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Ep 2106212 B1 (19) TZZ _Z _ _T (11) EP 2 106 212 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/4709 (2006.01) C07D 217/22 (2006.01) 02.04.2014 Bulletin 2014/14 C07D 217/24 (2006.01) A61P 35/00 (2006.01) (21) Application number: 08713186.8 (86) International application number: PCT/US2008/000736 (22) Date of filing: 22.01.2008 (87) International publication number: WO 2008/091555 (31.07.2008 Gazette 2008/31) (54) NUCLEAR RECEPTOR BINDING AGENTS NUKLEARREZEPTOR-BINDENDE WIRKSTOFFE AGENTS SE LIANT AUX RÉCEPTEURS NUCLÉAIRES (84) Designated Contracting States: (56) References cited: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR WO-A1-98/38168 WO-A1-2006/108107 HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT WO-A1-2006/116401 US-A- 2 848 356 RO SE SI SK TR US-A1- 2003 220 227 US-A1- 2004 138 244 (30) Priority: 22.01.2007 US 881476 P • HELLWINKEL D ET AL: "Heterocyclensynthesen 16.04.2007 US 907754 P mit MF/Al2O3-Basensystemen: 2- Arylbenzofurane und 2,3-Diarylisochinolin-1 (43) Date of publication of application: (2H)-one", SYNTHESIS, GEORG THIEME 07.10.2009 Bulletin 2009/41 VERLAG, STUTTGART, DE, no. 9, 1 September 1995 (1995-09-01), pages 1135-1141, (60) Divisional application: XP002208179, ISSN: 0039-7881, DOI: 10.1055/S- 13174659.6 / 2 647 376 1995-4057 • GERRIT H. VEENEMAN: "Non- Steroidal Subtype (73) Proprietor: GTx, Inc. Selective Estrogens", CURRENT MEDICINAL Memphis, TN 38103 (US) CHEMISTRY, vol. 12, no. 9, 1 May 2005 (2005-05-01), pages 1077-1136, XP55031059, (72) Inventors: ISSN: 0929-8673, DOI: • DALTON, James, T. 10.2174/0929867053764662 Lakeland, TN 38002 (US) • DIAMANTI-KANDARAKIS ET AL.: ’The Effect of a • MILLER, Duane, D. Pure Anti-androgen Receptor Blocker, Collierville, TN 38017-8799 (US) Flutamide, on the Lipid Profile in the Polycystic • MOHLER, Michael, L. Ovary Syndrome’ JOURNAL OF CLINICAL Memphis, TN 38134 (US) ENDOCRINOLOGY AND METABOLISM vol. 83, • WU, Zhongzhi 1998, pages 2699 - 2705, XP008131993 Collierville, TN 38107 (US) • PRICE ET AL.: ’Toremifene for the Prevention of • HONG, Seoung-Soo Prostate Cancer in Men with High Grade Prostatic Collierville, TN 38017 (US) Intraepithelial Neoplasia: Results of a Double- • SRIVASTAVA, Devesh Blind, Placebo Controlled, Phase IIB Clinical Apex, NC 27502 (US) Trial’THE JOURNAL OF UROLOGY vol. 176, 2006, pages 965 - 971, XP024990335 (74) Representative: Korn, Richard Mervyn Pearl Cohen Zedek Latzer Baratz UK LLP 15 Old Bailey London EC4M 7EF (GB) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 106 212 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 106 212 B1 • REMMERS ET AL.: ’Testosterone receptor • GÜNGÖR T ET AL: "Synthesis and blockade after trauma-hemorrhage improves characterizaion of 3-arylquinazoline and 3- cardiac and hepatic functions in males’ AM. J. arylquinazolinethione derivatives as selective PHYSIOL. - HEART CIRC. PHYSICOL. vol. 273, estrogen receptor beta modulators", JOURNAL 1997, pages 2919 - 2925, XP008131989 OF MEDICINAL CHEMISTRY, AMERICAN • MCKINNON ET AL.: ’Glaucoma: ocular CHEMICAL SOCIETY, US, vol. 49, 25 March 2006 Alzheimer’s diseases’ FRONTIERS IN (2006-03-25), pages 2440-2455, XP002396740, BIOSCIENCE vol. 8, 2003, pages S1140 - S1156, ISSN: 0022-2623, DOI: 10.1021/JM0509389 XP008131994 • PINTHUS ET AL.: ’Androgen Induces Adaptation to Oxidative Stress in Prostate Cancer: Implications for Treatment with Radiation Therapy’ NEOPLASIA vol. 9, pages 68 - 80, XP008132114 2 EP 2 106 212 B1 Description FIELD OF THE INVENTION 5 [0001] The present invention relates to a novel class of nuclear receptor binding agents (NRBAs). The NRBA are applicable for use in the prevention and/or treatment of a variety of diseases and conditions including, inter alia, prevention and treatment of hormone-related diseases including prostatic diseases, cancers, urogenital, gastrointestinal, inflam- mation, osteoporosis, peripheral vascular disease, oxidative damage related diseases such as Parkinson’s and stroke, ocular disorders, neuroprotection, arthritis, prostate cancer, benign prostate hyperplasia (BPH), hot flashes, breast 10 cancer, anti-angiogenic diseases, bladder cancer, and cardiovascular disease. BACKGROUND OF THE INVENTION [0002] The nuclear hormone receptor superfamily of ligand activated transcription factors is present in various tissues, 15 and responsible for a multitude of effects in these tissues. [0003] The nuclear receptor (NR) superfamily presently comprises approximately 48 different proteins, most of which are believed to function as ligand activated transcription factors, exerting widely different biological responses by regu- lating gene expression. Members of this family include receptors for endogenous small, lipophilic molecules, such as steroid hormones, retinoids, vitamin D and thyroid hormone. 