DOCSLIB.ORG

Ep 1380299 A1

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Ep 1380299 A1 Europäisches Patentamt *EP001380299A1* (19) European Patent Office Office européen des brevets (11) EP 1 380 299 A1 (12) EUROPEAN PATENT APPLICATION published in accordance with Art. 158(3) EPC (43) Date of publication: (51) Int Cl.7: A61K 31/55, A61P 13/08, 14.01.2004 Bulletin 2004/03 A61P 13/10 // C07D495:04 (21) Application number: 02713257.0 (86) International application number: (22) Date of filing: 29.03.2002 PCT/JP2002/003169 (87) International publication number: WO 2002/078712 (10.10.2002 Gazette 2002/41) (84) Designated Contracting States: • ATSUKI, Kaoru, c/o Kyowa Hakko Kogyo Co., Ltd AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU Sunto-gun, Shizuoka 411-8731 (JP) MC NL PT SE TR • OHNO, Tetsuji, c/o Kyowa Hakko Kogyo Co., Ltd Designated Extension States: Sunto-gun, Shizuoka 411-8731 (JP) AL LT LV MK RO SI • SHIRAKURA, Shiro, c/o Kyowa Hakko Kogyo Co., Ltd (30) Priority: 30.03.2001 JP 2001099799 Sunto-gun, Shizuoka 411-8731 (JP) • KARASAWA, Akira, (71) Applicant: KYOWA HAKKO KOGYO CO., LTD. c/o Kyowa Hakko Kogyo Co., Ltd Chiyoda-ku, Tokyo 100-8185 (JP) Sunto-gun, Shizuoka 411-8731 (JP) (72) Inventors: (74) Representative: VOSSIUS & PARTNER • YAMAGATA, Tsuyoshi, Siebertstrasse 4 c/o Kyowa Hakko Kogyo Co., Ltd 81675 München (DE) Sunto-gun, Shizuoka 411-8731 (JP) (54) REMEDIES FOR VESICAL STIMULATION IN ASSOCIATION WITH PROSTATAUXE 1 2 3 5 6 7 8 6 (57) The present invention provides a therapeutic X -X -X represents CR =CR -CR =CR , N(O)m=CR - 7 8 5 6 8 5 6 7 agent for bladder irritative symptoms associated with CR =CR ,CR=CR -N(O)m=CR ,CR=CR -CR =N 5 6 5 6 7 8 7 benign prostatic hyperplasia comprising, as an active in- (O)m,CR=CR -O, CR =CR -S, O-CR =CR ,S-CR= gredient, a tricyclic compound represented by formula CR8 or O-CR7=N; (I): Y represents -CH2S-, -CH2SO-, -CH2SO2-, -CH2O-, -CH=CH-, - (CH2)p-, -SCH2-, -SOCH2-, -SO2CH2-or -OCH2-; and R2 represents a hydrogen atom, substituted or unsub- stituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkoxy, ami- no, mono(substituted or unsubstituted lower alkyl)-sub- stituted amino, di(substituted or unsubstituted lower alkyl)-substituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkylamino, substituted or unsubsti- [wherein R1 represents a hydrogen atom, substituted or tuted arylamino or a substituted or unsubstituted heter- unsubstituted lower alkyl, substituted or unsubstituted oalicyclic group] or a pharmaceutically acceptable salt lower alkoxy or halogen; thereof. EP 1 380 299 A1 Printed by Jouve, 75001 PARIS (FR) EP 1 380 299 A1 Description Technical Field 5 [0001] The present invention relates to a therapeutic agent for bladder irritative symptoms associated with benign prostatic hyperplasia. Background Art 10 [0002] Benign prostatic hyperplasia is benign adenoma generated in a transitional zone of the prostate that wraps the urethra. Patients with benign prostatic hyperplasia complain of bladder outlet obstructive symptoms or bladder irritative symptoms. Examples of bladder outlet obstructive symptoms include a hesitation before urine flow starts, straining, a weak urinary stream, an intermittent urinary stream, dribbling at the end of urination, prolongation of uri- nation and overflow incontinence. Examples of bladder irritative symptoms include urinary frequency at daytime, urinary 15 frequency at night, urinary urgency, a feeling of incomplete emptying and a reduced voided volume per micturition. Functional obstruction and mechanical obstruction are involved in the development of these urinary disturbances due to benign prostatic hyperplasia. Further, these functional and mechanical obstructions cause secondary changes in detrusor muscle or nerves, which induce the complicated pathological phenomena such as bladder irritative symptoms and bladder outlet obstructive symptoms. 