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WO 2009/137104 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 12 November 2009 (12.11.2009) WO 2009/137104 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/137 (2006.01) A61K 31/5685 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/138 (2006.01) A61P 35/00 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, A61K 31/4196 (2006.01) CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (21) International Application Number: HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, PCT/US2009/002885 KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (22) International Filing Date: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, 7 May 2009 (07.05.2009) NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, (25) Filing Language: English UG, US, UZ, VC, VN, ZA, ZM, ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 61/127,025 9 May 2008 (09.05.2008) US GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, (71) Applicant (for all designated States except US): RA¬ TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, DIUS HEALTH, INC. [US/US]; 300 Technology ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Square, 5th Floor, Cambridge, MA 021 39-3520 (US). MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, (72) Inventors; and MR, NE, SN, TD, TG). (75) Inventors/Applicants (for US only): LYTTLE, C , Richard [CA/US]; 120 Edgehill Road, BaIa Cynwyd, PA Published: 19004 (US). HATTERSLEY, Gary [GB/US]; 14 Wood — with international search report (Art. 21(3)) man Drive, Stow, MA 01775 (US). O'DEA, Louis [IE/US]; 566 Main Street, Hingham, MA 02043-3 127 — before the expiration of the time limit for amending the (US). claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) (74) Agents: ABELLEIRA, Susan, M. et al; Hamilton, Brook, Smith & Reynolds, P.C., 530 Virginia Road, P.O. Box 9133, Concord, MA 01742-91 33 (US). (54) Title: COMBINATION THERAPY FOR BREASTCANCER COMPRISING AN ANTIESTROGENIC AGENT (57) Abstract: This invention relates to combination therapies for the treatment of breast cancer comprising administering to a subject in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof and an anti-estrogenic agent (e.g., an aromatase inhibitor, a SERM that is not the SERM of Formula I, a GNRH agonist, a GNRH antagonist, or an estrogen receptor downregulator) and to compositions (e.g., pharmaceutical compositions) comprising a compound of Formula I or a pharmaceuti- cally acceptable salt thereof and an anti-estrogenic agent. This invention also relates to a method of treating the side effects (e.g., vasomotor disturbances, osteoporosis and musculoskeletal complaints) associated with anti-estrogen therapy in a subject treated with one or more anti-estrogenic agents (e.g., an aromatase inhibitor, a SERM that is not the SERM of Formula I, a GNRH ago- nist, a GNRH antagonist or an estrogen receptor downregulator). The method comprises administering to the subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. COMBINATION THERAPY FOR BREASTCANCER COMPRISING AN ANTIESTROGENIC AGENT RELATED APPLICATION This application claims the benefit of U.S. Provisional Application No. 61/127,025, filed on May 9, 2008. The entire teachings of the above application is incorporated herein by reference. BACKGROUND OF THE INVENTION For decades, one of the mainstay treatments for breast cancer in humans has been the administration of tamoxifen and to a lesser extent, toremifene. Tamoxifen and toremifene are commonly referred to as Selective Estrogen Receptor Modulators (SERMs). The efficacy of the SERMs is putatively based on the ability to compete with endogenous estrogens (e.g., 17β-estradiol), thereby blocking the proliferative effects of these endogenous estrogens on mammary tissue. Both tamoxifen and toremifene are associated with side effects including hot flushes and stimulation of the endometrium in non-hysterectomized women, leading to an increase in uterine bleeding and uterine cancer. Interestingly, tamoxifen has been shown to confer a positive, estrogen-like benefit on the bone despite having an anti-estrogenic like effect on the breast. More recently, aromatase inhibitors have become popular in the treatment of ER(Estrogen Receptor)-dependent breast cancers. Aromatase inhibitors work by blocking the conversion of precursor compounds (e.g., androstenedione) into estrogens, such as estrone. Popular aromatase inhibitors include both steroidal agents, such as exemestane, and non-steroidal agents, such as letrozole and anastrozole. Despite the growing acceptance of the aromatase inhibitors, they suffer from notable side effects including bone loss, increased bone fractures, vasomotor disturbances (e.g., hot flashes) and joint aches and pains. These effects are what one might expect given the induction of estrogen withdrawal that the agents are precipitating. The combination of tamoxifen and anastrozole was included in the very large ATAC trial (Arimidex Tamoxifen Alone and in Combination trial). The combination arm of the trial (i.e., tamoxifen and anastrozole) was terminated early due to the failure to note any additional benefit relative to the tamoxifen monotherapy arm. By the conclusion of the study, anastrozole by itself appeared to be more effective at preventing breast cancer recurrence than tamoxifen. Despite the efficacy of aromatase inhibitors (e.g. anastrozole) and SERMs, such as tamoxifen and toremifene, both have serious issues for which combination therapy does not provide useful answers. A common method for treating hormone-dependent conditions, such as hormone-dependent breast cancer or hormone-dependent prostate cancer, is to treat a patient with an agent that shuts down the endogenous production of sex hormones (e.g. estradiol and testosterone). These agents include gonadotropin releasing hormone agonists (GNRH agonists), such as buserelin, goserelin, histrelin, leuprorelin, nafarelin and triptorelin as well as gonadotropin releasing hormone antagonists (GNRH antagonists), such as abarelix, cetrorelix and ganirelix. While the efficacy of these agents can be very impressive due to their ability to cease hormonal production, they carry very strong and potentially harmful side effects. In this sense, their side effect profile might be considered to be similar to aromatase inhibitors (particularly in females), but with potentially greater magnitude due to the severity of the hormonal shut down. Again, for the same reasons spoken about with respect to aromatase inhibitors and SERMs, the ability to treat the side effects of GNRH agonists and GNRH antagonists is quite limited due to the fact that the most desirable treatment therapy, which comprises replacing the lost hormones, is contraindicated. Clearly, new therapies are needed that can improve upon the side effect profile of one or more of these agents and/or increase their efficacy in treating breast cancer. The present application provides such therapies. SUMMARY OF THE INVENTION This invention relates to combination therapies for the treatment of breast cancer comprising administering to a subject in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof and an anti-estrogenic agent (e.g., an aromatase inhibitor, a SERM that is not the SERM of Formula I, a GNRH agonist, a GNRH antagonist or an estrogen receptor downregulator) and to compositions (e.g., pharmaceutical compositions) comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and an anti-estrogenic agent. This invention also relates to a method of treating the side effects (e.g., vasomotor disturbances, osteoporosis and musculoskeletal complaints) associated with anti- estrogen therapy in a subject treated with one or more anti-estrogenic agents (e.g., an aromatase inhibitor, a SERM that is not the SERM of Formula I, a GNRH agonist, a GNRH antagonist or an estrogen receptor downregulator). The method comprises administering to the subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. More specifically, the invention described herein relates to compositions comprising a compound of formula I or pharmaceutically acceptable salt thereof I and an anti-estrogenic agent (e.g., an aromatase inhibitor, a SERM that is not the SERM of Formula I, a GNRH agonist, a GNRH antagonist or an estrogen receptor downregulator). The composition can be a pharmaceutical composition further comprising a pharmaceutically acceptable excipient. In one embodiment, the composition comprises a compound of formula I, or a pharmaceutically acceptable salt thereof and an aromatase inhibitor. In a more particular embodiment, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable excipient. In a particular embodiment of this invention, the composition comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, and an aromatase inhibitor selected from the group consisting of: anastrozole, letrozole and exemestane. In another particular embodiment of this invention, the composition comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, and the aromatase inhibitor, anastrozole. In a more particular embodiment, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable excipient. In another particular embodiment of this invention, the composition comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, and the aromatase inhibitor, exemestane.
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