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(19) TZZ Z_T (11) EP 2 999 708 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C12P 33/16 (2006.01) C07J 1/00 (2006.01) 22.08.2018 Bulletin 2018/34 (86) International application number: (21) Application number: 14801828.6 PCT/IB2014/061590 (22) Date of filing: 21.05.2014 (87) International publication number: WO 2014/188353 (27.11.2014 Gazette 2014/48) (54) PROCESSES FOR THE PREPARATION OF DEHYDROEPIANDROSTERONE AND ITS INTERMEDIATES VERFAHREN ZUR HERSTELLUNG VON DEHYDROEPIANDROSTERON UND DESSEN ZWISCHENPRODUKTEN PROCÉDÉS DE PRÉPARATION DE DÉSHYDROÉPIANDROSTÉRONE ET DE SES INTERMÉDIAIRES (84) Designated Contracting States: • DAHANUKAR, Vilas AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Hyderabad 500008 (IN) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR (74) Representative: Bates, Philip Ian Reddie & Grose LLP (30) Priority: 21.05.2013 IN 2214CH2013 The White Chapel Building 10 Whitechapel High Street (43) Date of publication of application: London E1 8QS (GB) 30.03.2016 Bulletin 2016/13 (56) References cited: (73) Proprietor: Dr. Reddy’s Laboratories Ltd. EP-A2- 0 133 995 US-A- 4 791 057 500 034 Andhra Pradesh (IN) US-A- 5 604 213 US-B1- 6 284 750 US-B2- 8 227 208 (72) Inventors: • FRYSZKOWSKA, Anna • MARGARET G WARD ET AL: "Reversibility of Cambridge CB4 1GF (GB) Steroid Delta-Isomerase II. THE REACTION • QUIRMBACH, Michael Siegfried SEQUENCE IN THE CONVERSION OF 4054 Basel (CH) ANDROST-4-ENE-3,17-DIONE TO 3-HY • GORANTLA, Srikanth Sarat Chandra DROXYANDROST-5-EN-17-ONE BY SHEEP Hyderabad 500047 ADRENAL MICROSOMES", THE JOURNAL OF Andhra Pradesh (IN) BIOLOGICAL CHEMISTRY, vol. 241, no. 13, 10 • ALIETI, Sanjay Reddy July 1966 (1966-07-10), pages 3147-3153, Hyderabad 500090 XP55323075, Andhra Pradesh (IN) • THOMAS J L ET AL: "Human placental • POREDDY, Srinivas Reddy 3beta-hydroxy-5-ene-steroid dehydrogenase Nalgonda 508374 and steroid 5 -> 4-ene-isomerase: Purification Andhra Pradesh (IN) from microsomes, substrate kinetics, and • DINNE, Naresh Kumar Reddy inhibition by product steroids", JOURNAL OF Mahaboob Nagar 509125 STEROID BIOCHEMISTRY, PERGAMON PRESS Andhra Pradesh (IN) PLC, GB, vol. 31, no. 5, 1 November 1988 • TIMMANNA, Upadhya (1988-11-01), pages785-793, XP025204752, ISSN: Hyderabad 500014 0022-4731, DOI: 10.1016/0022-4731(88)90287-7 Andhra Pradesh (IN) [retrieved on 1988-11-01] 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 2 999 708 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 999 708 B1 • THOMAS J L ET AL: "Human placental • DANIEL L. PURICH ET AL.: ’The Enzyme 3beta-hydroxy-5-ene-steroid dehydrogenase Reference: A Comprehensive Guidebook to and steroid 5-> 4-ene-isomerase: Purification Enzyme Nomenclature, Reactions, and Methods’ from mitochondria and kinetic profiles, December 2002, page 782 AND 783, XP008182555 biophysical characterization of the purified • AGUS ET AL.: ’Aldo-keto Reductase Family 1 mitochondrial and microsomal enzymes", Member C3 (AKR1C3) Is a Biomarker and JOURNAL OF STEROID BIOCHEMISTRY, Therapeutic Target for Castration-Resistant PERGAMON PRESS PLC, GB, vol. 33, no. 2, 1 ProstateCancer’ MOLECULAR MEDICINE vol. 18, August 1989 (1989-08-01) , pages 209-217, 22 January 2013, pages 1449 - 1455, XP055296681 XP025223153, ISSN: 