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WO 2015/169173 Al 12 November 2015 (12.11.2015) P O P C T

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WO 2015/169173 Al 12 November 2015 (12.11.2015) P O P C T (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 WO 2015/169173 Al 12 November 2015 (12.11.2015) P O P C T (51) International Patent Classification: (74) Agent: CHINA SINDA INTELLECTUAL PROPERTY A61K 31/56 (2006.01) A61P 3/04 (2006.01) LTD.; B l 1th Floor, Focus Place, 19 Financial Street, A61P 35/00 (2006.01) A61P 3/06 (2006.01) Xicheng District, Beijing 100033 (CN). A61P 15/12 (2006.01) A61P 19/10 (2006.01) (81) Designated States (unless otherwise indicated, for every A61P 1/16 (2006.01) kind of national protection available): AE, AG, AL, AM, (21) International Application Number: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, PCT/CN20 15/077942 BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, 30 April 2015 (30.04.2015) KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (25) Filing Language: English MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (26) Publication Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (30) Priority Data: TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 2014 10192569.2 8 May 2014 (08.05.2014) CN (84) Designated States (unless otherwise indicated, for every (71) Applicants: SHANGHAI INSTITUTE OF PLANNED kind of regional protection available): ARIPO (BW, GH, PARENTHOOD RESEARCH [CN/CN]; 2140 Xietu GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, Road, Building#2, Room 502, Xuhui District, Shanghai TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, 200032 (CN). CHANGZHOU RUIMING PHARMA¬ TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, CEUTICAL COMPANY, LTD [CN/CN]; 1558 North DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Longjiang Road, Changzhou, Jiangsu 213 127 (CN). LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (72) Inventors: YANG, Jun; 2140 Xietu Road, Building#2, GW, KM, ML, MR, NE, SN, TD, TG). Room 502, Xuhui District, Shanghai 200032 (CN). SHI, Huijuan; 2140 Xietu Road, Building#2, Room 502, Xuhui Published: District, Shanghai 200032 (CN). XU, Wenping; 2140 X i — with international search report (Art. 21(3)) etu Road, Building#2, Room 502, Xuhui District, Shanghai 200032 (CN). (54) Title: ANORDRIN COMPOSITIONS AND METHODS FOR TREATING DISEASES (57) Abstract: The present invention provides methods and compositions for treating cancer, reducing side effects, and reducing postmenopausal symptoms comprising anordrin or analog thereof (such as anordrin) alone or in combination with at least one other agent selected from the group consisting of tamoxifen, raloxifene or functional equivalent thereof, and an aromatase inhibitor. ANO D COMPOSITIONS AND METHODS FO TREATING DISEASES 5 The invention re te to a d i for the treatment of cancer or other d comprising a of a r iri or analog thereof as a ordrin) alone or n n with agent 0 Estrogen binds to it receptors to regulate UNA transcri ption stimulate cell proliferation a t l metabolic many tissues during mammalian reproduction and development. Three genes f r estrogenic proteins been identified, encoding estrogen receptor E ) and | ¾ prot n coupled estrogen receptor ( E ) . i and have similar structural and fa ct na , o ntug activation 5 1 <A F ) D A binding d { BP )„ a di e tion domain and activation function domain AF 2), which is the ligand binding domain (LBD), They both belong to the nuclear super family of g nd d pen n transcription factors and have highly o serve D D and L regions (95%) They regulate UNA transcription p . ligand binding, which results i g nd re ep r that can din i e and translocate into ¾ the nucleus, where t ey d to estrogen response elements (EREs found in the promoters of estrogen-responsive genes. This type of modulation i typically referred to as t e classical estrogen pathway ER- and also regulate diverse biological functions through .membrane-initiated estrogen signaling (MIES), associating with plasma membrane by interaction with their ligand binding domain. The detailed molecular mechanisms of signaling b rnen¾bfane-associated Efts are still unclear. The modulatory effects of estrogen mediated by membrane- ssoc t d receptors cell proliferation, matrix/migration, metabolism and glucose homeostasis have been reviewed (I, 2 Furthermore, studies on E knockout i indicate that ER-a the dominant functional estrogen receptor, as compared t ER . Three transcription variants of EE -4 and 36, have bee found. E R 3 JO lacks the AF- domain and contains partial ligand binding domain. It has been