Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Patent
1987-06-16
1990-04-17
Lee, Mary C.
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
514169, 514182, 5142378, 514255, 514351, 514352, 514381, 514398, 514399, 514400, 514424, 514426, 514471, 514472, 514866, 544154, 544380, 546300, 546304, 546307, 546312, 548263, 548337, 548341, 548342, 548528, 549480, 549491, 549492, 552521, C07J 900, C07D26530, C07D29500, C07D21362, C07D21378, A61K 3113, A61K 31395, A61K 31495
Patent
active
049178261
DESCRIPTION:
BRIEF SUMMARY
FIELD OF INVENTION
This invention relates to novel compositions of matter. More particularly, the invention relates to cyclic hydrocarbons with an aminoalkyl sidechain that are useful for inhibiting phospholipase A2 and for treating diabetes and obesity.
INFORMATION DISCLOSURE
The important role of phospholipase A2 in mammalian metabolism through the formation of prostaglandins is now well known. See W. Vogt, Advances in Prostaglandins and Thromboxane Research, 3, p. 89 (1978); P. C. Isakson, et al., Advances in Prostaglandin and Thromboxane Research, 3, page 113, (1978). Phospholipase A2 is responsible for the hydrolysis of arachidonic acid-containing phospholipids, thereby providing substrate for the multiple enzymes of the arachidonic acid cascade.
The products of the arachidonic acid cascade are varied. These products include prostaglandins, thromboxanes, leukotrienes, and other hydroxylated derivatives of arachidonic acid. All of the foregoing are referred to as "eicosanoids." While generally the products of the cascade are beneficial, in certain disease processes and other conditions the excessive production of eicosanoids induces deleterious consequences such as inflammation (see paper by N. A. Plummer, et al.; abstracted in Journal of Investigative Dermatology, 68, p. 246 (1977)); erythema (N. A. Plummer, supra); platelet aggregation (B. B. Vargafting, J. Pharm. Pharmacol., 29, pp. 222-228 (1977)); and the release of SRS-A (slow reacting substance-anaphylaxis), a known mediator of allergic responses. The inhibition of phospholipase A2 prevents these and similar conditions mediated by the action of this enzyme.
Some inhibitors of phospholipase A2 are known. 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 phospholipase A2, but rather stimulate the synthesis of a phospholipase inhibiting factor called lipocortin, lipomodulin, or macrocortin.
Some examples of direct phospholipase A2 inhibition are known. Indomethacin, a drug with anti-inflammatory properties, has been shown to inhibit phospholipase A2 enzymes. See K. L. Kaplan, et al., Proc. Natl. Acad. Sci., 75, pp. 2955-2988 (1978).
Indomethacin has been shown to inhibit phospholipase A2 enzymes, isolated respectively from the venoms of Russell's Viper, Crotalus adamanteus, and bee, and from pig pancreas. Certain local anesthetics have been shown to inhibit phospholipase A2 activity by competing with calcium ion, which appears to be a requirement 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. 588-92 (1974). Bromphenacyl bromide has been shown to inhibit phospholipase A2 by acylating a histidine residue which is at the active site of the enzyme. See M. Roberts, et al., J. of Biol. Chem., 252, pp. 2405-2411 (1977). R. Blackwell, et al., British J. Pharmacy, 62, p. 79-89 (1978) has disclosed that mepacrine inhibits the activity of phospholipase A2 derived from perfused guniea pig lung. Certain butyrophenones are disclosed as phospholipase A2 inhibitors in U.S. Pat. No. 4,239,780. D. P. Wallach and V. J. R. Brown, Bioch. Pharmacol., 30, pp. 1315-24 (1981) also refer to several compounds that inhibit phospholipase A2.
Some of the steroids employed for synthesizing compounds of the present invention and useful in some of the methods of treatment are known. See the doctoral thesis, L. J. Griggs, "Part I. Synthetic Approaches to 5- and 16-Thiaestrone. Part II. Estrone with a Diazacholesterol Side Chain," University of Michigan (1965). These compounds are stated therein to be potential hypocholesterolemic agents. U.S. Pat. No. 3,370,070 discloses similar steroid compounds which are useful as hypocholesterolemic agents and as antibacterial, anti-protozoal, and anti-algal agents.
Some of the steroidal compounds herein are also referred to in U.
REFERENCES:
patent: 3084156 (1963-04-01), Counsell et al.
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patent: 3284474 (1966-11-01), Klimstra
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patent: 3370070 (1968-02-01), Klimstra
patent: 3639598 (1972-02-01), Klimstra
Klimstra et al., Hypocholesterolenic Agents VI, May 1966, pp. 323-325.
Bundy Gordon L.
Johnson Roy A.
Morton Douglas R.
Wallach, deceased Donald P.
Youngdale Gilbert A.
Koivuniemi Paul J.
Lee Mary C.
Richter J.
The Upjohn Company
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