WO 2012/113835 Al 30 August 2012 (30.08.2012) P O P C T

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WO 2012/113835 Al 30 August 2012 (30.08.2012) 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 2012/113835 Al 30 August 2012 (30.08.2012) P O P C T (51) International Patent Classification: LOPEZ, Daniela Melanie [VE/FR]; Universite Bordeaux A61K 31/357 (2006.01) A61P 19/10 (2006.01) 1 - Institut des Sciences Moleculaires (CNRS-UMR 5255) A61P 35/00 (2006.01) 2 rue Robert Escarpit, F-33607 Pessac Cedex (FR). (21) International Application Number: (74) Agents: BLOT, Philippe et al; Cabinet LAVOTX, 2, place PCT/EP2012/053017 d'Estienne d'Orves, F-75009 Paris (FR). (22) International Filing Date: (81) Designated States (unless otherwise indicated, for every 22 February 2012 (22.02.2012) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (25) Filing Language: English CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (26) Publication Language: English DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, (30) Priority Data: KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, 11305186.6 22 February 201 1 (22.02.201 1) EP MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (71) Applicant (for all designated States except US): INSTI- OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, TUT NATIONAL DE LA SANTE ET DE LA SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, RECHERCHE MEDICALE (INSERM) [FR/FR]; 101, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. Rue de Tolbiac, F-75013 Paris (FR). (84) Designated States (unless otherwise indicated, for every (72) Inventors; and kind of regional protection available): ARIPO (BW, GH, (75) Inventors/Applicants (for US only): QUIDEAU, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, Stephane [FR/FR]; Universite Bordeaux 1 - Institut des UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, Sciences Moleculaires (CNRS-UMR 5255) 2 rue Robert TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, Escarpit, F-33607 Pessac Cedex (FR). GENOT, Elisabeth DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, [FR/FR]; INSERM U1053 et Institut Europeen de Chimie LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, et Biologie 2 rue Robert Escarpit, F-33607 Pessac Cedex SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (FR). SALTEL, Frederic [FR/FR]; INSERM U1053 et In stitut Europeen de Chimie et Biologie 2 rue Robert E s Published: carpit, F-33607 Pessac Cedex (FR). DOUAT-CASASSUS, — with international search report (Art. 21(3)) Celine [FR/FR]; Universite Bordeaux 1 - Institut des Sci ences Moleculaires (CNRS-UMR 5255) 2 rue Robert Es carpit, F-33607 Pessac Cedex (FR). DELANNOY (54) Title: C-GLUCOSIDIC ELLAGITANNIN COMPOUNDS FOR USE FOR ALTERING THE SUPRAMOLECULAR AR RANGEMENT OF ACTIN AND FOR THE TREATMENT OF OSTEOPOROSIS, CANCER, BACTERIAL INFECTION AND VIRAL INFECTION FIGA (57) Abstract: The present invention concerns a C-glucosidic ellagitannin compound or a metabolite thereof for use for altering the supramolecular arrangement of actin in an individual suffering from osteoporosis, cancer, bacterial infection, or viral infection. It also pertains to pharmaceutical compositions comprising a C-glucosidic ellagitannin compound and/or metabolites thereof and one or more physiologically acceptable carriers. It finally concerns a C-glucosidic ellagitannin compound or a metabolite thereof, option - ally detectably labeled, for in vitro use as a tool for studying cellular mechanisms involving actin, or for detecting F-actin in a cell. C-GLUCOSIDIC ELLAGITANNIN COMPOUNDS FOR USE FOR ALTERING THE SUPRAMOLECULAR ARRANGEMENT OF ACTIN AND FOR THE TREATMENT OF OSTEOPOROSIS, CANCER, BACTERIAL INFECTION AND VIRAL INFECTION The present invention concerns a C-glucosidic ellagitannin compound, or a 5 metabolite, for use for altering the supramolecular arrangement of actin in an individual in need thereof. It also pertains to pharmaceutical compositions comprising a C-glucosidic ellagitannin compound and/or metabolites thereof and one or more physiologically acceptable carriers. It finally concerns a C-glucosidic ellagitannin compound or a metabolite thereof, optionally detectably labeled, for in vitro use as a tool for studying 10 cellular mechanisms involving actin, or for detecting F-actin in a cell. BACKGROUND OF THE INVENTION The actin cytoskeleton and cancer 15 Cancer is an unregulated proliferation of cells due to loss of normal controls, resulting in unregulated growth, lack of differentiation, local tissue invasion, and often, metastasis. Cancer can develop in any tissue or organ at any age. Many cancers are curable if detected at an early stage, and long-term remission is often possible in later stages. However, cure is not always possible and is not attempted in some advanced 0 cases. The development of drugs effective against cancer and having limited toxic side effects thus remains a critical need. As a tumor grows, nutrients are provided by direct diffusion from the circulation. As tumor volume increases, tumor angiogenesis factors are produced to promote formation of the vascular supply required for further tumor growth. 