Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1999-06-23
2003-08-19
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S569000
Reexamination Certificate
active
06608111
ABSTRACT:
I. FIELD OF THE INVENTION
The present invention relates to the field of pharmaceutical therapeutics. More specifically, the present invention relates to the use of estrogenic carboxylic acids in improved therapies for the treatment of a variety of symptoms and disease conditions in mammals. The present invention also relates to the field of chemical synthesis, more specifically, the synthesis of estrogenic carboxylic acids.
II. BACKGROUND OF THE INVENTION
A. Estrogens
Estrogens, such as (+)-17&bgr;-estradiol (E2), have physiological effects on males as well as females. In addition to their activity in reproductive tissue, they promote rapid weight gain in specific species, and have been marketed to fatten livestock quickly. Trenkle, A H: “The Mechanisms of Action of Estrogens in Feeds on Mammalian and Avian Growth.”
Proceedings of a Symposium: The Use of Drugs in Animal Feed
. National Academy of Science, Washington D.C. 150-164 (1968); Meyers, U.S. Pat. No. 5,420,161. Estrogens have long been prescribed for their beneficial effects by reducing susceptibility to osteoporosis and ameliorating menopausal and postmenopausal symptoms. Evans S F, Davie M W: “Low and Conventional Dose Transdermal Oestradiol Are Equally Effective at Preventing Bone Loss In Spine and Femur at All Post-Menopausal Ages.”
Clin Endocrinol
. 44:79-84 (1996); Agarwal S K, Judd H L: “Menopause.”
Curr Ther Endocrinol Metab
. 6:624-631 (1997). Long-term clinical studies suggest that estrogens may be beneficial in promoting cardiovascular health. Wilson P W: “The Impact of Estrogen on Cardiovascular Disease.” Perspective Studies: The Framingham Study.
Postgrad Med
51-53:89-90 (1989). More recently, estrogens have shown promise as an adjunct in treatment of Alzheimer's disease. Filley C M: “Alzheimer's Disease in Women.”
Am J Obstet Gynecol
176:1-7 (1997). Unfortunately, some estrogenic compounds administered in therapeutic doses are suspected carcinogens in target tissues including breast and uterus. Persson I: “Cancer Risk in Women Receiving Estrogen-Progestin Replacement Therapy.”
Maturitas
23:S37-45 (1996).
Non-steroidal estrogens and antiestrogens, including pharmaceuticals, environmental compounds, and phytochemicals, are currently receiving significant attention. This is understandable from the myriad potential applications increasingly being reported for estrogenic compounds, e.g., treating menopause- and post-menopause-related problems, as anti-carcinogens, alleviating osteoporosis, for contraceptive use, in estrogen-replacement therapy, treating prostatic disease, improving serum lipid profiles, etc. The multiplicity of estrogenic effects now being discovered has led many investigators to target specific populations for treatment with estrogen agonists and antagonists. Synthetic nonsteroidal compounds such as triphenylethylene derivatives (e.g., tamoxifen), dihydronapthalene derivatives (e.g., nafoxidine), and benzothiophene derivatives (e.g., raloxifene) exhibit estrogenic and anti-estrogenic activity in various tissues, these respective compounds showing specific advantages in the management of bone, uterine, serum cholesterol, and adipose tissue. See, generally, Trenkle, A H: “The Mechanisms of Action of Estrogens in Feeds on Mammalian and Avian Growth.”
Proceedings of a Symposium: The Use of Drugs in Animal Feed
. National Academy of Science, Washington D.C. 150-164 (1968); Evans S F, Davie M W: “Low and Conventional Dose Transdermal Oestradiol Are Equally Effective at Preventing Bone Loss In Spine and Femur at All Post-Menopausal Ages.”
Clin Endocrinol
. 44:79-84 (1996); Agarwal S K, Judd H L: “Menopause.”
Curr Ther Endocrinol Metab
. 6:624-631 (1997); Wilson P W: “The Impact of Estrogen on Cardiovascular Disease.” Perspective Studies: The Framingham Study.
Postgrad Med
51-53:89-90 (1989); Filley C M: “Alzheimer's Disease in Women.”
Am J Obstet Gynecol
176:1-7 (1997); Persson I: “Cancer Risk in Women Receiving Estrogen-Progestin Replacement Therapy.”
Maturitas
23:S37-45 (1996); Heer J, Billeter J R, Miescher K: “Totalsynthese der racemischen bisdehydro-doisynolsäure. Über oestrogene carbosäuren IV.”
Helv. Chim. Acta
28:1342-1354 (1945); Ke H Z, Chen H A, Simmons H A, Qi H, Crawford D T, Pirie C M, Chidsey-Frink K L, Ma Y F, Jee W S S, Thompson D D: “Comparative Effects of Droloxifene, Tamoxifen, and Estrogen on Bone, Serum Cholesterol, and Uterine Histology in the Ovariectomized Rat Model.”
