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i PZOO/OOl : Section 29 AUSTRALIA Patents Act 1990 NOTICE OF ENTITLEMENT We Jenapharm GmbH of Otto-Schott-Strasse 15, 07745 Jena, Germany, the Applicant in respect of Application No. 29741/95 state the following: ft• · · · ft0 1. Jenapharm GmbH is the Nominated Person in respect of the application. • · · 0 • ••ftft 2, The actual inventors of the invention, the subject of the application, are Sifgrid ft• · » ft ft β · SCHWARZ, Walter ELGER, Hans-Joachim SIEMANN, Gudrun REDDERSEN ft ft 3 ft · ft and Birgitt SCHNEIDER • • ft ftft • ft 9 ft ft • • <ί·ft 3 The Nominated Person is entitled to the grant of a patent in respect of the application because the said Nominated Person derived title to the invention from ft ft ft the actual inventors by virtue of assignment contract. • ft · eftft ft • ft··ft * • ft ft ftft 4 The Nominated Person is entitled to claim priority from the application listed in the • ft ft ft ftft ft declaration under Article 8 of the PCT because the Nominated Person is the ft ft ftft applicant in respect of the application listed in the declaration under Article 8 of the ft ft PCT, and because the application was the first application made in a Convention country in respect of the invention. ft » ft ftftft ft ft ft ft ·ft _ ________________ ._____________________________ 7 October, 1998 A member of the firm of DAVIES COLLISON CAVE for and on behalf of the applicant h i •o, -jpcwjnsxp.s .7/10)58, IjlKMM1 AU9529741 (12) PATENT ABRIDGMENT (11) Document No. AU-B-29741/95 (19) AUSTRALIAN PATENT OFFICE (10) Acceptance No. 699701 (54) Title ESTRA-1,3,5(10)-TRIENE DERIVATIVES, METHODS OF PREPARING SUCHCOMPOUNDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM International Patent Classification(s) (51)6 CO7J 041/00 A61K 031/56 C07J 043/00 C07J 053/00 (21) Application No.: 29741/95 (22) Application Date : 03.07.95 (87) PCT Publication Number: WO96/05216 (30) Priority Data (31) Number (32) Date (33) Country 4429397 09.08.94 DE GERMANY (43) Publication Date : 07.03.96 (44) Publication Date of Accepted Application : 10.12.98 (71) Applicant(s) JENAPHARM GMBH (72) Inventor(s) HANS-JOACHIM SIEMANN; SIGFRID SCHWARZ; WALTER ELGER; GUDRUN REDDERSEN; BIRGITT SCHNEIDER (74) Attorney or Agent DAVIES COLLISON CAVE , GPO Box 3876, SYDNEY NSW 2001 (57) Claim 1. Estra-l,3,5(lO)-trien derivatives of the general Formula I II O wherein R is a RT^N group, withR1 and R2, independently of each other, represent a hydrogen atom, a CrC5-alkyl residue or, together with the N atom, a polymethylenimino residue with 4 to 6 C atoms or a morpholine residue, R3 is a hydrogen atom or an alkyl group with 1-5 C atoms, R4 is a hydrogen atom, a hydroxy group, an esterified hydroxy group, a haloalkyl group with 1-5 C atoms or an alkoxy group with 1-5 C atoms, era· (11) AU-B-29741/95 -2- (10)699701 R3 and R6 are a hydrogen atom each or, together, stand for a methylene group, R7, R8 and R9, independently of each other, stand for a hydrogen atom or a hydroxy group, and ring B may contain one or two double bonds or R8 is an alkinyl residue with up to 5 carbon atoms with the proviso that R1 and R2 are hydrogen atoms, or at least one of the residues R3, R4, R3, Rfi or R7 is not hydrogen and R1 and R3 have a different meaning from each other , or R8 and R9 together may represent an oxygen atom with the proviso that at least one of the residues R3, R4, R3, R6 or R7 is different from hydrogen, or R3 and R8 may represent a vinylene or ethylene group. 4, Pharmaceutical compositions containing an estra-1,3,5(10)-trien derivative according to Claim 1 or 2 which may be combined with pharmaceutically safe adjuvants and carriers. OPI DATE 07/03/96 APPLN. ID 29741/95 AOJP DATE 26/04/96 PCT NUMBER PCT/DE95/00877 AU9529741 (51) Internationale Patentklassifikation 6 ; (11) Internationale VeroiTentlichungsnununer: WO 96/05216 C07J 41/00, A61K 31/56, C07J 53/00, Al (43) Internationales 43/00 Veroffentlichungsdatum: 22. Februar 1996 (22.02.96) (74) Anwalt: WABLAT, Wolfgang; Potsdamer Chaussee 48, D- (21) Internationales Aktenzeichen: PCT/DE95/00877 14129 Berlin (DE). (22) Internationales Anmeldedatum: 3. Juli 1995 (03.07.95) (81) Bestimmungsstaaten: AU, BG, BR, BY, CA, CN, CZ, FI, HU, (30) Prioritatsdaten: JP, KP, KR, KZ, LK, LV, MN, NO. NZ. PL, RO, RU, SK, P 44 29 397.6 9. August 1994 (09.08.94) DE UA, US, UZ, VN, europfiisches Patent (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE). (71) Anmelder (fiir alle Bestimmungsstaaten ausser US): JE- NAPHARM GMBH [DE/DE]; Otto-Schott-Strasse 15, VerSfTentlicht D-07745 Jena (DE). Mit internationalem Recherchenbericht. (71) Anmelder (nur fiir US): SIEMANN, Christei (Erbin des verstoibenen Erfinders) [DE/DE]; Fritz-Ritter-Strasse 6, D- 07747 Jena (DE). (72) Erflnder: SIEMANN, Hans-Joachim (verstorben). I 8 (72) Erfinder; und (75) Erflnder/Anmelder (nur fiir US): SCHWARZ, Sigfrid [DE/DE]; Ottogerd-Mtihlmann-Strasse 17, D-07743 Jena 1 (DE). ELGER, Walter [DE/DE]; SchorlemeraUee 12b, D-14195 Berlin (DE). REDDERSEN, Gudrun [DE/DE]; HUgelstrasse 25, D-07749 Jena (DE). SCHNEIDER, Birgitt , [DE/DE]; Damaschkeweg 19, D-07745 Jena (DE). (54) Title: ESTRA-1,3,5(10)-TRIENE DERIVATIVES, METHODS OF PREPARING SUCH COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM (54) Bezeichnung: ESTRA-1,3,5( 10)-TRIEN-DERIVATE, VERFAHREN ZU IHRER HERSTELLUNG UND DIESE VERBINDUNGEN ‘ ENTHALTENDE PHARMAZEUT1SCHE ZUSAMMENSETZUNGEN (57) Abstract The invention concerns novel estra-1,3,5(10)-triene amidosulphamates with an R-SO2-O- group in the 3-position, R being an R*R2N- group in which R* and R2, independently of each other, are a hydrogen atom, an alkyl group with 1 to 5 C-atoms or, together with the N-atom, a polymethyleneimino group with 4 to 6 C-atoms or a motpholino group. The compounds described are suitable for use in hormonal contraception and in climacteric hormone-replacement therapy (HRT), as well as in the treatment of gynaecological and andrological conditions. The compounds described thus only have a low hepatic oestrogenicity, Also described are methods of preparing the compounds described, plus the preparation of pharmaceutical compositions containing them. (57) Zusammenfaaeung Die Erfindung betrifft neue Estra-1,3,5(10)-trien-Amidosulfamate, welche an der 3-Position eine R-SCh-O-Gruppe tragen, wobei R cine R'R2N-Gnippe 1st, worin R* und R2 unabhingig voneinander ein Wasserstoffatora, einen Alkylrest mit 1-5 C-Atomen oder zusammen mit dem N-Atom einen Polymethylenimlnorest mit 4 bis 6 C-Atomen oder einen Morpholinorcst bedeuten. Die erfindungsgemaflen Verbindungen sind zur hormonalen Kontrazeption und in der klimakterischen Hormon-Replacement-Therapie (HRT) sowie zur Behandlung gyndkologischer und andrologischer Krankheitsbilder geeignet. Daher weisen die erfindungsgemaflen Verbindungen nur eine geringe hepatische Estrogenitat auf. Femer werdcn Verfahren zur Hentellung der erfindungsgemaflen Verbindungen beschrieben, sowie zur Herstellung pharmazeutischer ’ Zusammensetzungen. j ' 1 totifmnn I 1 Estra-1, 3, 5(10)-Trien Derivatives, Processes for their Preparation and Pharmaceutical Compositions containing these Compounds I Description This invention relates to new estra-1, 3, 5(10)-trien sulfamates. I 10 Estrogens play a major role in hormonal contraception and climacteric hormone replacement therapy (HRT) as well as in the treatment of gynecological (e.g. £ I mammary carcinoma) and andrological (e.g. prostate carcinoma) diseases. Ϊ; In HRT and for contraception, estrogens are predominantly used in combination 15 with a gestagen, e.g, levonorgestrel, desogestrel, gestodene, drospirorenone, norethisterone, cyproterone acetate, chlormadinone acetate and dienogest. For contraception, estrogens are required for reliable suppression of follicular maturation and ovulation. They will also substitute for widely suppressed 20 endogenic, ovarian secretion of estradiol. Such substitution is essential to maintenance of an artificial menstruation cycle and other functions of sexual organs, which would not be satisfactorily achievable by a gestagen alone. Endogenic estrogens also have important central nervous and metabolic functions I 25 in the female organism. Normal estrogen levels make a crucial contribution to individual comfort and wellbeing (L. Zichella; Clinical Management of the Menopausal Woman; Int. J. of Fertil. and Menop. Studies, 38, Suppl. 1 [1993], 15-22). Their presence, 3 0 through various mechanisms, may help in preventing development of cardiovascular diseases, for example, by generating "favourable" lipoprotein patterns in the blood (G. Samsioe; Hormone Replacement Therapy and Cardiovascular Disease; Int. J. of Fertil. and Menop. Studies, 38, Suppl. 1 [1993], 0 23-29), inhibition of lipid incorporation into vascular walls (T.B. Clarkson; 35 Experimental Effects of Progesterone versus Progestins on Arterial Wall; Gynecol, Endocrinol., 6: Suppl. 1 [1992], 15), reduction of blood pressure through JI4il-20.DOC ί \ , gwwtsiwwj »ws#?e? ? O f 2 5 ; favourable action on vascular tonus (R.A. Lobo; Estrogen and Cardiovascular i Disease; Ann, New York Acad. Sciences, 592 [1990], 286-294), reduction of j perfusion resistance in important vascular regions, attenuation of contractile stimuli } * on vascular muscle (C. Jiang et al.; Acute effect of 178-estradiol on rabbit j 5 coronary artery contractile responses to endothelin-1; Am. J. Physiol., 263 [1992], ; " H271-H275). The inner vascular walls, under the impact of estrogens, release j factors (prostacyclins) which counteract to the buildup of blood clots. Estrogens are additionally indispensable to women for preservation of the bone 10 structure. Their loss may cause osseous degradation (osteoporosis) (C. Christiansen; Prevention and Treatment of Osteoporosis with Hormone Replacement Therapy; Int. J. of Fertil. and Menop. Studies, 38, Suppl. 1 [1993], 45-54). These latter "central nervous" and "metabolic" effects of estrogens are major aspects in HRT, 15 Notwithstanding the numerous appreciable aspects of estrogen therapy, there still are certain unresolved problems which impose limitations on the therapeutic use of estrogens or may entail undesirable effects.