20 [0004] The nuclear receptor (NR) superfamily includes the steroid nuclear receptor subfamily, including the mineralo- corticoid receptor (MR) (or aldosterone receptor), the estrogen receptors (ER), ER alpha (ER-α) and ER beta (ER-β), the androgen receptor (AR), the progesterone receptors (PR), glucocorticoid receptors (GR) and others. Also closely related in structure are the estrogen related receptors (ERRs) ERR-alpha, ERR-beta and ERR-gamma. The steroid nuclear receptors perform important functions in the body, some of which are related to the transcriptional homeostasis 25 of electrolyte and water balance, growth, development and wound healing, fertility, stress responses, immunological function, and cognitive functioning. The effects may be mediated by cytosolic, mitochondrial or nuclear events. Accord- ingly, compounds that modulate (i.e. antagonize, agonize, partially antagonize, partially agonize) the activity of steroid nuclear receptors are important pharmaceutical agents that have specific utility in a number of methods, as well as for the treatment and prevention of a wide range of diseases and disorders modulated by the activity of steroid nuclear 30 receptors. For instance, ER-β is present in, among other tissues, brain, bone, immune system, gastrointestinal tract, lung, ovary, endometrium, prostate, vasculature, urogenital tract, salivary gland, etc. The role of ER beta in these tissues was confirmed by observed phenotypes in ER beta knockout mice. Pathologies in these tissues may be treated by administration of ER-β selective ligands. ER-β in some cases functions as an antagonist of ER- α through heterodimer- ization with ER-α. For instance, agonists of ER- β may block the proliferative influence of ER- α in tissues such as prostate 35 and breast where ER-α is known to promote neoplasia. In addition to its anti- ER-α mediated growth inhibition, ER-β autonomously inhibits proliferation and promotes differentiation of prostate and other cancers. ER- β is also believed to antagonize the proliferative effects AR in prostatic tissues. Prostatic hypertrophy and hyperplasia/dysplasia may result from a combination of androgenic stimulation of proliferation and/or failed activation of ER-β by locally synthesized estrogens. This hypertrophy or hyperplasia/dysplasia often leads to a variety of prostatic maladies such as BPH, prostatic 40 inflammatory atropy (a precursor to neoplasia), PIN, and CaP. Administration of exogenous ER-β agonists can be expected to provide prostatic anti-proliferation thereby being beneficial in the prevention or treatment of these prostatic diseases. Additionally, decreased side effects can be expected for ER-β selective agents compared to isoform nonse- lective ligands for treating many of these diseases. [0005] Non-lipid level dependent effects of estrogens on the vasculature are well known as evidenced by the cardio- 45 protection conferred to pre-menopausal women by endogenous estrogen. Estrogens produce a direct vasodilatation (i.e. decreased vascular contractility or vascular tone) on a wide variety of vascular tissues which reduces systemic vascular resistance and improves microvascular circulation. Estrogens also reduce vascular cell proliferation and mi- gration, vasoreactivity and hypertrophic remodeling, and vascular fibrosis. Although ER- α and ER-β are both thought to function in the vasculature, the deletion of ER-β as in knockout mice produces an elevation of blood pressure and 50 moderate cardiac hypertrophy suggesting ER-β has a role in maintenance of vascular tone and proliferation. This cu- mulatively suggests that ER- β agonists may have therapeutic utility in hypertension, and a variety of other cardiovascular diseases such atherosclerosis and congestive heart failure. Some of the rapid effects of estrogens, particularly in the vasculature are believed to be independent of protein expression (i.e. nongenomic). [0006] Members of the steroid nuclear receptor sub-family exhibit significant homology to each other and possess 55 closely related DNA and ligand binding domains. Given the close similarity in ligand binding domains of the steroid nuclear receptors, it is not surprising that many naturally occurring and synthetic molecules possess the ability to modulate the activity of more than one steroid nuclear receptor. [0007] The syntheses of isoquinolinone
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