Labeling and Synthesis of Estrogens and Their Metabolites
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Compositions Comprising Drospirenone Molecularly
(19) & (11) EP 1 748 756 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 9/00 (2006.01) A61K 9/107 (2006.01) 29.04.2009 Bulletin 2009/18 A61K 9/48 (2006.01) A61K 9/16 (2006.01) A61K 9/20 (2006.01) A61K 9/14 (2006.01) (2006.01) (2006.01) (21) Application number: 05708751.2 A61K 9/70 A61K 31/565 (22) Date of filing: 10.03.2005 (86) International application number: PCT/IB2005/000665 (87) International publication number: WO 2005/087194 (22.09.2005 Gazette 2005/38) (54) COMPOSITIONS COMPRISING DROSPIRENONE MOLECULARLY DISPERSED ZUSAMMENSETZUNGEN AUS DROSPIRENON IN MOLEKULARER DISPERSION DES COMPOSITIONS CONTENANT DROSPIRENONE A DISPERSION MOLECULAIRE (84) Designated Contracting States: (72) Inventors: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR • FUNKE, Adrian HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR D-14055 Berlin (DE) Designated Extension States: • WAGNER, Torsten AL BA HR MK YU 13127 Berlin (DE) (30) Priority: 10.03.2004 EP 04075713 (74) Representative: Wagner, Kim 10.03.2004 US 551355 P Plougmann & Vingtoft a/s Sundkrogsgade 9 (43) Date of publication of application: P.O. Box 831 07.02.2007 Bulletin 2007/06 2100 Copenhagen Ø (DK) (60) Divisional application: (56) References cited: 08011577.7 / 1 980 242 EP-A- 1 260 225 EP-A- 1 380 301 WO-A-01/52857 WO-A-20/04022065 (73) Proprietor: Bayer Schering Pharma WO-A-20/04041289 US-A- 5 569 652 Aktiengesellschaft US-A- 5 656 622 US-A- 5 789 442 13353 Berlin (DE) 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. -
IJCB 42B(1) 166-172.Pdf
Indian Journal of Chemistry Vol. 42B, January 2003, pp. 166-172 Synthesis and biological activity of 16-arylidene derivatives of estrone and estrone methyl ether Maninder Minu* & Dharam Paul lindal University In 5titutc of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India and G Leclercq & M Borras institut Jules Bordet, Association Hospitaliere de Bruxelles. Centre des Tumeurs de I'ULB, Rue Heger-Bordet 1- 1000, Belgiulll Received 24 April 200 I .. accepted (revised) 20 March 2002 The synthesis of 16-arylidene derivatives 3, 4, S, 6, 7. 8. 9, 10, 11, 12, 13, 14 and IS is described. These compounds have been tested at NCI, Bethesda, for their antineoplastic acti vity against the cell panel consisting of 60-ce!l lines and th e compounds 3, 4, S, 6 and 7 have also been tested for their ill vitro estrogenic / antiestrogenic activity; induction of ERE dependent luciferase inductio n was measured (MvLN celis). The formation of active steroids by aromatase has It was conceived that selective inhibitors of aroma been considered to play an important role in the de tase might be useful as a pharmacological tool to de velopment of human breast carcinoma t, at least one vice successful treatment approach for the hormonal third of all breast cancers establishing that. the estro dependent breast cancer. Our efforts were focused on gen-dependent carcinoma regresses following estro designing estrogen and estrogen methyl ether deriva 2 gen deprivation . In the postmenopausal women, the tives that might inhibit or possess antiestrogenic activ production of estrogen takes place in peripheral tissue ity. From these efforts, several 16-arylidine deriva 3 from inactive precursors by the action of aromatase . -
