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(12) Patent Application Publication (10) Pub. No.: US 2015/0284357 A1 Thatcher Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2015/0284357 A1 Thatcher Et Al US 20150284.357A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0284357 A1 Thatcher et al. (43) Pub. Date: Oct. 8, 2015 (54) COMPOSITIONS AND METHODS FOR Related U.S. Application Data TREATINGESTROGEN-RELATED MEDICAL DSORDERS (60) Provisional application No. 61/718,035, filed on Oct. 24, 2012, provisional application No. 61/809,101, (71) Applicants: Gregory R. THATCHER, Chicago, IL filed on Apr. 5, 2013. (US); Marton SIKLOS, Chicago, IL (US); Rui XIONG. Chicago, IL (US); THE BOARD OF TRUSTEES OF Publication Classification THE UNIVERSITY OF ILLINOIS, (51) Int. C. Urbana, IL (US) C07D 333/64 (2006.01) (72) Inventors: Gregory R. Thatcher, Chicago, IL C07D 409/2 (2006.01) (US); Marton Siklos, Chicago, IL (US); (52) U.S. C. Rui Xiong, Chicago, IL (US) CPC ............ C07D 333/64 (2013.01); C07D409/12 (2013.01) (21) Appl. No.: 14/438,361 (57) ABSTRACT (22) PCT Filed: Oct. 24, 2013 Disclosed is a compound of formula (I). or a pharmaceuti (86) PCT NO.: PCT/US13A66702 cally acceptable Salt thereof. Also disclosed are pharmaceu S371 (c)(1), tical compositions including the compound of formula (I) and (2) Date: Apr. 24, 2015 methods of using the compound of formula (I). Patent Application Publication Oct. 8, 2015 Sheet 1 of 9 US 2015/0284.357 A1 Pertissis as as a st GS re. e. e. e. - X is a a a Y294 a as a a a X 3 NAME A rp 3: . r x x . FIG. 1 Patent Application Publication Oct. 8, 2015 Sheet 2 of 9 US 2015/0284.357 A1 A 208 -X Tg wet is C&A ig NO-CiA 75 W ig 8Af-G's is 150 o is $2S a. toogiin ES s 2 f Stope EPSP After TBS End Sops fePSP FG. 2 Patent Application Publication Oct. 8, 2015 Sheet 3 of 9 US 2015/0284357 A1 A 88 B (so C 1. R& -- 38A d SRA 8-O-Rataxiisne 33 -- A - EN3 38- Aizo 38 x &A t-8As 28 -- FA s 73 S. 3. y & isM 88. is 8: 56 S. a 4 3 38 is No-oyia 1. & -- NC-SA-SN N-OA - SAE y S s 4. 8 s s 4. - og RS8) - logists & - og ER}{3}{R} FIG 3 Patent Application Publication Oct. 8, 2015 Sheet 4 of 9 US 2015/0284.357 A1 ippocampus R 3. S. 2. 1 - sks 98. 8 i SS SY N S- NY S - SC - Wild type eMS KO Widtype eS KO FIG. 4 Patent Application Publication Oct. 8, 2015 Sheet 5 of 9 US 2015/0284.357 A1 3. - Scopoianine NAE Wild Type enOS KO FIGS Patent Application Publication Oct. 8, 2015 Sheet 6 of 9 US 2015/0284.357 A1 SO F.G. 6 Patent Application Publication Oct. 8, 2015 Sheet 7 of 9 US 2015/0284.357 A1 C57Big R. SfS is $ 3.5 SS $5. is it is 20 as 3. 3s. 40 45 so 55 60 ss Titlyn LTES) FIG. 7 Patent Application Publication Oct. 8, 2015 Sheet 8 of 9 US 2015/0284.357 A1 s SS SE s xas S&Si3 s ray Sia, -eps 35. sists is fiex 3. s ts t 3. 90 Time (min) FIG. 8 Patent Application Publication Oct. 8, 2015 Sheet 9 of 9 US 2015/0284.357 A1 200 t $g Ws. s & S. is S. SS-8 Tes" as Tass is is sess Tse Tss Tstein TES FIG. 9 US 2015/02843.57 A1 Oct. 8, 2015 COMPOSITIONS AND METHODS FOR consisting of alkyl, —O— —N(H)— —S , —S(=O)—, TREATINGESTROGEN-RELATED MEDICAL and —C(=O)—. As is selected from the group consisting of DISORDERS alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocycle, and het eroaryl. A is selected from the group consisting of hydrogen, STATEMENT OF GOVERNMENT INTEREST halogen, alkyl, cyano, trifluoromethyl, aryl-heteroaryl 0001. This invention was made with government support wherein the aryl is substituted or unsubstituted (e.g., 1-(4- under contract number NIH RO1 CA102590 awarded by the fluorophenyl)-1H-1,2,3-triazolyl), and—OR. R. RandR National Institutes of Health. The government has certain are each independently selected from the group consisting of rights in the invention. hydrogen, alkyl, -SOR', -POR'R'', —C(=O)R', and -R-G. R', R' and R', at each occurrence, are indepen TECHNICAL FIELD dently selected from the group consisting of hydrogen and a 0002 The present invention relates to compounds, com pharmaceutically acceptable cation. R is alkyl or —OH. R. positions, and methods for treating and identifying estrogen at each occurrence, is independently selected from the group related medical disorders such as cancer, inflammation, consisting of a Substituent comprising 1 to 10 carbon atoms, osteoporosis, vaginal atrophy, central nervous diseases, and a Substituent comprising 1 to 10 carbonatoms and optionally cardiovascular system diseases. containing at least one nitrogen atom, a Substituent compris ing 1 to 10 carbon atoms and optionally containing at least BACKGROUND one C=O