20 [0003] At present, for examples, α1-receptor blockers, anti-androgen agents, plant preparations, amino acid prepa- rations, or the like are used as a therapeutic agent for benign prostatic hyperplasia. Among these, examples of the α1- receptor blockers include tamsulosin hydrochloride, prazosin hydrochloride, terazosin hydrochloride and urapidil. Ex- amples of the anti-androgen agents include chlormadinone acetate, allylestrenol, gestonorone caproate, oxendolone and finasteride. The α1-receptor blockers inhibit the functional urethral obstruction, that is, contractions of prostatic 25 smooth muscle induced by noradrenaline, secreted by stimulation of the sympathetic nerve, via the α1-receptor. The anti-androgen agents inhibit the mechanical obstruction, that is, a rise in urethral resistance resulting from the pressure caused by the enlarged prostate itself. However, although the α1-receptor blockers and anti-androgen agents are recognized to be effective for bladder outlet obstructive symptoms of benign prostatic hyperplasia, their effects on improvement of bladder irritative symptoms are insufficient. The plant preparations and amino acid preparations, which 30 have anti-inflammatory activity, anti-edema activity, or the like, improve the bladder irritative symptoms by alleviating the outflow obstruction at the bladder neck; but their effects are weak and the dose required is large so that they are a burden to aged people. Under these circumstances, there exists a need for a therapeutic agent to alleviate bladder irritative symptoms. [0004] Tricyclic compounds having the activity to prolong the intervals of bladder contractions and pharmaceutically 35 acceptable salts thereof are known as therapeutic agents for urinary incontinence (WO97/14672 and WO98/46587). However, it is not known that the compound groups have the activity to remit bladder irritative symptoms associated with benign prostatic hyperplasia. Disclosure of the Invention 40 [0005] The present invention relates to the following (1) to (27). (1) A therapeutic agent for bladder irritative symptoms associated with benign prostatic hyperplasia comprising, as an active ingredient, a tricyclic compound represented by formula (I): 45 50 55 [wherein R1 represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy or halogen; X1-X2-X3 represents CR5=CR6-CR7=CR8 (wherein R5,R6,R7and R8, which may be the same or different, each represent a hydrogen atom, substituted or unsubstituted lower alkyl, hydroxy, substituted or unsubstituted lower alkoxy, nitro, amino, mono(lower alkyl)-substituted amino, di(lower alkyl)-substituted amino, 2 EP 1 380 299 A1 6 7 8 6 7 8 substituted or unsubstituted lower alkanoylamino or halogen), N(O)m=CR -CR =CR (wherein R ,R and R have 5 6 8 the same significances as defined above, respectively, and m represents 0 or 1), CR =CR -N(O)m=CR (wherein 5 6 8 5 6 7 R ,R ,R and m have the same significances as defined above, respectively), CR =CR -CR =N (O)m (wherein R5,R6,R7and m have the same significances as defined above, respectively), CR5=CR6-O (wherein R5 and R6 5 have the same significances as defined above, respectively), CR5=CR6-S (wherein R5 and R6 have the same significances as defined above, respectively), O-CR7=CR8 (wherein R7 and R8 have the same significances as defined above, respectively), S-CR7=CR8 (wherein R7 and R8 have the same significances as defined above, 7 7 respectively) or O-CR =N (wherein R has the same significance as defined above); Y represents -CH2S-, -CH2SO-, -CH2SO2-, -CH2O-, -CH=CH-, 10 2 - (CH2)p- (wherein p represents an integer of 0 to 2), -SCH2-, -SOCH2-, -SO2CH2- or -OCH2-; and R represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkoxy, amino, mono(substituted or unsubstituted lower alkyl)-substituted amino, di(substi- tuted or unsubstituted lower alkyl)-substituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkylamino, substituted or unsubstituted arylamino or a substituted or 15 unsubstituted heteroalicyclic group] or a pharmaceutically acceptable salt thereof. (2) A therapeutic agent for bladder irritative symptoms associated with benign prostatic hyperplasia comprising, as an active ingredient, a tricyclic compound represented by formula (Ia): 20 25 [wherein R1 and X1-X2-X3 have the same significances as defined above, respectively; a Y represents -CH2SO2-, -SCH2-, -SOCH2-, -SO2CH2- or -OCH2-; and a when Y is -CH2SO2-, -SCH2-, -SOCH2- or -SO2CH2-, 30 R2a represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alke- nyl, trifluoromethyl, substituted or unsubstituted lower alkoxy, amino, mono(substituted or unsubstituted lower alkyl)-substituted amino, di(substituted or unsubstituted lower alkyl)-substituted amino, substituted or unsubstitut- ed aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkylamino, substituted or unsub- stituted arylamino, a substituted or unsubstituted heteroalicyclic group or formula (II) : 35 40 (wherein n is 0 or 1; R3 and R4, which may be the same or different, each represent a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl or trifluoromethyl, or R3 and R4 may be combined together with the adjacent carbon atom 45 to form cycloalkyl; and Q represents hydroxy, substituted or unsubstituted lower alkoxy, amino