(12) Patent Application Publication (10) Pub. No.: US 2006/0110428A1 De Juan Et Al
US 200601 10428A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0110428A1 de Juan et al. (43) Pub. Date: May 25, 2006 (54) METHODS AND DEVICES FOR THE Publication Classification TREATMENT OF OCULAR CONDITIONS (51) Int. Cl. (76) Inventors: Eugene de Juan, LaCanada, CA (US); A6F 2/00 (2006.01) Signe E. Varner, Los Angeles, CA (52) U.S. Cl. .............................................................. 424/427 (US); Laurie R. Lawin, New Brighton, MN (US) (57) ABSTRACT Correspondence Address: Featured is a method for instilling one or more bioactive SCOTT PRIBNOW agents into ocular tissue within an eye of a patient for the Kagan Binder, PLLC treatment of an ocular condition, the method comprising Suite 200 concurrently using at least two of the following bioactive 221 Main Street North agent delivery methods (A)-(C): Stillwater, MN 55082 (US) (A) implanting a Sustained release delivery device com (21) Appl. No.: 11/175,850 prising one or more bioactive agents in a posterior region of the eye so that it delivers the one or more (22) Filed: Jul. 5, 2005 bioactive agents into the vitreous humor of the eye; (B) instilling (e.g., injecting or implanting) one or more Related U.S. Application Data bioactive agents Subretinally; and (60) Provisional application No. 60/585,236, filed on Jul. (C) instilling (e.g., injecting or delivering by ocular ion 2, 2004. Provisional application No. 60/669,701, filed tophoresis) one or more bioactive agents into the Vit on Apr. 8, 2005. reous humor of the eye. Patent Application Publication May 25, 2006 Sheet 1 of 22 US 2006/0110428A1 R 2 2 C.6 Fig. -
UNITED STATES PATENT OFFICE 2,636,042 WATER-SOLUBLE HORMONE COMPOUNDS Ralph Salkin, Jackson Heights, N.Y., Assignor to S
Patented Apr. 21, 1953 2,636,042 UNITED STATES PATENT OFFICE 2,636,042 WATER-SOLUBLE HORMONE COMPOUNDS Ralph Salkin, Jackson Heights, N.Y., assignor to S. B. Penick and Company, New York, N. Y., a corporation of Delaware No Drawing. Application July 8, 1949 Serial No. 103,759 5 Claims. (C. 260-39.4) 1. 2 My invention relates to an improvement in the ether, and the sulfate is then Salted out of the manufacture of water-soluble compounds of the aqueous solution by the addition of a, caustic estrane series, and in particular it is concerned solution under cooling. The liberated hormone With an improvement in the synthesis of alkali sulfate is extracted into a suitable Solvent, for and alkaline-earth metal salts of the sulfates of 5 instance butanol, pyridine being preferred how the estranes. ever. The hormone sulfate solution is exhaus The estranes to which my invention applies are tively extracted with ether to remove the solvent. steroids having a free hydroxyl group in the The resultant semicrystalline product is recrys 3-position and a hydroxy or keto group in the tallized from a dilute monohydric alcohol. Or 17-position of the molecule, such as estrone, O Water to give the pure sterol.ester. equilin, equilenin, estradiol and similar com In order to get pure ester Salts, I have found pounds. it essential that the tertiary amine-sulfur trioxide These products which are commonly known as adduct be absolutely pure when being reacted With conjugated estrogens can be obtained from nat the hormones. Improved yields and more readily ural sources such as the urine of pregnant mares purifiable light colored granular products result, or of stallions. -