0022-4731, DOI: • DATABASE GENBANK [Online] 28 January 2014 10.1016/0022-4731(89)90296-3 [retrieved on COPELANDET AL.: ’SPHINGOMONAS WITTICHII 1989-08-01] RW1, COMPLETE GENOME’, XP003032425 • BAWA ET AL.: ’Enzymatic Reduction of Ketones Retrieved from NCBI Database accession no. to Optically Active Secondary Alcohols’ CP000699 JOURNAL OF PHYSICAL SCIENCE vol. 19, no. ISSUE, 2008, pages 1 - 5, XP055296669 • JONES ET AL.: ’Steroids and steroidases.VI. On the C-17 specificity of the 5-3-ketoisomerase of Pseudomonas testosterone and evidence for substrate micelle formation’ CANADIAN JOURNAL OF CHEMISTRY vol. 46, no. 9, 1968, pages 1459 - 1465, XP055296672 2 EP 2 999 708 B1 Description INTRODUCTION 5 [0001] The present application relates to a regioselective and stereoselective processes for the preparation of dehy- droepiandrosterone (DHEA) and processes for its intermediates. BACKGROUND OF THE INVENTION 10 [0002] Dehydroepiandrosterone (DHEA) also known as androstenolone or prasterone or 3 β-hydroxyandrost-5-en-17- one or 5-androsten-3β-ol-17-one, is an important endogenous steroid hormone and has the structure of formula (I). 15 20 [0003] Dehydroepiandrosterone (DHEA) is a key intermediate in the synthesis of steroidal molecules, including but not limited to abiraterone acetate, a drug used in the treatment of castration-resistant prostate cancer. [0004] An article by J.Bryan Jones et al., "Steroids and steroidases.VI. On the C-17 specificity of the Δ5-3-ketoisomer- 25 ase of Psudomonas testosterone and evidence for substrate micelle formation," Candian Journal of Chemistry, 46,1459-1465 (1968) describes a process for the preparation of androst-5-ene-3,17-dione , an intermediate used for the preparation of DHEA. The process disclosed in the said reference involves reacting androst-4-ene-3,17-dione with potassium t-butoxide in t-butyl alcohol under nitrogen atmosphere for 90 minutes at 20°C, followed by quenching the reaction mass by rapid addition of 10% aqueous acetic acid, adding excess sodium bicarbonate, extracting with ether, 30 evaporating at room temperature and recrystallization from acetone to give androst-5-ene-3,17-dione. [0005] However, the above process is disadvantageous in that, it involves the use of higher amounts of base i.e., 10 equivalents of potassium tert-butoxide, results in the formation of oxidized impurities of androst-5-ene-3,17-dione and has workup procedure which may not suitable on an industrial scale and thereby results in low and unsatisfactory yields. [0006] Accordingly, there remains a need to provide improved processes for preparing androst-5-ene-3,17-dione that 35 eliminates and reduces the drawbacks of the prior art in a convenient manner. [0007] Chinese Patent Application Publication No. 102212099 disclose a multistep process for the preparation of dehydroepiandrosterone starting from 16-dehydropregnenolone acetate and involves the reaction steps as depicted in Scheme 1 below. 40 45 [0008] Chinese Patent Application Publication No. 102603841 disclose a multistep process for the preparation of dehydroepiandrosterone from 4-androsten-3,17-dione, and involves the reaction steps as depicted in Scheme 2 below. 