Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-01-11
2003-10-14
Padmanabhan, Sreeni (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06632834
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to compositions and methods for treating conditions responsive to estrogen. The compositions and methods utilize estrogen agonist/antagonist compounds. In both men and post-menopausal women, conditions such as rheumatoid arthritis, colon cancer, tissue wounds, skin wrinkles and cataracts are treated with the compositions and methods of the present invention.
BACKGROUND OF THE INVENTION
In premenopausal women, 17&bgr;-estradiol produced by the ovaries is the chief circulating estrogen. Serum estradiol concentrations are low in preadolescent girls and increase at menarche. In women, they range from about 100 pg per milliliter (367 pmol per liter) in the follicular phase to about 600 pg per milliliter (2200 pmol per liter) at the time of ovulation. They may rise to nearly 20,000 pg per milliliter (70,000 pmol per liter) during pregnancy. After menopause, serum estradiol concentrations fall to values similar to or lower than those in men of similar age (5 to 20 pg per milliliter [18 to 74 pmol per liter]) (Yen, S. S. C. and Jaffe, R. B., eds.
Reproductive Endocrinology: Physiology, Pathophysiology and Clinical Management,
3rd ed. Philadelphia: W. B. Saunders, (1991)).
Steroidal estrogens are formed ultimately from either androstenedione or testosterone as immediate precursors. The reaction involves aromatization of the A ring, and it is catalyzed in three steps by a monooxygenase enzyme complex (aromatase) that uses NADPH and molecular oxygen as cosubstrates, (Miller, W. L.,
Endocr. Rev.,
9:295-318 (1988)). In the first step of the reaction, C 19 (the angular methyl group residing on C 10 of the androgen precursor) is hydroxylated. A second hydroxylation results in the elimination of the newly formed C 19 hydroxymethyl group, and a final hydroxylation on C 2 results in the formation of an unstable intermediate that rearranges to form the phenolic A ring. The entire reaction consumes three molecules of NADPH.
Aromatase activity resides within a transmembrane glycoprotein (P
450,arom
) that is homologous with the cytochrome P
450
family of monooxygenases (Nebert, D. W. and Gonzalez, F. J.,
Annu. Rev. Biochem.
56:945-993, (1987); Corbin, C. J., et al.,
Proc. Natl. Acad. Sci. USA,
85:8948-8952, (1988)); also essential is a ubiquitous flavoprotein, NADPH-cyctochrome P
450
reductase. Both proteins are localized in the endoplasmic reticulum of ovarian granulosa cells, testicular Sertoli and Leydig cells, adipocytes, placental synctiotrophoblasts, the preimplantation blastocyst, and various brain regions, including the hypothalamus.
The ovaries are the principle source of estrogen in premenopausal women. The major secretory product is estradiol, synthesized by granulosa cells from androgenic precursors provided by thecal cells. Secreted estradiol is oxidized reversibly to estrone, and both of these estrogens can be converted to estriol. These transformations take place mainly in the liver, where interconversion between estrone and estradiol is catalyzed by 17-hydroxysteroid dehydrogenase.
In men and postmenopausal women, the principle source of estrogen is adipose tissue. In this and in other peripheral tissues, estrone is synthesized from dehydroepiandrosterone, which is secreted by the adrenal cortex. Thus, the contribution of adipose tissue estrogens is regulated, in part by the availability of androgenic precursors (Mendelson, C. R. and Simpson, E. R.,
Mol. Cell Endocrinol.,
52:169-176, (1987)).
