Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1991-03-08
1992-01-21
Springer, David B.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546152, 546172, 546174, 546176, 546178, 546180, C07D40512, A61K 3147
Patent
active
050828495
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
Leukotrienes (LT) are metabolites of arachidonic acid formed by oxygenation by a novel lipoxygenase specific for the C-5 position of the arachidonic acid. This forms 5-hydroperoxytetraenoic acid (5-HPETE). The latter is further transformed into an unstable epoxide intermediate leukotriene A.sub.4. The LTA.sub.4 can then form the peptidoleukotrienes. The LTC.sub.4 is formed by glutathione addition with 5-transferase. LTC.sub.4 may then be metabolized to LTD.sub.4 and LTE.sub.4 by successive elimination of a .delta.-glutamyl residue and glycine. This pathway has received much attention during the past few years and means have been sought as to how leukotriene antagonist properties could be established, i.e., researchers have been seeking a means to antagonize one or more of the arachidonic acid metabolites known as the peptido-leukotrienes LTC.sub.4, LTD.sub.4 and LTE.sub.4. These are also known as the cysteinyl leukotrienes and they primarily affect smooth muscle and other cells having cotractile capacity. In general these C.sub.4, D.sub.4 and E.sub.4 leukotrienes have been shown to play a key role in hypersensitivity reactions. They have bronchospastic action and activate airway smooth muscle. Inhalation studies on healthy volunteers and asthmatic subjects have corroborated that LTC.sub.4 and LTD.sub.4 are potent inducers of airway obstruction such as stimulation of mucous secretion. In addition, asthmatics are hyperreactive to inhaled leukotrienes which are involved with the pathogenesis of asthma such as allergic pulmonary disorders of asthma, hay fever and allergic rhinitis. These peptido-leukotrienes also are powerful spasmogens, increase vascular permeability and are involved with the pathogenesis of certain inflammatory diseases such as bronchitis, ectopic and atopic eczema and psoriasis. They are the bioactive components of Slow-Reacting-Substance of Anaphylaxis (SRS-A). In addition, LTC.sub.4, LTD.sub.4 and LTE.sub.4 may also decrease blood pressure by an action on the heart, because cysteinyl leukotrienes reduce myocardial contractility and coronary blood flow. The hypotensive phase is usually preceded by an initial pressor effect which is primarily a consequence of generalized arteriolar constriction.
Emphasis has been directed for several years to the synthesis of compounds which are LTD.sub.4 antagonists. It is thought that such compounds would be of significant value in the regulation of coronary flow rate and contractile force of the heart. They would also be useful in the treatment of hypersensitivity and bronchospastic disorders involving smooth muscle such as asthma, hay fever and allergic rhinitis. It is further thought that inflammatory conditions such as bronchitis, ectopic and atopic eczema and psoriasis could be controlled.
There is currently a number of Leukotriene D.sub.4 antagonists being developed. These include a number of compounds contained in patent applications which are assigned to the same assignee as the present invention. These include U.S. Pat. Nos.: 4,920,132, 4,920,130, 4,920,133, 4,918,081 and 4,920,131.
SUMMARY OF THE INVENTION
This invention relates to quinolinyl-benzopyran compounds having LTD.sub.4 antagonist properties and to therapeutic compositions and methods for the treatment of disorders which result from LTD.sub.4 activity. In general, the compounds of this invention can be described by general Formula I ##STR1## where: A is O, S, ##STR2## or a carbon-carbon single B is a carbon-carbon single bond, O, S, SO, SO.sub.2, NR.sub.1, ##STR3## D is O, S, NR.sub.1, ##STR4## or a carbon-carbon single bond; E is a carbon-carbon single bond or ##STR5## a is 0-1; b is 0-1; c is 0-3; d is 0-3; e is 0-3; f is 0-3; n is 0-2; halo, nitro, haloalkyl, cyano or acyl; --(CH.sub.2).sub.x -M-(CH.sub.2).sub.y -X; R.sub.3 ; ##STR6## provided at least one R.sub.2 group and no more than two non-geminal R.sub.2 groups are R.sub.3 at the same time; provided M and A or B are not geminal oxygen atoms; aralkoxy, amino, mono- and di-alkylamino, aralkylamino, acy
REFERENCES:
patent: 4282230 (1981-08-01), Hoehn
patent: 4661499 (1987-04-01), Young
patent: 4769461 (1988-09-01), Musser
Campbell Henry F.
Huang Fu-Chich
Learn Keith S.
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