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(12) United States Patent (10) Patent No.: US 6,927,224 B2 Kaltenbach Et Al

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(12) United States Patent (10) Patent No.: US 6,927,224 B2 Kaltenbach Et Al USOO6927224B2 (12) United States Patent (10) Patent No.: US 6,927,224 B2 Kaltenbach et al. (45) Date of Patent: Aug. 9, 2005 (54) SELECTIVE ESTROGEN RECEPTOR Evans, R.M., “The Steroid and Thyroid Hormone Receptor MODULATORS Superfamily”, Science, vol. 240, pp. 889-895 (1988). Jordan, V.C. et al., “Endocrine Pharmacology of Antiestro (75) Inventors: Robert F. Kaltenbach, Wilmington, DE gens as Antitumor Agents', Endocrine Reviews, Vol. 11, No. (US); Simon P. Robinson, Stow, MA 4, pp. 578-610 (1990). (US); George L. Trainor, Wilmington, Kedar, R.P. et al., “Effects of tamoxifen on uterus and DE (US) ovaries of postmenopausal women in a randomised breast cancer prevention trial”, Lancet, vol. 343, pp. 1318-1321 (73) Assignee: Bristol Myers Squibb Company, (1994). Princeton, NJ (US) Love, R.R. et al., “Effects of Tamoxifen on Bone Mineral (*) Notice: Subject to any disclaimer, the term of this Density in Postmenopausal Women with Breast Cancer', patent is extended or adjusted under 35 The New England Journal of Medicine, vol. 326, No. 13, pp. U.S.C. 154(b) by 0 days. 852-856 (1992). Love, R.R. et al., “Effects of Tamoxifen on Cardiovascular Risk Factors in Postmenopausal Women', Annals of Internal (21) Appl. No.: 10/216,253 Medicine, vol. 115, pp. 860-864 (1991). (22) Filed: Aug. 9, 2002 McCague, R. et al., “Synthesis and Estrogen Receptor Binding of 6,7-Dihydro-8-phenyl-9-4-2-(dimethylami (65) Prior Publication Data no)ethoxyphenyl-5H-benzocycloheptene, a Nonisomeriz US 2003/0105148 A1 Jun. 5, 2003 able Analogue of Tamoxifen. X-ray Crystallographic Stud ies”, J. Med. Chem. vol. 29, pp. 2053-2059 (1986). Related U.S. Application Data McDonnell, D.P. et al., “Analysis of Estrogen Receptor (60) Provisional application No. 60/311,466, filed on Aug. 11, Function in Vitro Reveals Three Distinct Classes of Anties 2001. trogens', Molecular Endocrinology, Vol. 9, No. 6, pp. (51) Int. Cl." ........................ A61K 31/24: CO7C 311/00 659-669 (1995). (52) U.S. Cl. ....................... 514331; 514/367; 514/539; Parker, M.G., “Action of pure antiestrogens in inhibiting 514/602; 514/603; 514/604; 514/605; 514/445; estrogen receptor action', Breast Cancer Research and 549/65; 546/234; 548/167; 560/12; 564/89; Treatment, vol. 26, pp. 131-137 (1993). 564/97; 564/86; 564/88; 564/91; 564/87; Tasset, D. et al., “Distinct Classes of Transcriptional Acti 564/99; 562/98 vating Domains Function by Different Mechanisms”, Cell, (58) Field of Search ................................. 514/605, 331, vol. 62, pp. 1177–1187 (1990). 514/367, 539, 602, 603, 604, 445; 562/98; Tonetti, D.A. et al., “PoSSible mechanisms in the emergence 549/65; 546/234; 548/167; 560/12; 564/89, of tamoxifen-resistant breast cancer, Anti-Cancer Drugs, 97, 86, 88,91, 87, 99 vol. 6, pp. 498–507 (1995). Tora, L. et al., “The Human Estrogen Receptor Has Two (56) References Cited Independent Nonacidic Transcriptional Activation Func U.S. PATENT DOCUMENTS tions”, Cell, vol. 59, pp. 477–487 (1989). TZukerman, M.T. et al., “Human Estrogen Receptor Trans 5,681835. A 10/1997 Willson activational Capacity is Determined by both Cellular and 6,005.003 A 12/1999 Nique Promoter Context and Mediated by Two Functionally Dis FOREIGN PATENT DOCUMENTS tinct Intramolecular Regions, Molecular Endocrinology, vol. 8, No. 1, pp. 21-30 (1994). WO WO 99/08682 2/1999 WO WO 01/26651 4/2001 (Continued) WO WO 01/77055 10/2001 WO WO 01/77.057 10/2001 Primary Examiner-Laura L. Stockton (74) Attorney, Agent, or Firm-Jacqueline M. Cohen; OTHER PUBLICATIONS Elliott Korsen Willson, T.M. et al., “3-4-(1, 2-Diphenylbut-1-enyl)phenyl)acrylic Acid: A Non-Steroi (57) ABSTRACT dal Estrogen with Functional Selectivity for Bone over The present invention provides, inter alia, triphenylethylene Uterus in Rats", J. Med. Chem., vol. 37, pp. 1550–1552 derivatives, such as, 3-4-6-(3-Methoxy-phenyl)-8,9- (1994). dihydro-7H-benzocyclohepten-5-yl-phenyl-acrylic acid, Weatherman, R.V. et al., “Differential SERM activation of as Selective estrogen receptor modulators. Also provided are the estrogen receptors (ERC. and ERB) at AP-1 sites”, methods for the treatment and/or prevention of estrogen Chemistry & Biology, vol. 8, pp. 427-436 (2001). Stimulated diseases in mammals including breast, uterine, Database CAPLUS Online Chemical Abstracts Service, ovarian, prostrate and colon cancer, osteoporosis, cardiovas Columbus, Ohio, U.S., Database accession No. 121:34956 cular disease, and benign proliferative disorders, as well as XP0022222761 *RNs: 155701-59–0, 155701-64-4, pharmaceutical compositions of the compounds of the 155701-70–5, 155701–71–6* abstract (1994). present invention. Eaker, E.D. et al., “Cardiovascular Disease in Women', Circulation, vol. 88, No. 4, Part 1, pp. 1999–2009 (1993). 