Autoimmune diseases, such as rheumatoid arthritis, involve aberrant regulation of cellular and humoral mediated immunity and are frequently associated with abnormal or enhanced T cell, B cell and macrophage effector functions directed towards self antigens. The activation of these cellular components towards self antigens is believed related to the break in feedback mechanisms associated with self tolerance. Autoimmune diseases encompass a whole spectrum of clinical entities and despite the differences in the target organ have many similarities. These include their preponderance in females of child bearing age with a female to male ratio varying from 50:1 in Hashimoto's thyroiditis to 10:1 in systemic lupus erythematosus (SLE) to 2:1 in Myasthenia gravis (Ahmed et al.,
Am J. Path.,
121:531 (1985)). In addition, these diseases are all characterized by the chronicity, the tendency of clinical remission and “flare ups” for poorly understood reasons, and the involvement of other organs. While the presence of autoantibodies, inappropriate expression of class II antigens, macrophage activation and T cell infiltration to the target organ have been described in essentially all of the autoimmune diseases, neither the triggering mechanisms which result in disease activation nort disease progression are well understood. Accordingly, therapy for these diseases is largely unsatisfactory and involves the use of gold salts, methotrexate, antimalarials, glucocorticoids (methylprednisolone), and other immunosuppressives as well as plasmaphoresis and attempts at inducing tolerance. Treatment of autoimmune diseases has not improved significantly over the past decade and primarily is associated with the use of nonsteroidal and steroidal anti-inflammatory agents to treat the symptoms of the disease. Clearly while suppression of the specific immune response directed against the host is necessary, generalized immunosuppression as with glucocorticoids has major liabilities in terms of side effect profile and the propensity of the immunosuppressed subject to be at greater risk for other infectious and non-infectious diseases.
Polymorphonuclear leukocytes (PMNL) play a regulatory role in inflammatory diseases. These cells, when activated, synthesize and release oxygen-centered molecules, chemo-attractants, and hydrolytic enzymes. There is evidence that the oxygen-centered molecules play a detrimental role in a number of diseases such as chronic inflammatory diseases, rheumatoid arthritis, SLE, and others. In the case of an autoimmune disease, SLE, for example, the initiation of an inflammatory response is self antigen stimulating one's host neutrophils or PMNLs to secrete strong oxidants which damage surrounding cells and tissue.
Estrogen appears to be involved with autoimmune diseases although its role in disease progression or regression is complex and dependent on the nature of the autoimmune disease. Estrogen for example appears to have ameliorating effect on rheumatoid arthritis while having an exacerbating effect on systemic lupus (Chander & Spector;
Ann. Rheum. Dis.
50:139). As reported by Jansson (
Free Rad. Res. Comms.,
14(3):195-208, (1991)), estrogen increased the activity of an enzyme generated by PMNLS, myeloperoxidase, which regulates the production of oxidants from hydrogen peroxide. This enzyme converts hydrogen peroxide to hypochlorous acid, a strong oxidant. By increasing the enzyme's activity, and thus the presence of hypochlorous acid, the likelihood of increased oxidative stress on tissues, cells and various macromolecules in chronic inflammatory/autoimmune diseases is enhanced.
EP 664 125 A1 reports that inhibition of myeloperoxidase may be accomplished by treatment with certain 3-aroyl benzothiophines. Excess myeloperoxidase is associated with conditions which include systemic lupus erythematosis, Hashimoto's thyroiditis, myasthenia gravis, rheumatoid arthritis and multiple sclerosis.
Estrogen has been demonstrated to have a suppressive role on T cell function and yet an immunostimulatory effect on B cells. Therefore, estrogen-like compounds should prove beneficial in diseases associated with activated T cells including rheumatoid arthritis, multiple sclerosis, Guillan Barre syndrome and Hashimoto's thyroiditis through inhibition of T cell function (Holmadahl, J.,
Autoimmun.
2:651 (1989).
In addition to the suppressive effects of estrogen on T cells, estrogen may have additional protective roles. Marui et al., (
J. Clin. Invest.
92:1866 (1993)) have recently reported that antioxidants suppress en
Day Wesley W.
Lee Andrew G.
Rosati Robert L.
Thompson David D.
Benson Gregg C.
Crissey Todd M.
Hui San-ming
Padmanabhan Sreeni
Pfizer Inc.
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