NINDS Custom Collection II
ACACETIN ACEBUTOLOL HYDROCHLORIDE ACECLIDINE HYDROCHLORIDE ACEMETACIN ACETAMINOPHEN ACETAMINOSALOL ACETANILIDE ACETARSOL ACETAZOLAMIDE ACETOHYDROXAMIC ACID ACETRIAZOIC ACID ACETYL TYROSINE ETHYL ESTER ACETYLCARNITINE ACETYLCHOLINE ACETYLCYSTEINE ACETYLGLUCOSAMINE ACETYLGLUTAMIC ACID ACETYL-L-LEUCINE ACETYLPHENYLALANINE ACETYLSEROTONIN ACETYLTRYPTOPHAN ACEXAMIC ACID ACIVICIN ACLACINOMYCIN A1 ACONITINE ACRIFLAVINIUM HYDROCHLORIDE ACRISORCIN ACTINONIN ACYCLOVIR ADENOSINE PHOSPHATE ADENOSINE ADRENALINE BITARTRATE AESCULIN AJMALINE AKLAVINE HYDROCHLORIDE ALANYL-dl-LEUCINE ALANYL-dl-PHENYLALANINE ALAPROCLATE ALBENDAZOLE ALBUTEROL ALEXIDINE HYDROCHLORIDE ALLANTOIN ALLOPURINOL ALMOTRIPTAN ALOIN ALPRENOLOL ALTRETAMINE ALVERINE CITRATE AMANTADINE HYDROCHLORIDE AMBROXOL HYDROCHLORIDE AMCINONIDE AMIKACIN SULFATE AMILORIDE HYDROCHLORIDE 3-AMINOBENZAMIDE gamma-AMINOBUTYRIC ACID AMINOCAPROIC ACID N- (2-AMINOETHYL)-4-CHLOROBENZAMIDE (RO-16-6491) AMINOGLUTETHIMIDE AMINOHIPPURIC ACID AMINOHYDROXYBUTYRIC ACID AMINOLEVULINIC ACID HYDROCHLORIDE AMINOPHENAZONE 3-AMINOPROPANESULPHONIC ACID AMINOPYRIDINE 9-AMINO-1,2,3,4-TETRAHYDROACRIDINE HYDROCHLORIDE AMINOTHIAZOLE AMIODARONE HYDROCHLORIDE AMIPRILOSE AMITRIPTYLINE HYDROCHLORIDE AMLODIPINE BESYLATE AMODIAQUINE DIHYDROCHLORIDE AMOXEPINE AMOXICILLIN AMPICILLIN SODIUM AMPROLIUM AMRINONE AMYGDALIN ANABASAMINE HYDROCHLORIDE ANABASINE HYDROCHLORIDE ANCITABINE HYDROCHLORIDE ANDROSTERONE SODIUM SULFATE ANIRACETAM ANISINDIONE ANISODAMINE ANISOMYCIN ANTAZOLINE PHOSPHATE ANTHRALIN ANTIMYCIN A (A1 shown) ANTIPYRINE APHYLLIC -
Part I Biopharmaceuticals
1 Part I Biopharmaceuticals Translational Medicine: Molecular Pharmacology and Drug Discovery First Edition. Edited by Robert A. Meyers. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2018 by Wiley-VCH Verlag GmbH & Co. KGaA. 3 1 Analogs and Antagonists of Male Sex Hormones Robert W. Brueggemeier The Ohio State University, Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Columbus, Ohio 43210, USA 1Introduction6 2 Historical 6 3 Endogenous Male Sex Hormones 7 3.1 Occurrence and Physiological Roles 7 3.2 Biosynthesis 8 3.3 Absorption and Distribution 12 3.4 Metabolism 13 3.4.1 Reductive Metabolism 14 3.4.2 Oxidative Metabolism 17 3.5 Mechanism of Action 19 4 Synthetic Androgens 24 4.1 Current Drugs on the Market 24 4.2 Therapeutic Uses and Bioassays 25 4.3 Structure–Activity Relationships for Steroidal Androgens 26 4.3.1 Early Modifications 26 4.3.2 Methylated Derivatives 26 4.3.3 Ester Derivatives 27 4.3.4 Halo Derivatives 27 4.3.5 Other Androgen Derivatives 28 4.3.6 Summary of Structure–Activity Relationships of Steroidal Androgens 28 4.4 Nonsteroidal Androgens, Selective Androgen Receptor Modulators (SARMs) 30 4.5 Absorption, Distribution, and Metabolism 31 4.6 Toxicities 32 Translational Medicine: Molecular Pharmacology and Drug Discovery First Edition. Edited by Robert A. Meyers. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2018 by Wiley-VCH Verlag GmbH & Co. KGaA. 4 Analogs and Antagonists of Male Sex Hormones 5 Anabolic Agents 32 5.1 Current Drugs on the Market 32 5.2 Therapeutic Uses and Bioassays -
