Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-01-10
1996-05-07
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514471, 549 65, 549441, A61K 3134, A61K 3138, C07D33332, C07D33334
Patent
active
055147020
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to compounds having activity to inhibit lipoxygenase enzymes, to pharmaceutical compositions comprising these compounds, and to a medical method of treatment More particularly, this invention concerns certain substituted arylamidoalkyl-N-hydroxyurea compounds which inhibit leukotriene biosynthesis, to pharmaceutical compositions comprising these compounds, and to a method of inhibiting lipoxygenase activity and 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 converted 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 fast 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.
SUMMARY OF THE INVENTION
In its principal embodiment, the present invention provides certain substituted amidoalkyl-N-hydroxyurea and aminoalkylurea compounds which inhibit lipoxygenase enzyme activity. The compounds are useful in the treatment of allergic and inflammatory disease states in which leukotrienes play a role including asthma, allergic rhinitis, rheumatoid arthritis and gout, psoriasis, adult respiratory distress syndrome, inflammatory bowel disease, endotoxin shock syndrome, ischememia induced myocardial injury, atherosclerosis and central nervous system pathology resulting from the formation of leukotrienes following stroke or subarachnoid hemorrhage.
The compounds of the present invention are of the formula ##STR1## or a pharmaceutically acceptable salt thereof wherein R.sup.1 is selected from the group consisting of hydrogen, alkyl of from one to six carbon atoms, alkenyl of from two to six carbon atoms, cycloalkyl of from three to six carbon atoms, and
REFERENCES:
patent: 4407822 (1983-10-01), Lafon
patent: 4897422 (1990-11-01), Summers
Brooks Dee W.
Dellaria Joseph F.
Moore Jimmie L.
Sallin Kevin J.
Abbott Laboratories
Janssen Jerry F.
Rotman Alan L.
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