found localized t the cell membrane and ytoso Since ER~ is restricted to modulating IES and was ound to be uniquely expressed n t oxi n re sted cancer cells, such as ; A MB 2 and Heel MIES modulated b membrane-associated E is thought to be responsible for re to anti-estrogen therapy found by s researchers (3,4 Orphan G prote n coupled receptor 30 (G E was found to bind E ( beta d estrogen) (5) and modulate l proliferation, resulting resistance to an i estr gen therapy. However, its physiological ft n t n still a matter of controversy investigators (3) u shown to exhibit cardiovascular metabolic defects, with no effect fertility (6). T GPER may he involved the modulation of e trogen ediaied metabolic signaling. The decreased production of estrogen in postmenopausal women leads to that may adversely affect their of life for decades.. Hormone (estrogen) replacement therapy HRT/ERT has bee utilised to treat these symptoms since the 40s. Studies showing increased risk of breast and cancer, as well thromboembolism morbidity, associated with HRT have lead to a recent decline in its , and postmenopausal symptoms remain a problem for many older women. Selective estrogen receptor (S RM ) have n utilized as treatments to regulate estrogen signaling the 1990s. However, lac of a more complete understanding of the molecular mechanisms involved and interfering cro ss talk between selective with different estrogen receptors have made it difficult to design treatment regimens that avoid the development of drug resistance d serious side effects daring clinical Tamoxifen was marketed as an antagon t of the estrogen c ss al pathway to treat breast cancer patients, and was als reported s agonist of ES - 6, potentially leading to anti-estrogen therapy resistance while stimulating the growth of endometrial epithelium cells, resulting in nd i cancer (7, 8) Raloxifene was marketed as an upgraded version of tamoxifen, having fewer side effects and the advantages of inhibiting cancer cell migration and preventing postmenopausal , such as osteoporosis. raloxifene can still cause serious side effects m to tamoxifen treatment, such thromboembolism and non-alcohol steatohepatitis (NASH) ( , ). The detailed mechanisms responsible for the side effects a s by either raloxifene or tamoxifen are still unclear Ipri avone is a der ative of p yto orn one and it metabolite binds to the ER- LSD with lower affinity than E2 exhibiting reduced estrogenic effects. The metabolites of ipritlavone and isofiavoue show comparable binding affinity and activity with ER j as and they have been utilised in some countries a a medicine to prevent osteoporos . However, their effectiveness was not supported! la at least one clinical trial ( ) . Moreover, potential side effects as seen with traditional HRT are still a concern to some investigators (12). 2 7 -d ethyi A n0r 5 an d tan - 1 -dtol (anordio!) first reported a ti estroge activity by m i in the 1960s ( 3 1.4 } Li, .L e eri ed anordiol using propionic acid to d propiona e an rdrin, AN ) in 5 Anordrin marketed as an antiiertiiiiv medicine using the brand nanie A -53 in Chun beginning Estrogen i known to hormone-induced cancer, and anordrin, a s m estrogen receptor antagonist, n l found ife i n cell growth ( , 1 ) , A s .non-prescription in China, Chinese physicians it as anti-tumor agent for nearly decade under legally licensed conditions. However, results 0 reported for patients during clinical therapy. s clinical an anti-tumor agent was stopped in 998 after the introduction of the clinical trial law in China, and ai of the r clinical dat were never collected studied. The disclosures of all publications, patents, n applications and published patent applications referred to herein are hereb incorporated herein by reference In their entirety . The present application in. one aspect provides a d of treating a cancer n individual comprising ad in tering to the individual: a) a effective amount of n anord n or analog thereof (such as anordrin); a d optionally ) an effective of at. least one other agent selected from 0 the group consisting of tamoxifen., raloxifene or functional equivalent thereof, an an r n a se inhibitor. n some embodiments, these s provided a method of reducing s de effect of eas! one other by anordtin or analog thereof (such as anordrin), comprising administering to the individual effective amount o anordrin or analog thereof h anordrin) in combination with the other agent, wherein t e other agent is selected f m group consisting of tamoxifen, 5 raloxifene or functional equivalent thereof, and an o e inhibitor.
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