Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1989-10-16
1991-03-19
Shen, Cecilia
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
552521, C07J 4100
Patent
active
050012347
DESCRIPTION:
BRIEF SUMMARY
FIELD OF INVENTION
This invention encompasses novel cyclic hydrocarbons substituted with an aminoalkyl sidechain that are useful for inhibiting adverse physiological symptoms associated with phospholipase A2 and for treating hypoglycemia associated diseases such as diabetes and obesity.
BACKGROUND
Phospholipase A2 hydrolyses arachidonic acid containing phospholipids, thereby providing substrate to the multiple enzymes of the arachidonic acid cascada. The metabolites of the arachidonic acid cascade are varied and include prostaglandins, thromboxanes, leukotrienes, or other hydroxylated derivatives of arachidonic acid. The role of phospholipase A2 in the formation of prostaglandins in mammalian metabolism is well known, see W. Vogt, Advances in Prostaglandins and Thromboxane Research, 3, p. 89 (1978) and P. C. Isakson, et al., Advances in Prostaglandin and Thromboxane Research, 3, page 113, (1978). Generally, these metabolites are beneficial but in certain disease processes or other conditions the excessive production of arachidonic acid metabolites causes deleterious consequences such as inflammation, erythema, platelet aggregation, or allergic responses. The inhibition of phospholipase A2 prevents these and similar conditions.
The actual inhibition of phospholipase A2 takes place on a cellular level, therefore, administration of phospholipase A2 inhibitory compounds can be by any manner that will allow for phospholipase A2 inhibition in the affected tissues or organs. The precise mechanisms of the disease processes or conditions which stimulate the arachidonic acid cascade are not clearly understood. The essential prerequisite, however, is enhanced activity of the phospholipases which provide arachidonate to the series of reactions designated as the arachidonic acid cascade. One aspect of the present invention is to block the action of the phospholipases and cut off the flow of arachidonic acid into the cascade, irrespective of the stimulus or stimuli which may be present. Thus, the inhibition of phospholipase A2 of this invention is suitable for treating seemingly unrelated diseases whose common element is the stimulation of the arachidonic acid cascade.
Hyperglycemia refers to a condition commonly found in patients suffering from mature onset diabetes mellitus or other diseases which cause impairment of pancreatic function. Hyperglycemic patients with non-insulin dependent diabetes mellitus (NIDDM) with insulin resistance exhibit elevated serum glucose levels. Failure to adequately control elevated serum glucose levels can cause myocardioischemia, stroke, peripheral vascular disease, lethargy, coma, blindness, kidney failure or death. One important means of treating these patients uses oral antidiabetic agents instead of conventional treatment for hyperglycemic conditions such as restriction of carbohydrate intake or insulin injection.
INFORMATION DISCLOSURE
Some inhibitors of phospholipase A2 are known. Certain local anesthetics have been shown to inhibit phospholipase A2 activity by competing with calcium ion, which appears to be necessary for phospholipase activity. see W. Vogt, Advances in Prostaglandin and Thromboxane Research, 3, p. 89 (1978) and E. Vallee et al., J. Pharm.
Pharmacol., 31, pp. 588-592 (1974). R. J. Flower and G. J. Blackwell have shown that certain anti-inflammatory steroids induce biosynthesis of a phospholipase A2 inhibitor which prevents prostaglandin generation, see Nature, 278, p. 456 (1979). These steroids are not direct inhibitors of phospholipass A2, but rather stimulate the synthesis of a phospholipase inhibiting factor called lipocortin, lipomodulin, or macrocortin.
Some direct phospholipase A2 inhibitors are known. Indomethacin, a drug with anti-inflammatory properties, has been shown to inhibit phospholipase A2 enzymes isolated from the venoms of Russell's Viper, Crotalus adamanteus, and bee, and from pig pancreas; see K. L. Kaplan, et al., Proc. Natl. Acad. Sci., 75, pp. 2955-2988 (1978). Bromphenacyl bromide has been shown to inhibit phospholipase A2 by acylati
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Bundy Gordon L.
Youngdale Gilbert A.
Chang Celia
Koivuniemi Paul J.
Shen Cecilia
The Upjohn Company
Wright Debbie K.
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