group, and a Substituent comprising 1 to 10 carbon 0003. In addition to developmental functions, estrogens atoms and optionally containing at least one nitrogen and/or have been found to reduce incidence of coronary heart disease at least one C=O group. G. at each occurrence, is indepen (1), maintain bone mineral density (2), and in the CNS, pro dently selected from the group consisting of hydrogen and mote neuronal Survival (3, 4) and hippocampal neurogenesis —ONO, wherein at least one of R. R. and R is -R-G, and (5-7). Neuro-imaging studies reveal that estrogen therapy wherein at least one occurrence of G is —ONO. improves cerebral blood flow and performance in hippocam 0006. Also provided herein is a compound of formula (I), pal-dependent memory tasks in humans (8, 9). Other obser wherein Ra, at each occurrence, is independently selected Vational Studies have found that estrogen helps alleviate age from the group consisting of alkyl, cycloalkyl, cycloalkyla related cognitive decline by preserving executive function in lkyl, heterocyclealkyl, and alkylheterocyclealkyl, wherein the frontal lobe (10). any carbon atom on the alkyl group, together with an alky 0004 Raloxifene (EVISTA) is a second generation selec lene, may form a cycloalkyl, and wherein alkyl may be unsub tive estrogen receptor modulator (SERM) used clinically for stituted or substituted with 1, 2, or 3 oxo substituents. the treatment of osteoporosis in postmenopausal women, which acts as an antiestrogen in breast and endometrium 0007 Also provided herein is a compound of formula (I), (17-21). Raloxifene, however, increases the lifetime risk of wherein Ra, at each occurrence, is independently selected thromboembolism (23). Raloxifene has been found to from the group consisting of alkyl, alkylheterocyclealkyl, and enhance levels of vasodilatory NO through action on endot heterocyclealkyl. helial nitric oxide synthase (eNOS) (24-26), and, the 0008 Also provided herein is a compound of formula (I), increased thromboembolic events have been attributed to wherein A is selected from the group consisting of halogen decreased eNOS activity in postmenopausal women (27). NO and —OR. inhibits thrombus formation through inhibition of platelet recruitment, adhesion and aggregation (28). The next genera 0009. The compound of formula (I) may comprise a com tion SERM, arzoxifene (41, 42), a prodrug of desmethylar pound of formula (I-i), a compound of formula (I-ii), a com Zoxifene (DMA) was designed to improve the pharmacoki pound of formula (I-iii), a compound of formula (I-iv), a netic (PK) profile relative to raloxifene, from which it differs compound of formula (I-V), or a compound of formula (I-vi) by only one atom (43. 44). (I-i) SUMMARY 0005. In one aspect, disclosed is a compound of formula (I) (I) 7 f A4, \ f (I-ii) 21 S-X. A- y S S or a pharmaceutically acceptable salt thereof. A is selected from the group consisting of halogen, trifluoromethyl, and X-A-A —OR. A. is selected from the group consisting of halogen, trifluoromethyl, and —OR. X is selected from the group US 2015/02843.57 A1 Oct. 8, 2015 -continued atoms and optionally containing at least one nitrogen and/or (I-iii) at least one C=O group. G. at each occurrence, is indepen dently selected from the group consisting of hydrogen and —ONO, wherein at least one of R. R. and R is -R-G, and wherein at least one occurrence of G is —ONO. 0010 Also provided herein is a compound of formula (I-i), a compound of formula (I-ii), a compound of formula (I-iii), a compound of formula (I-iv), a compound of formula (I-V). or a compound of formula (I-vi), wherein Ra, at each occur rence, is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocyclealkyl, and (I-iv) alkylheterocyclealkyl, wherein any carbon atom on the alkyl group, together with an alkylene, may form a cycloalkyl, and wherein alkyl may be unsubstituted or substituted with 1, 2, or 3 oxo substituents. 0011. Also provided herein is a compound of formula (I-i), a compound of formula (I-ii), a compound of formula (I-iii), a compound of formula (I-iv), a compound of formula (I-V). or a compound of formula (I-vi), wherein Ra, at each occur rence, is independently selected from the group consisting of (I-v) alkyl, alkylheterocyclealkyl, and heterocyclealkyl. 0012. The compound of formula (I) may comprise a com pound of formula (Ia) (Ia) Rs (I-vi) N Z f O \ I s S. ^ O N X-A-A r) ; A. S N S or a pharmaceutically acceptable salt thereof. A is selected or a pharmaceutically acceptable salt thereof.
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