Load more

Recommended publications
  • 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
    [Show full text]
  • Wipf Group І University of Pittsburgh
    Wipf Group І University of Pittsburgh Serene Tai Research Topic Seminar 1st April 2017 Serene Tai @ Wipf Group Page 1 of 44 4/15/2017 v Prostate - compound tubuloalveolar exocrine gland of the male reproductive system - about the size of a walnut v Prostate cancer - uncontrolled growth of cells in the prostate gland - prostate adenocarcinoma is the major cancer type - 1 in 7 men will be diagnosed with prostate cancer in their lifetime - average age 66; rare before 40 v Symptoms - no symptoms in the early stage - pain and blood in urination, frequent urination, pain in bones and other areas occur in advanced stages American Cancer Society, Cancer Facts & Figures 2017 2 Serene Tai @ Wipf Group Page 2 of 44 4/15/2017 3 Serene Tai @ Wipf Group Page 3 of 44 4/15/2017 v AR is a ligand-dependent nuclear transcription factor that belongs to the steroid hormone receptor superfamily v AR gene encodes a protein of 919 amino acids (110 kDa) v Consists of 4 major functional domains: - N-terminal domain (NTD) - DNA binding domain (DBD) - Hinge region - Ligand binding domain (LBD) v Structure of full length AR has not been solved Acta Pharmacologica Sinica. 2015, 36, 3-23 J. Carcinog. 2011, 10, 20 ACS Chem. Biol. 2016, 11, 2499−2505 4 Serene Tai @ Wipf Group Page 4 of 44 4/15/2017 v Accounts for more than half the size of AR v Contains transactivation function (AF1) v The polyglutamine (polyQ - CAG) and polyglycine (polyG - GGC) tracts affect AR transactivation activity v A combination of experimental and computational analysis suggest that the NTD exists as partially folded protein intermediate (neither full random coil nor stable globular comformation) v Flexible for binding with multiple structurally diverse protein partners Biochem.
    [Show full text]
  • Effects of Anti-Androgen, Tzp-4238 and Chlormadinone Acetate on the Adrenal Cortex -Histo- Pathological and Immunocyto- Chemical Studies
    ACTA HISTOCHEM. CYTOCHEM. Vol. 27, No. 4, pp. 365-372, 1994 EFFECTS OF ANTI-ANDROGEN, TZP-4238 AND CHLORMADINONE ACETATE ON THE ADRENAL CORTEX -HISTO- PATHOLOGICAL AND IMMUNOCYTO- CHEMICAL STUDIES- MASANORI MURAKOSHI, RIE INADA, MASASHI TAGAWA, KAZUHIRO IIZUKA, SHUUJI MASUDA, MINORU SUZUKI, ATSUSHI MIZOKAMI* AND KEIICHI WATANABE ** Safety Research Department, Teikoku Hormone Mfg. Co. Ltd., 1604 Shimosakunobe, Takatsu-ku, Kawasaki 213, *Department of Molecular Cell Biology, University of Occupational and Environmental Health, Kitakyushu 806 and **Department of Pathology, Tokai University School of Medicine, Bohseidai, Isehara-city, Kanagawa 259-11 Received for publication May 12, 1994, in revised form July 22, 1994 and re-revised form August 24, 1994 The atrophic effects of two synthetic steroidal anti-androgens, chlormadinone acetate (CMA) and TZP-4238, on the adrenal gland of rats were investigated by histopathological and immunocytochemical procedures. Male Sprague-Dawley rats were divided into four experimental groups. Group 1 consisted of intact controls. Groups 2 and 3 received TZP-423810 mg/kg/day and CMA 50 mg/kg/day p.o., respective- ly, for 3 weeks. Group 4 received distilled water containing 2% Tween 80 instead of TZP-4238 or CMA. CMA caused marked atrophy of the adrenal gland. Histopathologically, the remarkable atrophy was observed in the adrenal cortical cells of zonae fasciculata and reticularis. Intracellular localization of glutathione-peroxidase (GSH-PO) which effectively reduces the lipid peroxides, was mainly observed in the cytoplasmic matrix (cytosol GSH-PO) near the mitochondria or lipid droplets. In ddition, immunoreactivi- ty of intramitochondrial GSH-PO (mitochondrial GSH-PO) was less than that in the controls.