50 55 3 EP 2 999 708 B1 5 10 15 20 [0009] Chinese Patent Application Publication No. 102603839 describes a multistep synthetic process for preparation of dehydroepiandrosterone starting from 16-dehydropregnenolone acetate, which involves (i) preparation of 16-dehy- dropregnenolone acetate oxime (ii) Beckmann rearrangement of 16-dehydropregnenolone acetate oxime to obtain de- hydroepiandrosterone acetate (iii) hydrolysis of dehydroepiandrosterone acetate to give dehydroepiandrosterone. The reaction steps of the said process are depicted in Scheme 3 below. 25 30 35 40 [0010] Chinese Patent Application Publication No. CN 101362789 and 101717422, Korean patent application Publi- 45 cation No. 2004040555 also discloses synthetic processes for the preparation of dehydroepiandrosterone. [0011] The above described synthetic processes for the preparation of dehydroepiandrosterone includes multiple steps, and a sequence of protection/deprotection steps in order to achieve a stereo- and regioselective reduction at position C3 and may not be suitable for commercial scale synthesis. [0012] Mamoli et al., in US2186906 describes biochemical hydrogenation process for the conversion of a keto-com- 50 pound of the cyclopentano-10,13-dimethyl-poly-hydro-phenanthrene series ( Δ4,5-androstendione) into a corresponding hydroxyl compound of the same series (Δ4,5-androstenole-17-one-3) which comprises subjecting such keto compound to the action of a reducing yeast-containing fermentation solution. [0013] Misaki et al., in US4791057 describes highly sensitive quantitative assay method for a component (which is a 3β-hydroxysteroid or a 3-ketosteroid) in a specimen to be assayed, which involves the steps of causing this component 55 in the specimen to take part in the 3 β-hydroxysteroid & 3-ketosteroid cycling reaction and measuring a detectable change in the reaction system comprising a 3β -hydroxysteroid oxidase and or 3 β-hydroxysteroid dehydrogenase. In the cycling reaction, 3β-hydroxysteroid oxidase consumes O 2 and converts 3-hydroxy steroid to a 3-ketosteroid, 3 β-hydroxysteroid dehydrogenase in the presence of reduced NAD(P) + converts 3-ketosteroid to a 3-hydroxy steroid and generate NAD(P). 4 EP 2 999 708 B1 The 3β-hydroxysteroid & 3-ketosteroid cycling reaction described in the said patent is schematically represented in Scheme 4 below: 5 10 15 20 [0014] Though the above references discloses a enzymatic conversion of 3-hydroxy steroid to 3-keto steroids or vice- versa, they do not disclose a process for the preparation of dehydroepiandrosterone and there remains a complex challenge in developing an improved process which displays required regioselectivity by reducing the 3-oxo group of the steroid leaving the 17-oxo group intact and stereoselectivity by producing the corresponding 3 β-hydroxy compound. [0015] The process according to the present application relates to an enzymatic process for the preparation of dehy- 25 droepiandrosterone. The enzymatic reduction process of the present application is eco-friendly, cost-effective and com- mercially viable. [0016] J. Biol. Chem. Vol 241(13) pp 3147-3153 (1966), J. Steroid Biochem. Vol 31(5) pp 785-793 (1988) and J. Steroid Biochem. Vol 33(2) pp 209-217 (1989) disclose the regiospecific reduction ofΔ 5-androstene-3,17-dione (II) to 3β-hydroxyandrost-5-en-17-one (I) using a mammalian ketoreductase enzyme in the presence of NADH.
