Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-11-05
1998-09-29
Stockton, Laura L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548146, 548238, 5462704, 5462714, 514340, 514365, A61K 3142, A61K 31425, A61K 3144, C07D26314
Patent
active
058146482
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP95/01127 filed Jun. 7, 1995.
TECHNICAL FIELD
This invention relates to novel N-hydroxyurea compounds. The compounds of the present invention inhibit the action of the lipoxygenase enzyme and are 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 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. Arachidonic acid is 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 and are the subject of several review articles. Any drug that inhibits lipoxygenase is expected to provide significant new therapy for both acute and chronic inflammatory conditions. (See H. Masamune and L. S. Melvin, Sr., Annual Reports in Medicinal Chemistry: 24 (1989) pp71-80 (Academic), B. J. Fitzsimmons and J. Rokach, Leukotrienes and Lipoxygenases (1989) pp427-502 (Elsevier)) and D. G. Batt, Progress in Med. Chem.29 (1992) p 1.
WO 92/22543(1992) discloses N-hydroxyurea and hydroxamic acid compounds as inhibitors of the lipoxygenase enzyme.
BRIEF DISCLOSURE OF THE INVENTION
The present invention provides novel N-hydroxyurea compounds of the following chemical formula (I): ##STR2## and the pharmaceutically acceptable salts thereof, wherein A is C.sub.1 -C.sub.4 alkylene, CH(R), CH(R)CH.sub.2 or CH(R)CH.sub.2 CH.sub.2, in which R is methyl or ethyl; m and n are each zero or one; R.sup.1 and R.sup.2 are each hydrogen, C.sub.1 -C.sub.4 alkyl or C.sub.2 -C.sub.6 alkenyl; X is O or S; Y is O, S, CH.dbd.CH or C.tbd.C; Ar.sup.1 is phenyl or phenyl mono-substituted with halogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 halo-substituted alkyl or C.sub.1 -C.sub.4 halo-substituted alkoxy; and Ar.sup.2 is phenylene, pyridylene or phenylene mono- or di-substituted with halogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 halo-substituted alkyl or C.sub.1 -C.sub.4 halo-substituted alkoxy.
The compounds of the formula (I) inhibit the 5-lipoxygenase enzyme. Therefore the compounds are useful for treating a medical condition for which a 5-lipoxygenase inhibitor is needed, in a mammalian subject, e.g., a human subject. The compounds are especially useful for treating allergic and inflammatory conditions. This invention also embraces pharmaceutical compositions which comprise a compound of the formula (I) and a pharmaceutically acceptable carrier.
A preferred group of compounds of the invention consists of the compounds of the formula (I), wherein n is zero; R.sup.1 and R.sup.2 are each hydrogen; X is O; Ar.sup.1 is phenyl or 4-fluorophenyl; and Ar.sup.2 is 1,3-phenylene or 1,3-phenylene having one substituent selected from halogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 halo-substituted alkyl and C.sub.1 -C.sub.4 halo-substituted alkoxy.
Within this preferred group, a particularly preferred subgroup of compounds are those wherein A is CH.sub.2, CH.sub.2 CH.sub.2, CH(CH.sub.3) or CH(CH.sub.3)CH.sub.2 ; Ar.sup.2 is 1,3-phenylene or 1,3-phenylene having one fluoro substituent; m is one; and Y is O. Within this particularly preferred subgroup, Ar.sup.1 is preferably attached to the 4-position of the oxazoline ring, and the carbon atom to which Ar.sup.1 is attached preferably has the (R)-configuration.
Particularly preferred individual compounds
REFERENCES:
patent: 5288751 (1994-02-01), Brooks et al.
patent: 5464849 (1995-11-01), Mano et al.
Ando Akemi
Stevens Rodney William
Appleman Jolene W.
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
Stockton Laura L.
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