Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1991-07-10
1992-12-29
Siegel, Alan
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514445, 514448, 549 65, 549 76, 549 77, 549 61, 549 72, A61K 3138, C07D33332, C07D33322
Patent
active
051751836
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to compounds which inhibit lipoxygenase enzymes, to pharmaceutical compositions containing these compounds, and to methods of inhibiting lipoxygenase enzymes in human and animal hosts in need of such treatment. More particularly, this invention concerns certain aryl-, arylalkyl- and arylcyclopropyl-N-hydroxyurea compounds which inhibit lipoxygenase enzymes, to pharmaceutical compositions containing these compounds, and to methods of treating disease states mediated by products of the arachidonic acid cascade.
BACKGROUND OF THE INVENTION
The lipoxygenases are a family of enzymes which catalyze the oxygenation of arachidonic acid. The enzyme 5-lipoxygenase converts arachidonic acid to 5-hydroperoxyeicosatetraenoic acid (5-HPETE). This is the first step in the metabolic pathway yielding 5-hydroxyeicosatetraenoic acid (5-HETE) and the important class of mediators, the leukotrienes (LT's). Similarly 12- and 15-lipoxygenase, convert arachidonic acid to 12- and 15-HPETE respectively. Biochemical reduction of 12-HPETE leads to 12-HETE, while 15-HPETE is the precursor of the class of biological agents known as the lipoxins.
A variety of biological effects are associated with these products from lipoxygenase metabolism of arachidonic acid and they have been implicated as mediators in various disease states. For example, the LTC.sub.4 and LTD.sub.4 are potent constrictors of human airways in vitro and aerosol administration of these substances to non-asthmatic volunteers induces broncho-constriction. LTB.sub.4 and 5-HETE are potent chemotactic factors for inflammatory cells such as polymorphonuclear leukocytes. They also have been found in the synovial fluid of rheumatoid arthritic patients. The biological activity of the leukotrienes has been reviewed by Lewis and Austin (J. Clinical Invest. 73, 889, 1984) and by Sirois (Adv. Lipid Res. 21, 78, 1985).
Thus, lipoxygenase enzymes play an important role in the biosynthesis of mediators of asthma, allergy, arthritis, psoriasis, inflammatory bowel disease, gout, adult respiratory distress syndrome, endotoxin shock and inflammation. Blocking these enzymes interrupts the biochemical pathways involved in these disease states.
BACKGROUND ART
Relatively few compounds are known from the prior art which are inhibitors of the lipoxygenase enzymes. Among the lipoxygenase inhibitors known to the art are: AA-861, a 5-lipoxygenase inhibitor, disclosed in U.S. Pat. No. 4,393,075, issued Jul. 12, 1983 to Terao et al.; pyrazolo pyridines, which are 5-lipoxygenase inhibitors, disclosed in European Patent Application of Irikura et al., S.N. 121,806, published Oct. 17, 1984; arachidonyl hydroxamic acid, a 5-lipoxygenase inhibitor, disclosed in E. J. Corey et al., J. Am. Chem. Soc., 106, 1503 (1984) and European Patent Application of P. H. Nelson, S.N. 104,468, published Apr. 4, 1984; BW755C, an inhibitor of 5- and 12-lipoxygenases, disclosed in Radmark et al., FEBS Lett., 110, 213 (1980); nordihydro-guariaretic acid, an inhibitor of 5- and 15-lipoxygenases, disclosed in Morris et al., Prostaglandins, 19, (1980); REV-5901, a 5-lipoxygenase inhibitor, disclosed in Coutts, Meeting Abstract 70, Prostaglandins and Leukotrienes '84; quinoline N-oxides, 5-lipoxygenase inhibitors disclosed in European patent application of Hashizumo et al., Ser. No. 128,374, published Dec. 19, 1984 and benoxaprofen, disclosed in J. Walker, Pharm. Pharmacol., 31, 778 (1979).
SUMMARY OF THE INVENTION
The compounds of this invention possess unexpected activity as inhibitors of lipoxygenase enzymes, and reduce the biosynthesis of leukotrienes B.sub.4, C.sub.4, D.sub.4 and E.sub.4. The compounds and compositions containing these compounds are useful for the treatment of disease states in mammals, which disease states are mediated by the leukotrienes B.sub.4, C.sub.4, D.sub.4 and E.sub.4.
The compounds of this invention have the structural formula, I: ##STR1## where A is a divalent radical selected from the group consisting of alkylene of from one to six carbon atoms, al
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Brooks Dee W.
Rodriques Karen E.
Summers James B.
Abbott Laboratories
Janssen Jerry F.
Siegel Alan
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