Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-04-13
1997-04-01
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514369, 514374, 514376, 548182, 548202, 548204, 548225, 548235, A61K 3142, A61K 31425, C07D26330, C07D27720
Patent
active
056165960
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to compounds having activity to inhibit lipoxygenase enzyme activity, to pharmaceutical compositions comprising these compounds, and to a medical method of treatment. More particularly, this invention concerns certain substituted arylalkynyl- and ((heteroaryl)alkynyl)-N-hydroxyureas which inhibit leukotriene biosynthesis, to pharmaceutical compositions comprising these compounds and to a method of inhibiting leukotriene biosynthesis.
BACKGROUND OF THE INVENTION
5-Lipoxygenase is the first dedicated enzyme in the pathway leading to the biosynthesis of leukotrienes. This important enzyme has a rather restricted distribution, being found predominantly in leukocytes and mast cells of most mammals. Normally 5-lipoxygenase is present in the cell in an inactive form; however, when leukocytes respond to external stimuli, intracellular 5-lipoxygenase can be rapidly activated. This enzyme catalyzes the addition of molecular oxygen to fatty acids with cis,cis-1,4-pentadiene structures, converting them to 1-hydroperoxy-trans,cis-2,4-pentadienes. Arachidonic acid, the 5-lipoxygenase substrate which leads to leukotriene products, is found in very low concentrations in mammalian cells and must first be hydrolyzed from membrane phospholipids through the actions of phospholipases in response to extracellular stimuli. The initial product of 5-lipoxygenase action on arachidonate is 5-HPETE which can be reduced to 5-HETE or convened to LTA.sub.4. This reactive leukotriene intermediate is enzymatically hydrated to LTB.sub.4 or conjugated to the tripeptide glutathione to produce LTC.sub.4. LTA.sub.4 can also be hydrolyzed nonenzymatically to form two isomers of LTB.sub.4. Successive proteolytic cleavage steps convert LTC.sub.4 to LTD.sub.4 and LTE.sub.4. Other products resulting from further oxygenation steps have also been described in the literature. Products of the 5-lipoxygenase cascade are extremely potent substances which produce a wide variety of biological effects, often in the nanomolar to picomolar concentration range.
The remarkable potencies and diversity of actions of products of the 5-lipoxygenase pathway have led to the suggestion that they play important roles in a variety of diseases. Alterations in leukotriene metabolism have been demonstrated in a number of disease states including asthma, allergic rhinitis, rheumatoid arthritis and gout, psoriasis, adult respiratory distress syndrome, inflammatory bowel disease, endotoxin shock syndrome, atherosclerosis, ischemia induced myocardial injury, and central nervous system pathology resulting from the formation of leukotrienes following stroke or subarachnoid hemorrhage.
The enzyme 5-lipoxygenase catalyzes the first step leading to the biosynthesis of all the leukotrienes and therefore inhibition of this enzyme provides an approach to limit the effects of all the products of this pathway. Compounds which inhibit 5-lipoxygenase are thus useful in the treatment of disease states such as those listed above in which the leukotrienes play an important role.
U.S. Pat. No. 4,738,986 to Kneen, et al. discloses and claims N-(3-phenoxycinnamyl)acetohydroxamic acid, its salts and related compounds having utility for inhibiting lipoxygenase and cyclooxygenase enzymes.
European Patent Application 299 761 to Salmon, et al. discloses and claims certain (substituted phenoxy)phenylalkenyl hydroxamic acids and their salts which are useful as agents for inhibiting lipoxygenase and cyclooxygenase activity.
European Patent Application (Case number 4824) to Brooks, et al. discloses and claims certain substituted alkynyl ureas and hydroxamic acid, which do not contain spacer groups, having lipoxygenase inhibiting activity.
SUMMARY OF THE INVENTION
In its principal embodiment, the present invention provides certain N-[((substituted)aryl)alkynyl]- and N-[((substituted)heteroary)alkynyl]-N-hydroxyurea compounds which inhibit 5-lipoxygenase enzyme activity and thus leukotriene biosynthesis and are useful in the treatment of allergic and inflammat
REFERENCES:
patent: 4738986 (1988-04-01), Kneen et al.
patent: 5214204 (1993-05-01), Dellaria et al.
patent: 5288751 (1994-02-01), Brooks et al.
Chemical Abstracts, vol. 117(3), issued 20 Jul. 1992, (Columbus, Ohio), Brooks et al., "Preparation . . . Inhibitors", see Abstract 263466, WO-92-01,682, 06 Feb. 1992.
Chemical Abstracts, vol. 117(15), issued 12 Oct. 1992, (Columbus, Ohio), Ardo et al., "Preparation . . . Inhibitors", see abstract 263,466q, WO-92 10,469, 25 Jun. 1992.
Basha Anwer
Bhatia Pramila
Brooks Clint D. W.
Craig Richard A.
Ratajczyk James D.
Abbott Laboratories
Browder Monte R.
Rotman Alan L.
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