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A TTX Mwashout Vehicle Or E2 M"Washout Patent Application Publication May 26, 2005 Sheet 1 of 16 US 2005/0113453 A1

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A TTX Mwashout Vehicle Or E2 M US 20050113453A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0113453 A1 Scanlan et al. (43) Pub. Date: May 26, 2005 (54) DEVELOPMENT OF NEW SELECTIVE Related U.S. Application Data ESTROGEN RECEPTOR MODULATORS (60) Provisional application No. 60/513,235, filed on Oct. (76) Inventors: Thomas S. Scanlan, San Francisco, CA 21, 2003. (US); Martin J. Kelly, Portland, OR (US); Jian Qiu, Portland, OR (US); Publication Classification Sandra Tobias, San Francisco, CA (US); Oline K. Ronnekleiv, Portland, (51) Int. Cl." ...................... A61K 31/195; A61K 31/137 OR (US) (52) U.S. Cl. ......................... 514/567; 514/649; 562/442; 564/338 Correspondence Address: WOODCOCKWASHIBURN LLP (57) ABSTRACT ONE LIBERTY PLACE, 46TH FLOOR The present disclosure concerns a new class of Selective 1650 MARKET STREET estrogen receptor modulators (SERMs). The disclosure also PHILADELPHIA, PA 19103 (US) includes the identification of a previously unknown mem brane associated estrogen receptor. Methods for making and (21) Appl. No.: 10/970,242 using the disclosed SERMs are disclosed, including phar maceutical formulations of the disclosed novel compounds (22) Filed: Oct. 20, 2004 in useful compositions. Baclofen TTX Baclofen A TTX MWashout Vehicle or E2 M"Washout Patent Application Publication May 26, 2005 Sheet 1 of 16 US 2005/0113453 A1 A Baclofen TTX + Baclofen TTX Washout Vehicle or E2 Washout R1 R2 (vehicle) , V R2 (E2) Y WS -Time 10 2O 30 40 F.G. 1 Patent Application Publication May 26, 2005 Sheet 2 of 16 US 2005/0113453 A1 FIG 2 Patent Application Publication May 26, 2005 Sheet 3 of 16 US 2005/0113453 A1 Voltage (mV) - 160 - 140 - 120 - 100 ra O O Control O Baclofen FIG. 3A D Voltage (mV) - 160 - 140 - 120 -100 -80 -8O O Control O Baclofen FG. 3B Patent Application Publication May 26, 2005 Sheet 4 of 16 US 2005/0113453 A1 FIG. 4A Patent Application Publication May 26, 2005 Sheet 5 of 16 US 2005/0113453 A1 FIG. 4C FIG. 4D Patent Application Publication May 26, 2005 Sheet 6 of 16 US 2005/0113453 A1 FIGS Patent Application Publication May 26, 2005 Sheet 7 of 16 US 2005/0113453 A1 120 100 60 20 Patent Application Publication May 26, 2005 Sheet 8 of 16 US 2005/0113453 A1 B 12O G E. 100 8O 9. (i) s 60 () E 40 th g 2O O Oil EB STX STX 21g 5ug FIG. 7B Patent Application Publication May 26, 2005 Sheet 9 of 16 US 2005/0113453 A1 A Baclofen i h 10 pA 2 min Patent Application Publication May 26, 2005 Sheet 10 of 16 US 2005/0113453 A1 Patent Application Publication May 26, 2005 Sheet 11 of 16 US 2005/0113453 A1 Baclofer E2 A BS Sr. 888883: S.S. S. as 3. 8s. &rs: : - 20 pA 2 min 20 pA 2 min C Baclof i 20 pA 2 in D BISE is - 20 pA 2 min Patent Application Publication May 26, 2005 Sheet 12 of 16 US 2005/0113453 A1 Patent Application Publication May 26, 2005 Sheet 13 of 16 US 2005/0113453 A1 A E2 Baclofen " B E2 Baclofen Gs peptide. SESses 20 pA 2 min E2 C Baclofen " Patent Application Publication May 26, 2005 Sheet 14 of 16 US 2005/0113453 A1 140 120 100 Patent Application Publication May 26, 2005 Sheet 15 of 16 US 2005/0113453 A1 A Arcuate h Tissue Single Neurons Control 2 3 4 5 6 I (bp) TH 223 2O7 GAD PKCS 251 AC VI 235 GAPDH 212 F.G. 14A B Arcuate Tissue Single Neurons Control F.G. 14B Patent Application Publication May 26, 2005 Sheet 16 of 16 US 2005/0113453 A1 Endoplasmic reticulum Itered Cell Functions Protein Synthesis RNA Synthesis FIG 15 US 2005/0113453 A1 May 26, 2005 DEVELOPMENT OF NEW SELECTIVE SERMS may act as either agonists or antagonists to Selec ESTROGEN RECEPTOR MODULATORS tively modulate one or more estrogen receptorS. Certain SERM compounds have mixed estrogenic and anti-estro CROSS-REFERENCE TO RELATED genic activities and act as estrogen receptor agonists in Some APPLICATION tissues and as estrogen receptor antagonists in other tissues. 0001) This application claims benefit under 35 USC 0008 Estrogens, such as 17(3-estradiol, have been 119(e) of U.S. Provisional Application No. 60/513,235, filed thought to exert their effects by binding to one of two Oct. 21, 2003, the entirety of which is herein incorporated by nuclear estrogen receptors, (ER).C. or (ER)?. Because (ER)Cl. reference. and (ER)? are found in different tissues and have been demonstrated to have different biological roles, researchers ACKNOWLEDGEMENT OF GOVERNMENT have focused on the development of SERMs that effect a SUPPORT response by selectively binding to either (ER).C. or (ER) B. 0002 This invention was made with Government support 0009. Two examples of nonsteroidal SERMs that exhibit under Grant Nos. NS 35944, NS 38809, DA 05158, DA different activities towards (ER)C. and (ER)? are tamoxifen 10703, and DK57574. The Government has certain rights in and raloxifene. Tamoxifen and raloxifene have been devel this invention. oped