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  • DHEA Sulfate, and Aging: Contribution of the Dheage Study to a Sociobiomedical Issue

    DHEA Sulfate, and Aging: Contribution of the Dheage Study to a Sociobiomedical Issue

    Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: Contribution of the DHEAge Study to a sociobiomedical issue Etienne-Emile Baulieua,b, Guy Thomasc, Sylvie Legraind, Najiba Lahloue, Marc Rogere, Brigitte Debuiref, Veronique Faucounaug, Laurence Girardh, Marie-Pierre Hervyi, Florence Latourj, Marie-Ce´ line Leaudk, Amina Mokranel, He´ le` ne Pitti-Ferrandim, Christophe Trivallef, Olivier de Lacharrie` ren, Stephanie Nouveaun, Brigitte Rakoto-Arisono, Jean-Claude Souberbiellep, Jocelyne Raisonq, Yves Le Boucr, Agathe Raynaudr, Xavier Girerdq, and Franc¸oise Foretteg,j aInstitut National de la Sante´et de la Recherche Me´dicale Unit 488 and Colle`ge de France, 94276 Le Kremlin-Biceˆtre, France; cInstitut National de la Sante´et de la Recherche Me´dicale Unit 444, Hoˆpital Saint-Antoine, 75012 Paris, France; dHoˆpital Bichat, 75877 Paris, France; eHoˆpital Saint-Vincent de Paul, 75014 Paris, France; fHoˆpital Paul Brousse, 94804 Villejuif, France; gFondation Nationale de Ge´rontologie, 75016 Paris, France; hHoˆpital Charles Foix, 94205 Ivry, France; iHoˆpital de Biceˆtre, 94275 Biceˆtre, France; jHoˆpital Broca, 75013 Paris, France; kCentre Jack-Senet, 75015 Paris, France; lHoˆpital Sainte-Perine, 75016 Paris, France; mObservatoire de l’Age, 75017 Paris, France; nL’Ore´al, 92583 Clichy, France; oInstitut de Sexologie, 75116 Paris, France; pHoˆpital Necker, 75015 Paris, France; qHoˆpital Broussais, 75014 Paris, France; and rHoˆpital Trousseau, 75012 Paris, France Contributed by Etienne-Emile Baulieu, December 23, 1999 The secretion and the blood levels of the adrenal steroid dehydro- number of consumers. Extravagant publicity based on fantasy epiandrosterone (DHEA) and its sulfate ester (DHEAS) decrease pro- (‘‘fountain of youth,’’ ‘‘miracle pill’’) or pseudoscientific asser- foundly with age, and the question is posed whether administration tion (‘‘mother hormone,’’ ‘‘antidote for aging’’) has led to of the steroid to compensate for the decline counteracts defects unfounded radical assertions, from superactivity (‘‘keep young,’’ associated with aging.
  • Spironolactone for Adult Female Acne

    Spironolactone for Adult Female Acne

    ® PPracticalEDIATRIC DERMATOLOGY Pearls From the Cutis Board Spironolactone for Adult Female Acne Many cases of acne are hormonal in nature, meaning that they occur in adolescent girls and women and are aggravated by hormonal fluctuations such as those that occur during the menstrual cycle or in the setting of underlying hormonal imbalances as seen in polycystic ovary syndrome. For these patients, antihormonal therapy such as spironolactone is a valid and efficacious option. Herein, initiation and utilization of this medication is reviewed. Adam J. Friedman, MD copy What should you do during the first Evaluation of these women with acne for the visit for a patient you may start possibility of hormonal imbalance may be necessary, on spironolactone? with the 2 most common causes of hyperandrogen- Some women will come in asking about spironolac- ismnot being polycystic ovary syndrome and congeni- tone for acne, so it is important to identify potential tal adrenal hyperplasia. The presence of alopecia, candidates for antihormonal therapy: hirsutism, acanthosis nigricans, or other signs of • Women with acne flares that cycle androgen excess, in combination with dysmenor- with menstruation Dorhea or amenorrhea, may be an indication that the • Women with adult-onset acne or persistent- patient has an underlying medical condition that recurrent acne past teenaged years, even needs to be addressed. Blood tests including testos- in the absence of clinical or laboratory signs terone, dehydroepiandrosterone, follicle-stimulating of hyperandrogenism hormone, and luteinizing hormone would be appro- • Women on oral contraceptives (OCs) who priate screening tests and should be performed dur- exhibit moderate to severe acne, especially ing the menstrual period or week prior; the patient with a hormonal patternCUTIS clinically should not be on an OC or have been on one within • Women not responding to conventional ther- the last 6 weeks of testing.