EURL GUIDANCE on SUBSTANCES INCLUDED in the SUBSTANCE CATEGORIES LISTED in ANNEX I of SANTE 2017/11987
DRAFT 24 September 2019 (EURLs ANSES, BVL and WFSR) EURL GUIDANCE ON SUBSTANCES INCLUDED IN THE SUBSTANCE CATEGORIES LISTED IN ANNEX I of SANTE 2017/11987 1. A1a Stilbenes (EURL WFSR Wageningen) Cfr. Substances listed for Group A1 in the MMPR Guidance 2. A1b Antithyroid agents (EURL WFSR Wageningen) Cfr. Substances listed for Group A2 in the MMPR Guidance 3. A1c Steroids (EURL WFSR Wageningen) Cfr. Substances listed for Group A3 in the MMPR Guidance 17b-Testosterone (4-Androsten-17b-ol-3-one) 17a-Testosterone (4-Androsten-17a-ol-3-one) 17a-Boldenone 17b-Boldenone Clostebol (CLTb) (4-androsten-4-chloro-17ß-ol-3-one) CLAD (4-chloro-4-androst-3,17-dione) (chloorandrosteendion) a-Estradiol (17a-Estradiol) 17b-estradiol (17ß-estradiol) Methylboldenone (1,4-Androstadien-17a-methyl-17b-ol-3-one) 17a-Methyltestosterone (4-Androsten-17a-methyl-17b-ol-3-one) 17b-Nortestosterone (b-nandrolone) 17α-Nortestosterone (4-estren-17a-ol-3-one) Ethinylestradiol (EE2) 17a-Trenbolone 17b-Trenbolone 16b-hydroxy-stanozolol Megestrol Melengestrol Chlormadinone Medroxyprogesterone Progesterone (P1) (4-Pregnene-3,20-dione (Pregnen(4)-3,20-dione)) Androsten-17ß-ol-3-one [1,(5a)-] (17b-1-testosteron) Mestranol (Ethynylestradiol 3-methyl ether) Fluoxymesterone (FMT) (4-androsten-9a-fluoro-17a-methyl-11ß,17ß-diol-3-one) DHEA (5-androsten-3b-ol-17-one) ethyl-5ß-estrane-3a,17ß-diol [17α-] (EED) Exemestane (6-Methyleneandrosta-1,4-diene-3,17-dione) Mesterolone (Androviron) Dromostanolone (Drostanolone) 2a-Methyl-5a-androstan-3a-ol-17-one -
(12) United States Patent (10) Patent No.: US 8,828,435 B2 Hewitt Et Al
USOO88284.35B2 (12) United States Patent (10) Patent No.: US 8,828,435 B2 Hewitt et al. (45) Date of Patent: Sep. 9, 2014 (54) BUCCAL DELIVERY SYSTEM 2002/0114833 A1 8/2002 Abu-IZZa et al. 2004/0019026 A1 1/2004 Schwartz ...................... 514,177 2004/0028732 A1 2/2004 Falkenhausen et al. (75) Inventors: Ernest Alan Hewitt, Windsor Downs 2004/0037878 A1 2/2004 Szamosi et al. (AU); Richard James Stenlake, Double 2006, O141027 A1 6, 2006 Cioli Day (AU) FOREIGN PATENT DOCUMENTS (73) Assignee: Lingual Consegna Pty Ltd (AU) EP 215635 3, 1987 (*) Notice: Subject to any disclaimer, the term of this GB 1248.189 9, 1971 patent is extended or adjusted under 35 W. wo: iii. U.S.C. 154(b) by 85 days. WO WO9904758 2, 1999 WO WOO189485 11, 2001 (21) Appl. No.: 13/021,578 WO 2004075877 A1 9, 2004 (22) Filed: Feb. 4, 2011 OTHER PUBLICATIONS (65) Prior Publication Data Velaz I., et al., “Effect of PEG 4000 on the Dissolution Rate of Naproxen”, European Journal of Drug Metabolism & US 2011 FO123619 A1 May 26, 2011 Pharmacokinetics, vol. 23, No. 2, pp. 103-108 (Apr.-Jun. 1998). Runkel, R., et al., "Naproxen Oral Absorption Characteristics'. Related U.S. Application Data Chem. Pharm. Bull. vol. 70, No. 7, pp. 1457-1466 (197p). Ranucci E. et al., “Pharmacokinetic Results on Naproxen Prodrugs (63) Continuation of application No. 1 1/910.902, filed as Based on Poly(ethyleneglycol)s', J Biomater Sci Polymer Edn, vol. application No. PCT/AU2006/000472 on Apr. 7, 2006, 6, No. -