for the treatment and/or prevention of Osteoporosis, cardiovascular disease and breast cancer in addition to the FIELD treatment and/or prevention of a variety of other disease 0003. This disclosure concerns novel compounds and states. Both compounds have been shown to exhibit an methods for their use, including Selective estrogen receptor Osteoprotective effect on bone mineral density combined modulators and methods for making Such Selective estrogen with a positive effect on plasma cholesterol levels and a receptor modulators. greatly reduced incidence of certain types of cancer. Unfor tunately, tamoxifen and raloxifene both induce Side effects BACKGROUND Such as hot flushes and tamoxifen promotes life-threatening disorders, Such as endometrial cancer. 0004 Estrogens are an important class of steroidal hor mones that Stimulates the development and maintenance of 0010. The present disclosure includes novel nonsteroidal fundamental Sexual characteristics in humans. In addition, SERMs that elicit the desired effects of hormone replace estrogens have been demonstrated to affect a variety of ment therapy without inducing the negative effects of hor diverse biological processes. Many of the incidental effects mone replacement therapy or those of known Selective of estrogens are positive, including the maintenance of bone estrogen receptor modulators. density, central nervous System function and preservation of memory. However, estrogens also have been demonstrated SUMMARY to have Serious negative effects, including promoting the 0011. The present disclosure includes novel compounds, development of breast and endometrial cancers. compositions and methods for making and using the com 0005 Based upon a life expectancy of nearly eighty years pounds and compositions. Generally, the disclosed com in the United States, a woman can expect to spend about a pounds function as Selective estrogen receptor modulators third of her lifetime in a post-menopausal State. A woman's (SERMs). In one aspect, the compounds have Formula 1 and estrogen levels drop dramatically during menopause and include hydrates and pharmaceutically acceptable prodrugs menopausal women often experience many Side affects and Salts thereof. Moreover, all chiral, diastereomeric and asSociated with the reduction in estrogen production. To geometric isomeric forms of the disclosed Formulas are treat these conditions, physicians often prescribe hormone intended. replacement therapy, which primarily consists of the admin istration of estrogen in combination with progestin. Formula 1 0006. In light of the more serious side effects associated R M-Air-Y-G-Z. with current hormone replacement therapy, including increased risk of ischemic Stroke, myocardial infarction, thromboembolism, cerebrovascular disease, and endome trial carcinoma, a significant amount of research has been carried out to identify effective nonsteroidal estrogen and antiestrogenic compounds. N/ 0007. A large number of compounds have been described that either mimic or block the effects of the most potent estrogen, 17B-estradiol. Compounds that bind to an estrogen 0012. With reference to Formula 1, R can be E or Z with receptor and Stimulate many of the same biological effects as respect to M and R represents a hydrogen or a lower 17B-estradiol are termed "estrogen receptor agonists.” Com aliphatic group, X is an ortho, meta or para positioned pounds that inhibit the binding of 17 B-estradiol to an estro hydrogen, hydroxyl, protected hydroxy, alkoxy, Sulfhydryl, gen receptor or interfere with the effects of 17,3-estradiol thioether, amino (-NRR wherein R and Rare indepen binding to an estrogen receptor are referred to as “estrogen dently hydrogen or lower alkyl) or a halogen; M comprises receptor antagonists.” Compounds that affect different estro a ketone, amide or Sulfonamide group. Ar represents an gen receptors with different potencies are typically referred aromatic group and can be any aromatic group, including, to as Selective estrogen receptor modulators (SERMs). without limitation, phenyl, biphenyl, 1-napthyl, 2-napthyl, US 2005/0113453 A1 May 26, 2005 and including heteroaryl groups, Such as, by way of example, furan, thiophene, pyrrole, imidazole, oxazole, thia Zole, pyridine, and quinoline groups. Y can be attached at - V Y-G Formula 3 any position, Such as at the ortho, meta or para position x1 Y, relative to M. In one aspect, Y is a heteroatom, Such as a \ / nitrogen or oxygen. In certain embodiments of the disclosed SERMs according to Formula 2 Y represents a phenyl group. R Q-N V 1. R Formula 2 0015 Thus, compounds according to Formula 3 can have, for example, Formula 4 or 5. With respect to Formulas 4 and 5, R, X, R', and Y are defined as above with respect to Formula 1. 0013 With continued reference to Formulas 1 and 2, G Formula 4 includes a linker group, Such as a lower alkyl group, a hydrocarbon chain, an oligoethylene glycol chain or the like.
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