The leukotrienes (LT's) play potent roles in hypersensitivity and inflammatory reactions in various biological systems. They are formed from arachidonic acid by a pathway that requires the action of the enzyme, 5-lipoxygenase (5-LO). Leukotrienes C.sub.4 (LTC.sub.4), D.sub.4, and E.sub.4 are sulfidopeptides that dramatically constrict the pulmonary airways and small blood vessels and that are believed to play an important role in the pathophysiology of active anaphylaxis, asthma and vasospastic disease. Thus antagonists of LTC.sub.4, D.sub.4, E.sub.4, 5-LO, and active anaphylaxis are expected to be useful as anti-allergy agents. Another leukotriene, LTB.sub.4, has inflammatory properties and has been detected in exudates from human inflammatory disease including psoriasis. In addition, leukotrienes have been found to accumulate during the crisis stage of myocardial infarction. As a result, 5-LO inhibitors are expected to be useful in the treatment of inflammation, psoriasis, and myocardial infarction.
The compounds of the invention are flavonoids that are useful in the treatment of inflammation, psoriasis, and myocardial infarction as evidenced by their ability to antagonize 5-LO in an in vitro assay. They are active as anti-allergic compounds as indicated by their abilities to antagonize the effects of LTC.sub.4 in vitro on guinea pig ilial tissue and to antagonize 5-LO in an in vitro assay. Preferred compounds of the invention demonstrate an additional property, the ability to inhibit edema in a rat anaphylaxis test, which is indicative of anti-allergy activity.
Antagonists of SRS-A (slow reacting substance of anaphylaxis), the main components of which are LTC.sub.4, D.sub.4, and E.sub.4, are known but are structurally quite different from the flavonoids of the present invention. They include sodium 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-4-oxo-8-propyl -4H-1-benzopyran-2-carboxylate (FPL 55712) and its analogs. FPL 55712, however, is a glycerol containing a non-phenyl substituted chromone moiety. German Offenlegungsschrift, DE No. 3,416,230, European Pat. No. 0108592, and U.S. Pat. Nos. 4,518,613, 4,448,729, 4,424,231, and 3,882,148 also disclose SRS-A antagonists that are aryloxyalkane carboxylic acid derivatives.
U.S. Pat. No. 4,495,198 discloses chromonoxypropanolamines with alkyl substitution on the nitrogen as antihypertensive agents and U.S. Pat. No. 4,501,755 discloses isoflavones as anti-inflammatory agents. Neither patent, however, discloses the flavonoids of this invention.
USPTO Backgrounds
USPTO Backgrounds