(12) United States Patent (10) Patent No.: US 7,723,320 B2 Bunschoten Et Al
US007723320B2 (12) United States Patent (10) Patent No.: US 7,723,320 B2 Bunschoten et al. (45) Date of Patent: May 25, 2010 (54) USE OF ESTROGEN COMPOUNDS TO DE 23,36434. A 4, 1975 INCREASE LIBDO IN WOMEN WO WO96 O3929 A 2, 1996 (75) Inventors: Evert Johannes Bunschoten, Heesch OTHER PUBLICATIONS (NL); Herman Jan Tijmen Coelingh Bennink, Driebergen (NL); Christian Holinka CF et al: “Comparison of Effects of Estetrol and Taxoxifen Franz Holinka, New York, NY (US) with Those of Estriol and Estradiol on the Immature Rat Uterus'; Biology of Reproduction; 1980; pp. 913-926; vol. 22, No. 4. (73) Assignee: Pantarhei Bioscience B.V., Al Zeist Holinka CF et al; "In-Vivo Effects of Estetrol on the Immature Rat (NL) Uterus'; Biology of Reproduction; 1979: pp. 242-246; vol. 20, No. 2. Albertazzi Paola et al.; "The Effect of Tibolone Versus Continuous Combined Norethisterone Acetate and Oestradiol on Memory, (*) Notice: Subject to any disclaimer, the term of this Libido and Mood of Postmenopausal Women: A pilot study': Data patent is extended or adjusted under 35 base Biosis "Online!; Oct. 31, 2000: pp. 223-229; vol. 36, No. 3; U.S.C. 154(b) by 1072 days. Biosciences Information Service.: Philadelphia, PA, US. Visser et al., “In vitro effects of estetrol on receptor binding, drug (21) Appl. No.: 10/478,264 targets and human liver cell metabolism.” Climacteric (2008) 11(1) Appx. II: 1-5. (22) PCT Filed: May 17, 2002 Visser et al., “First human exposure to exogenous single-dose oral estetrol in early postmenopausal women.” Climacteric (2008) 11(1): (86). -
United States Patent Of?Ce 3,409,643 Patented Nov
i United States Patent Of?ce 3,409,643 Patented Nov. 5, 1968 l 2 ’ 3,409,643 choire when preparing esters atI C-17 of l7a-alkynyl-l7? PROCESS FOR THE PREPARATION OF 1711 hydroxy steroids and particularly ' ALKYNL -l7?-ALKANOYLOXY STEROIDS of those steroids which OF THE ANDROSTANE AND ESTRANE also possess functions or systems ,(e.g. 3-methoxy-A2'5(1°> SERIES , and 3-ethoxy-A3,5.-) which are highly reactive or sensitive Elliot L. Shapiro, Cedar Grove, N.J., assignor to Schering Corporation, Bloom?eld, N.J., a corporation of New hydroxyl group. Thus, Jersey preparation of 3-methoxy-17a-ethinyl-2,5(10)-esteradien . No Drawing. Filed Mar. 11, 1966, Ser. No. 533,435 17,8-01 l7_-aeetate (an intermediate in the preparation of 10 Claims. (Cl. 260-—397.5) therapeutically valuable l9-n0r steroids) via methods 10 \ known in the art involves reacting 3-methoxy-l7a-ethinyl 2,5 ( 10)-estradien-17B-ol withv acetic anhydride in pyridine ' _ABSTRACT OF THE DISCLOSURE at elevated temperatures or with acetyl chloride in pyri A novel process for the preparation of 17a-alkynyl dine. Both the aforementioned reaction mediums cause l7?-alkanoyloxy steroids of the androstane and estrane ' involving destruction of the existing series comprises subjecting a 17~keto steroid of the andro A-ring sys em such as conversion of the 3-methoxy stane and estrane series to the ' ' Azimol- sys‘em to a 3-keto-l9-nor-A4- system or to an acetylide and adding in situ to the 17a-alkynyl-l7B-hy aromatic A-ring system (i.e. -
REVIEW Steroid Sulfatase Inhibitors for Estrogen