Bone
20:31-39 (1997); Sato M, Rippy M K, Bryant H U: “Raloxifene, Tamoxifen, Nafoxidine, or Estrogen Effects on Reproductive and Nonreproductive Tissues in Ovariectomized Rats.”
FASEB J
10:905-912 (1996); Dodge J A, Glasebrook A L, Magee D A, Phillips D L, Sato M, Short L L, Bryant H U: “Environmental Estrogens: Effects on Cholesterol Lowering and Bone in the Ovariectomized Rat.”
J Steroid Biochem Molec Biol
59:155-161(1996); Hart J E: “Endocrine Pathology of Estrogens: Species Differences.”
Pharmac Ther
47:203-218 (1990); Heywood R, Wadsworth P F: “The Experimental Toxicology of Estrogens.”
Pharmac Ther
8:125-142 (1980); Baker V L, Draper M, Paul S, Allerheiligen S, Glant M, Shifren J, Jaffe R B: “Reproductive Endocrine and Endometrial Effects of Raloxifene Hydrochloride, A Selective Estrogen Receptor Modulator, in Women with Regular Menstrual Cycles.”
J Clin Endocrin Metab
83:6-13 (1998); Danzo B J: “Environmental Xenobiotics May Disrupt Normal Endocrine Function by Interfering with the Binding of Physiological Ligands to Steroid Receptors and Binding Proteins.”
Environ Health Perspect
105:294-301 (1997); Baker V L, Jaffe R B: “Clinical Uses of Antiestrogens.”
Obstet Gynecol Surv
51:45-59 (1996); Knight D C, Eden J A: “A Review of the Clinical Effects of Phytoestrogens.”
Obstet Gynecol
87:897-904 (1996); Cooper R L, Kaviock R J: “Endocrine Disruptors and Reproductive Development: A Weight-of-Evidence Overview.”
J Endocrinol
152:159-166 (1997); Reubinoff B E, Wurtman J, Rojansky N, Adler D, Stein P, Schenker J G, Brzezinski A: “Effects of Hormone Replacement Therapy on Weight, Body Composition, Fat Distribution, and Food Intake in Early Postmenopausal Women: A Prospective Study.”
Fertil Steril
64:963-968 (1995).
B. Doisynolic Acids and Related Estrogenic Compounds
Doisynolic acids, named after their discoverer, Edward Doisy, are estrogenic compounds originally obtained from alkali fusion of estrone and equilenin. “Doisynolic acid,” from estrone, contains a phenolic moiety; and “bisdehydrodoisynolic acid” (BDDA), from equilenin, possesses a &bgr;-naphtholic moiety. Both types are seco-steroids, i.e., the steroidal D-ring is cleaved. See Miescher K: “On Doisynolic Acids, A New Class of Estrogens.”
Chem Rev
43:367-384 (1948); Fieser L F, Fieser M:
Natural Products Related to Phenanthrene
, 347-353 (3rd Ed., Reinhold Publishing Corp., New York, N.Y. 1949). Meyers and Kolb reported the conversions of E2 and estrone under very mild conditions into doisynolic acids, which, in turn, exhibited estrogenic and antiestrogenic activity depending on dosage. Meyers C Y, Kolb V M: “Facile and Selective Chlorination and Cleavage of Some Cyclanones and Cyclanols With the CCl
4
-KOH-t-BuOH Reagent. In situ Conversions of Estrones and Estradiols into Dichlorodoisynolic Acids.”
J Org Chem
43:1985-1990 (1978). A number of related pseudo-seco-steroid acids (most of them containing only two rings or a shifted C ring) also have been prepared. These compounds have been cited as exhibiting varying degrees of estrogenicity. Meyers C Y, Kolb V M, Gass G H, Rao B R, Roos C F, Dandliker W B: “Doisynolic-Type Acids—Uterotropically Potent Estrogens which Compete Poorly with Estradiol for Cytosolic Estradiol Receptors.
J Steroid Biochem
31:393-404 (1988).
It has been reported that (±)-Z-doisynolic acid is more estrogenic than (+)-E-doisynolic acid (C-14, S configuration) derived from estrone or E2. Anner G, Miescher K: Hydrierungs—Und Umlagerungs-Reaktion in der Doisynolsäure—Reihe. Oestrogene Carbonsäuren XII.
Helv. Chim. Acta
29 (1946) 1889-1895; and Die tota
Adler Stuart R.
Banz William J.
Dandliker Walter B.
Hou Yuqing
Meyers Cal Y.
Senniger Powers Leavitt & Roedel
Southern Illinois University Office of Research, Development and
Travers Russell
Wang Shengiun
LandOfFree
Method for treating or preventing prostatic conditions does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method for treating or preventing prostatic conditions, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for treating or preventing prostatic conditions will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3103554