9 Claims, No Drawings US 6,927,224 B2 Page 2 OTHER PUBLICATIONS Uterine Hypertrophy in Ovariectomized Rats', J. Clin. Wagner, B.L. et al., “16O-substituted analogs of the anti Invest., vol. 93, pp. 63–69 (1994). progestin RU486 induce a unique conformation in the Chow, J. et al., “Estrogen Maintains Trabecular Bone Vol human progesterone receptor resulting in mixed agonist ume in Rats Not Only by Suppression of Bone Resorption activity”, Proc. Natl. Acad. Sci. USA, Vol. 93, pp. but Also by Stimulation of Bone Formation”, J. Clin. Invest., 8739–8744 (1996). vol. 89, pp. 74–78 (1992). Beekman, J.M. et al., “Transcriptional Activation by the Estrogen Receptor Requires a Conformational Change in the Scanlan, Thomas S., “Differential SERM activation of the Ligand Binding Domain', Molecular Endocrinology, Vol. 7, estrogen receptors (ERC. and ERB) at AP-1 sites”, Chem No. 10, pp. 1266–1274 (1993). istry & Biology, vol. 8, No. 5, pp. 427-436 (2001) Black, L.J. et al., “Raloxifene (LY139481 HCl) Prevents (XP002220838). Bone Loss and Reduces Serum Cholesterol without Causing PCT International Search Report mailed Feb. 26, 2003. US 6,927,224 B2 1 2 SELECTIVE ESTROGEN RECEPTOR lates endometrial tissue growth and prevents bone loSS. MODULATORS Estrogens are an important class of Steroidal hormones that Stimulate the development and maintenance of fundamental CROSS-REFERENCE TO RELATED Sexual characteristics in humans. In the past, estrogens have APPLICATIONS been found useful in the treatment of certain medical con ditions and diseases. For example estradiol, a Steroid hor This application claims the priority benefit of U.S. Pro mone produced by the ovary, is useful in the treatment of visional Application No. 60/311,466, filed Aug. 11, 2001, osteoporosis, cardiovascular disease, premenstrual the disclosure of which is incorporated herein by reference Syndrome, Vaso motor Symptoms associated with in its entirety. menopause, atrophic vaginitis, Kraurosis Vulvae, female hypogonadism, primary ovarian failure, excessive hair FIELD OF THE INVENTION growth and prostatic cancer. Hormone replacement therapy (HRT) with estrogen has This invention pertains to triphenylethylene derivatives, been determined to be a clinically effective treatment for such as, 3-4-6-(3-Methoxy-phenyl)-8,9-dihydro-7H Osteoporosis in post-menopausal women. However, leSS benzocyclohepten-5-yl)-phenyl-acrylic acid, as selective than 15% of eligible women are currently prescribed HRT estrogen receptor modulators. This invention also provides 15 despite clinical trials that have demonstrated a 50% reduc methods for the treatment and/or prevention of estrogen tion in hip fractures and a 30% reduction in cardiovascular Stimulated diseases in mammals including breast, uterine, disease. Non-compliance arises from patient and physician ovarian, prostrate and colon cancer, Osteoporosis, cardiovas concerns over the two fold increased risk of endometrial cular disease, and benign proliferative disorders, as well as cancer observed with HRT employing estrogen alone as well pharmaceutical compositions of the compounds of the as the association between estrogen therapy and breast present invention. cancer. Although unproven in the clinic, this Suspected risk for breast cancer has led to HRT being contraindicated in a BACKGROUND OF THE INVENTION Significant percentage of post-menopausal women. Approximately 180,000 women are diagnosed with breast Co-therapy with progestins has been shown to protect the cancer each year in the United States. Most of these women 25 uterus against cancer while maintaining the Osteoprotective are cured of their disease by Surgery and local radiotherapy. effects of the estrogen, however the progestin introduces However, nearly 60,000 women go on to develop metastatic other Side effects Such as withdrawal bleeding, breast pain breast cancer each year, and 45,000 of these patients even and mood Swings. tually die from their malignancies. While metastatic breast In light of the more Serious Side effects associated with cancer is rarely curable, it is treatable with modern phar estrogen therapy, including myocardial infarction, maceuticals that prolong patient Survival and reduce the thromboembolism, cerebrovascular disease, and endome morbidity associated with metastatic lesions. Foremost trial carcinoma, a significant amount of research has been among these therapies are hormonal manipulations that carried out to identify effective nonsteroidal estrogen and include selective estrogen receptor modifiers (SERMs). antiestrogenic compounds. In general, Such compounds may SERMs are Small ligands of the estrogen receptor that are be characterized as both estrogenic and antiestrogenic capable of inducing a wide variety of conformational 35 because, while they all bind to the
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