99 REVIEW Steroid sulfatase inhibitors for estrogen- and androgen-dependent cancers Atul Purohit and Paul A Foster1 Oncology Drug Discovery Group, Section of Investigative Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK 1School of Clinical and Experimental Medicine, Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham B15 2TT, UK (Correspondence should be addressed to P A Foster; Email: [email protected]) Abstract Estrogens and androgens are instrumental in the maturation of in vivo and where we currently stand in regards to clinical trials many hormone-dependent cancers. Consequently,the enzymes for these drugs. STS inhibitors are likely to play an important involved in their synthesis are cancer therapy targets. One such future role in the treatment of hormone-dependent cancers. enzyme, steroid sulfatase (STS), hydrolyses estrone sulfate, Novel in vivo models have been developed that allow pre-clinical and dehydroepiandrosterone sulfate to estrone and dehydroe- testing of inhibitors and the identification of lead clinical piandrosterone respectively. These are the precursors to the candidates. Phase I/II clinical trials in postmenopausal women formation of biologically active estradiol and androstenediol. with breast cancer have been completed and other trials in This review focuses on three aspects of STS inhibitors: patients with hormone-dependent prostate and endometrial 1) chemical development, 2) biological activity, and 3) clinical cancer are currently active. Potent STS inhibitors should trials. The aim is to discuss the importance of estrogens and become therapeutically valuable in hormone-dependent androgens in many cancers, the developmental history of STS cancers and other non-oncological conditions. -
University Microfilms, Inc., Ann Arbor, Michigan ADRENOCORTICAL STEROID PROFILE IN
This dissertation has been Mic 61-2820 microfilmed exactly as received BESCH, Paige Keith. ADRENOCORTICAL STEROID PROFILE IN THE HYPERTENSIVE DOG. The Ohio State University, Ph.D., 1961 Chemistry, biological University Microfilms, Inc., Ann Arbor, Michigan ADRENOCORTICAL STEROID PROFILE IN THE HYPERTENSIVE DOG DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of the Ohio State University By Paige Keith Besch, B. S., M. S. The Ohio State University 1961 Approved by Katharine A. Brownell Department of Physiology DEDICATION This work is dedicated to my wife, Dr. Norma F. Besch. After having completed her graduate training, she was once again subjected to almost social isolation by the number of hours I spent away from home. It is with sincerest appreciation for her continual encouragement that I dedi cate this to her. ACKNOWLEDGMENTS I wish to acknowledge the assistance and encourage ment of my Professor, Doctor Katharine A. Brownell. Equally important to the development of this project are the experience and information obtained through the association with Doctor Frank A. Hartman, who over the years has, along with Doctor Brownell, devoted his life to the development of many of the techniques used in this study. It is also with extreme sincerity that I wish to ac knowledge the assistance of Mr. David J. Watson. He has never complained when asked to work long hours at night or weekends. Our association has been a fruitful one. I also wish to acknowledge the encouragement of my former Professor, employer and good friend, Doctor Joseph W.