5 Almost from inception, a tumor may shed cells into the circulation. Although most circulating tumor cells die as a result of intravascular trauma, an occasional cell may adhere to the vascular endothelium and penetrate into surrounding tissues, generating independent tumors (metastases) at distant sites. Metastatic tumors grow in much the same manner as primary tumors and may subsequently give rise to other metastases. 0 Experiments suggest that through random mutation, a subset of cells in the primary tumor may acquire the ability to invade and migrate to distant sites, resulting in metastasis. In non cancer cells, adhesion to the extracellular matrix and to neighbouring cells 5 plays a central role in the control of cell survival, growth, differentiation, motility, and tissue integrity. Upon oncogenic transformation, profound changes occur in the organization of the actin cytoskeleton, manifesting on cell morphology and motility. Increased proliferation, a hallmark of cancer cells, is highly dependent upon actin dynamics and cell adhesion. Adhesive interactions involve specialized transmembrane receptors that are linked to the cytoskeleton through junctional plaque proteins. The synthesis of several actin-binding proteins, including a-actinin, vinculin, tropomyosin and profilin, is down- regulated in transformed cells and overexpressing these proteins in tumor cells suppresses the transformed phenotype, which allows them to be considered as tumor suppressors. The actin cytoskeleton and osteoporosis Osteoporosis is a progressive metabolic bone disease that decreases bone density with deterioration of bone structure. Skeletal weakness leads to fractures with minor or inapparent trauma, particularly in the thoracic and lumbar spine, wrist, and hip. Acute or chronic back pain is common. Prevention and treatment involve calcium and vitamin D supplements, exercises to maximize bone and muscle strength and minimize the risk of falls, and drug therapy to preserve bone mass or stimulate new bone formation. Normally, bone formation and resorption are closely coupled. Osteoblasts (cells that make the organic matrix of bone and then mineralize bone) and osteoclasts (cells that resorb bone) are regulated by parathyroid hormone (PTH), calcitonin, estrogen, vitamin D, various cytokines, and other local factors such as prostaglandins. Peak bone mass in men and women occurs by the mid 20s. Bone mass plateaus for about 10 yr, during which time bone formation approximately equals bone resorption. After this, bone loss occurs at a rate of about 0.3 to 0.5% per year. Beginning with menopause, bone loss accelerates in women to about 3 to 5% per year for about 5 to 7 year. The major mechanism is increased bone resorption, which results in decreased bone mass and microarchitectural deterioration, even though other mechanisms also contribute to osteoporosis. The mechanisms of bone loss may involve local changes in the production of bone-resorbing cytokines (such as increases in cytokines that stimulate bone resorption), impaired formation response during bone remodeling (probably caused by age-related decline in the number and activity of osteoblasts), and other factors such as a decline in local and systemic growth factors. The goals of treatment against osteoporosis are to preserve bone mass, prevent fractures, decrease pain, and maintain function. The rate of bone loss can be slowed with drugs (e.g. bisphosphonates or other anti-resorptive drugs) and, when possible, modification of risk factors. Calcium and vitamin D intake and physical activity must be adequate for drug treatment to be effective. Bisphosphonates are first-line drug therapy. By inhibiting bone resorption, bisphosphonates preserve bone mass and can decrease vertebral and hip fractures by 50%. All increase bone mineral density and decrease risk of at least vertebral fractures. However, osteonecrosis of the jaw has been associated with use of bisphosphonates. Risk factors also include bisphosphonate use and cancer. Bisphosphonates may further be associated with atrial fibrillation, but the mechanism is not clear and there has been no association with increased cardiovascular mortality. Estrogen can preserve bone density and prevent fractures. Most effective if started within 4 to 6 yr of menopause, estrogen may slow bone loss and possibly reduce fractures even when started much later. However, use of estrogen increases the risk of thromboembolism and endometrial cancer and may increase the risk of breast cancer. The risk of endometrial cancer can be reduced in women with an intact uterus by taking a progestin with estrogen. However, taking a combination of a progestin and estrogen increases the risk of breast cancer, coronary artery disease, stroke, and biliary disease.
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