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    Évaluation biologique in vitro d’inhibiteurs de la stéroïde sulfatase ayant un effet SERM Mémoire Charles Ouellet Maîtrise en physiologie-endocrinologie Maître ès sciences (M.Sc.) Québec, Canada © Charles Ouellet, 2013 Résumé Initialement, les cancers du sein sont majoritairement hormonodépendants, c’est-à-dire qu’ils sont stimulés par les hormones estrogéniques endogènes. Une première approche pour traiter ce type de cancer consiste à utiliser un antiestrogène pour bloquer l’activation du récepteur des estrogènes dans le tissu mammaire. Une seconde approche consiste à inhiber la synthèse des estrogènes par l’utilisation d’inhibiteurs spécifiques pour certaines enzymes clés de la stéroïdogénèse. La stéroïde sulfatase (STS), une enzyme impliquée dans la biosynthèse des estrogènes, constituerait une importante cible thérapeutique. Dans le cadre de ce mémoire, je discuterai d’un nouveau projet de recherche qui consiste à développer des composés à double-action combinant les deux types d’approches nommées précédemment. Nous cherchons à développer une molécule non-stéroïdienne qui serait en mesure d’inhiber la STS mais également de bloquer le récepteur des estrogènes dans le tissu mammaire. Notre composé doit donc posséder un effet SERM (Selective Estrogen Receptor Modulator), c’est-à-dire de jouer le rôle d’un antagoniste dans le tissu mammaire tout en jouant le rôle d’un agoniste dans d’autres tissus (i.e. tissu osseux) où l’action des estrogènes est importante. Dans ce mémoire, j’aborderai rapidement la synthèse chimique des deux générations de composés pour m’attarder davantage sur les tests biologiques in vitro nécessaires à l’évaluation de leur potentiel à double-action.
  • New Estrone Oxime Derivatives: Synthesis, Cytotoxic Evaluation and Docking Studies

    New Estrone Oxime Derivatives: Synthesis, Cytotoxic Evaluation and Docking Studies

    molecules Article New Estrone Oxime Derivatives: Synthesis, Cytotoxic Evaluation and Docking Studies Catarina Canário 1 , Mariana Matias 1, Vanessa Brito 1, Adriana O. Santos 1, Amílcar Falcão 2,3 , Samuel Silvestre 1,4,* and Gilberto Alves 1 1 CICS-UBI–Health Sciences Research Centre, University of Beira Interior, 6200-506 Covilhã, Portugal; [email protected] (C.C.); [email protected] (M.M.); [email protected] (V.B.); [email protected] (A.O.S.); [email protected] (G.A.) 2 Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal; [email protected] 3 CIBIT-Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, 3000-548 Coimbra, Portugal 4 CNC–Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal * Correspondence: [email protected] Abstract: The interest in the introduction of the oxime group in molecules aiming to improve their biological effects is increasing. This work aimed to develop new steroidal oximes of the estrane series with potential antitumor interest. For this, several oximes were synthesized by reaction of hydroxylamine with the 17-ketone of estrone derivatives. Then, their cytotoxicity was evaluated in six cell lines. An estrogenicity assay, a cell cycle distribution analysis and a fluorescence microscopy study with Hoechst 3358 staining were performed with the most promising compound. In addition, molecular docking studies against estrogen receptor α, steroid sulfatase, 17β-hydroxysteroid dehy- drogenase type 1 and β-tubulin were also accomplished. The 2-nitroestrone oxime showed higher Citation: Canário, C.; Matias, M.; Brito, V.; Santos, A.O.; Falcão, A.; cytotoxicity than the parent compound on MCF-7 cancer cells.