4 alkoxyalkoxy, C.sub.1-4 alkylthio, hydroxy, halo, cyano, amino, C.sub.1-4 alkylamino, di (C.sub.2-8) alkylamino, C.sub.2-6 alkanoylamino, carboxy, C.sub.2-6 alkoxycarbonyl, phenyl optionally substituted with one to three substituents selected from C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, cyano and halo, phenoxy optionally substituted with one to three substituents selected from C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, cyano and halo, phenylthio optionally substituted with one to three substituents selected from C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, cyano and halo, and phenylsulfinyl optionally substituted with one to three substituents selected from C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, cyano and halo; and optionally substituted with one to three substituents selected from C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, halo, C.sub.1-4 alkoxy, hydroxy, phenyl optionally substituted with one to three substituents selected from C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, cyano and halo, phenoxy optionally substituted with one to three substituents selected from C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, cyano and halo, and phenylthio optionally substituted with one to three substituents selected from C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, cyano and halo; --(CHR.sup.1).sub.m --Q.sup.1 (CHR.sup.2).sub.n --, --O--(CHR.sup.1).sub.j --Q.sup.2 -- and --(CHR.sup.1)--O--N.dbd. in which the N.dbd. moiety is attached to the cycloalkene ring; and in which Q.sup.1 is O, S, SO, SO.sub.2, NR.sup.3, CH.dbd.N--O or CO, Q.sup.2 is O, S, SO, SO.sub.2 or NR.sup.3, and R.sup.1, R.sup.2 and R.sup.3 are each hydrogen or C.sub.1 -C.sub.4 alkyl, m and n are each an integer from 0 to 4 and j is an integer from 1 to 4; C.sub.2-4 alkoxyalkyl, C.sub.1-4 alkylthio, hydroxy, halo, cyano or amino; acceptable metabolically cleavable group.

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