Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-01-18
1997-09-09
Reamer, James H.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514315, 514449, 549479, A61K 3134
Patent
active
056657684
DESCRIPTION:
BRIEF SUMMARY
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 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) and B. J. Fitzsimmons and J. Rokach, Leukotrienes and Lipoxygenases (1989) pp427-502 (Elsevier)).
More particularly, International Patent Publications Nos. WO 92/09566 and WO 92/09567, and U.S. Pat. No. 5,187,192, disclose a wide variety of N-hydroxyurea and hydroxamic acid compounds as inhibitors of the lipoxygenase enzyme. WO 92/09566 discloses some N-cycloalkenyl-N-hydroxyurea compounds having a heteroaryl substituent on the cycloalkene ring. However, none of the N-(heteroarylcycloalkenyl)-N-hydroxyurea compounds of WO 92/09566 has a further substituent containing an aromatic group attached to the heteroaryl group. In WO 92/09567 and U.S. Pat. No. 5,187,192, none of the N-hydroxyureas has an unsaturated ring (cycloalkene ring) attached to the N-hydroxyurea grouping.
BRIEF DISCLOSURE OF THE INVENTION
The present invention provides novel N-hydroxyurea compounds of the following chemical formula I: ##STR1## and the pharmaceutically acceptable salts thereof, wherein each R.sup.1, independently, is hydrogen, hydroxy, chloro, fluoro, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 haloalkyl or C.sub.1 -C.sub.4 haloalkoxy; R.sup.2 is hydrogen or C.sub.1 -C.sub.4 alkyl; R.sup.3 is hydrogen, chloro, fluoro or C.sub.1 -C.sub.4 alkyl; X is O, S, SO or SO.sub.2 ; Z is methylene or ethylene; A is divalent radical derived from furan, thiophene, pyridine, benzofuran, benzothiophene or quinoline, or one of these groups having one substituent selected from chloro, fluoro, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 haloalkyl and C.sub.1 -C.sub.4 haloalkoxy; n is 1, 2 or 3; and M is hydrogen or a pharmaceutically acceptable cation.
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 R.sup.2 and R.sup.3 are each hydrogen, X is O or S, A is unsubstituted furan or unsubstituted thiophene and n is 1. Within this preferred group, particularly preferred compounds are those wherein R.sup.1 is 4-fluoro; A is unsubstituted furan; and Z is ethylene.
Particularly preferred individual compounds of the invention are: and
DETAILED DESCRIPTI
REFERENCES:
patent: 5169854 (1992-12-01), Brooks et al.
patent: 5187192 (1993-02-01), Brooks et al.
patent: 5478822 (1995-12-01), Hoshino et al.
patent: 5521212 (1996-05-01), Ikeda et al.
Kawai et al, Chemical Abstracts, vol. 120, #133, 919Q Mar. 1994.
Kawai Akiyoshi
Stevens Rodney W.
Ginsburg Paul H.
Pfizer Inc.
Reamer James H.
Richardson Peter C.
Zielinski Bryan C.
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