Organic compounds -- part of the class 532-570 series – Organic compounds – Hydroxamic acids – chalcogen analogs or salts thereof
Patent
1996-05-24
1998-08-11
Jordan, Kimberly
Organic compounds -- part of the class 532-570 series
Organic compounds
Hydroxamic acids, chalcogen analogs or salts thereof
562621, C07C 5302
Patent
active
057928827
DESCRIPTION:
BRIEF SUMMARY
This is a national stage application, filed pursuant to 35 U.S.C. .sctn.371, of PCT international application number PCT/JP94/01349, filed Aug. 15, 1994.
TECHNICAL FIELD
This invention relates to novel N-hydroxyurea compounds. The compounds of the present invention inhibit the action of lipoxygenase enzyme and are useful in the prevention, 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. 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.
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) pp71-80 (Academic Press) and B. J. Fitzsimmons and J. Rokach, Leukotrienes and Lipoxygenases, (1989) pp427-502 (Elsevier)).
More particularly, International Patent Publications Nos. WO 92/09567 and WO 92/09566 disclose a wide variety of N-hydroxyurea and hydroxamic acid compounds as inhibitors of the lipoxygenase enzyme. These include compounds of the following structural type I: ##STR2## in which Ar represents an aromatic group, X represents a non-aromatic ring system, A represents an optional hydrocarbon spacer group and R is either alkyl or an optionally-substituted amino group. In WO 92/09567, the non-aromatic moiety X is a saturated, carbocyclic ring having from 3 to 8 carbons, and there is no mention of the possibility of unsaturation in the X group. In WO 92/09566, the non-aromatic moiety X is shown as a carbocyclic ring having from 3 to 8 carbons, which can optionally contain a double bond. However, all of the examples of cycloalkene compounds in WO 92/09566 are cyclobutene or cyclohexene compounds and there is no suggestion that these unsaturated compounds are preferred.
Surprisingly, therefore, the present inventors have discovered that a small genus of N-hydroxyurea compounds of the general structure I, in which X is a cyclopentenyl group and Ar is an optionally-substituted 3-phenoxyphenyl group, have advantageous properties as lipoxygenase inhibitors.
BRIEF DISCLOSURE OF THE INVENTION
The present invention provides the dextrorotatory isomers of N-hydroxyurea compounds of the following chemical formula II: ##STR3## and the pharmaceutically acceptable salts thereof, wherein R.sup.1 is hydrogen, fluoro or chloro; and R.sup.2 is hydrogen or methyl.
The compounds of formula II inhibit the 5-lipoxygenase enzyme. Therefore they 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 (+)-isomers are especially useful for treating or preventing allergic and inflammatory conditions. This invention also embraces pharmaceutical compositions which comprise a (+)-isomer of the formula II or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The (+)-isomers of the compounds of formula II show outstanding potency as lipoxygenase inhibitors. Moreover, they exhibit excellent metabolic stability towards glucuronidation.
Particularly preferred compounds of the invention are:
DETAILED DESCR
Kawai Akiyoshi
Stevens Rodney W.
Ginsburg Paul H.
Jones Dwayne C.
Jordan Kimberly
Pfizer Inc.
Richardson Peter C.
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