Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1990-04-19
1992-05-12
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514422, 514425, 514473, 514408, 548541, 548543, 548544, 548545, 548546, 549478, 549493, 549494, A61K 3140, C07D30702, C07D20700
Patent
active
051128489
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to organic compounds which inhibit lipoxygenase enzymes. It also relates to methods and compositions for inhibiting lipoxygenase enzymes in human and animal hosts in need of such treatment.
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 (LTs).
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 LTs C4 and D4 are potent constrictors of human airways in vitro, and aerosol administration of these substances to non-asthmatic volunteers induces broncho-constriction. LTB4 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. Leukotrienes have also been implicated as important mediators in allergic rhinitis, psoriasis, adult respiratory distress syndrome, Crohn's disease, inflammatory bowel disease, endotoxin shock, and ischemia induced myocardial injury among others. The biological activity of the LTs has been reviewed by Lewis and Austen (J. Clinical Invest. 73, 889, 1984 and by J. Sirois (Adv. Lipid Res. 21, 78, 1985).
The product 12-HETE has been found in high levels in epidermal tissue of patients with psoriasis. The lipoxins have recently been shown to stimulate elastase and superoxide ion release from neutrophils.
Thus, lipoxygenase enzymes are believed to play an important role in the biosynthesis of mediators of asthma, allergy, arthritis, psoriasis, and inflammation. Blocking these enzymes interrupts the biochemical pathways believed to be involved in these disease states.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention there are 5- and/or 12-lipoxygenase inhibiting compounds of the formula: ##STR1## wherein R.sub.1 is hydrogen, C.sub.1 to C.sub.4 alkyl, C.sub.2 to C.sub.4 alkenyl, or --NR.sub.2 R.sub.3, wherein R.sub.2 and R.sub.3 are independently selected from hydrogen, C.sub.1 to C.sub.4 alkyl, hydroxyl, aryl or substituted aryl wherein substituents are selected from halo, nitro, cyano, C.sub.1 to C.sub.12 alkyl, alkoxy, halosubstituted alkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl and alkylsulfonyl; with the proviso that R.sub.2 and R.sub.3 are not both hydroxyl; alkyl, C.sub.1 to C.sub.6 alkoyl, arylalkyl or aroyl; alkenylene;
Y is selected independently- at each occurrence from hydrogen, halogen, hydroxy, cyano, halosubstituted alkyl, C.sub.1 to C.sub.12 alkyl, C.sub.2 to C.sub.12 alkenyl, C.sub.1 to C.sub.12 alkoxy, C.sub.3 to C.sub.8 cycloalkyl, aryl, aryloxy, aroyl, C.sub.1 to C.sub.12 arylalkyl, C.sub.2 to C.sub.12 arylalkenyl, C.sub.1 to C.sub.12 arylalkoxy, C.sub.1 to C.sub.12 arylthioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylalkylamino, arylalkylaminocarbonyl, alkoxyalkoxyalkyl, alkoxyalkyl, arylalkoxyalkyl, arylathioalkoxyalkyl and substituted derivatives of aryl, aryloxy, aroyl, C.sub.1 to C.sub.12 arylalkyl, C.sub.2 to C.sub.12 arylalkenyl, C.sub.1 to C.sub.12 arylalkoxy, C.sub.1 to C.sub.12 arylthioalkoxy, arylalkoxyalkyl or arylthioalkoxyalkyl wherein substituents are selected from halo, nitro, cyano, C.sub.1 to C.sub.12 alkyl, alkoxy and halosubstituted alkyl; to C.sub.12 alkoyl.
The substituent(s) Y can be substituted at any of the positions on the aromatic ring.
Examples of compoun
REFERENCES:
patent: 3664397 (1972-02-01), Raines et al.
patent: 3982922 (1976-09-01), Krenzer et al.
patent: 4185020 (1980-01-01), White et al.
patent: 4717413 (1988-01-01), Baker et al.
Niyagishima et al., Chem. Pharm. Bull., vol. 22(10) pp. 2283-2287, 1974.
Brooks Dee W.
Gunn Bruce P.
Holms James H.
Summers James B.
Abbott Laboratories
Chang Celia
Ivy C. Warren
Janssen Jerry F.
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