    [Show full text]
  • Marrakesh Agreement Establishing the World Trade Organization
    No. 31874 Multilateral Marrakesh Agreement establishing the World Trade Organ ization (with final act, annexes and protocol). Concluded at Marrakesh on 15 April 1994 Authentic texts: English, French and Spanish. Registered by the Director-General of the World Trade Organization, acting on behalf of the Parties, on 1 June 1995. Multilat ral Accord de Marrakech instituant l©Organisation mondiale du commerce (avec acte final, annexes et protocole). Conclu Marrakech le 15 avril 1994 Textes authentiques : anglais, français et espagnol. Enregistré par le Directeur général de l'Organisation mondiale du com merce, agissant au nom des Parties, le 1er juin 1995. Vol. 1867, 1-31874 4_________United Nations — Treaty Series • Nations Unies — Recueil des Traités 1995 Table of contents Table des matières Indice [Volume 1867] FINAL ACT EMBODYING THE RESULTS OF THE URUGUAY ROUND OF MULTILATERAL TRADE NEGOTIATIONS ACTE FINAL REPRENANT LES RESULTATS DES NEGOCIATIONS COMMERCIALES MULTILATERALES DU CYCLE D©URUGUAY ACTA FINAL EN QUE SE INCORPOR N LOS RESULTADOS DE LA RONDA URUGUAY DE NEGOCIACIONES COMERCIALES MULTILATERALES SIGNATURES - SIGNATURES - FIRMAS MINISTERIAL DECISIONS, DECLARATIONS AND UNDERSTANDING DECISIONS, DECLARATIONS ET MEMORANDUM D©ACCORD MINISTERIELS DECISIONES, DECLARACIONES Y ENTEND MIENTO MINISTERIALES MARRAKESH AGREEMENT ESTABLISHING THE WORLD TRADE ORGANIZATION ACCORD DE MARRAKECH INSTITUANT L©ORGANISATION MONDIALE DU COMMERCE ACUERDO DE MARRAKECH POR EL QUE SE ESTABLECE LA ORGANIZACI N MUND1AL DEL COMERCIO ANNEX 1 ANNEXE 1 ANEXO 1 ANNEX
    [Show full text]
  • INFOLETTER 5 – COVID-19 04 April 2020
    INFOLETTER 5 – COVID-19 04 April 2020 Content overview Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19)……………………………………………………………………………………….............3 EMA advice on the use of NSAIDs for Covid-19 ................................................................................... 9 Intranasal corticosteroids in allergic rhinitis in COVID-19 infected patients: An ARIA-EAACI statement ................................................................................................................................................ 9 Spinal anaesthesia for patients with coronavirus disease 2019 and possible transmission rates in anaesthetists: retrospective, single-centre, observational cohort study ............................10 Italian Society of Interventional Cardiology (GISE) Position Paper for Cath lab‐specific Preparedness Recommendations for Healthcare providers in case of suspected, probable or confirmed cases of COVID‐19 .............................................................................................................10 ECMO for ARDS due to COVID-19 ........................................................................................................11 The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2........................................................................................12 Performance of VivaDiagTM COVID‐19 IgM/IgG Rapid Test is inadequate for diagnosis of COVID‐19
    [Show full text]
  • Federal Register / Vol. 60, No. 80 / Wednesday, April 26, 1995 / Notices DIX to the HTSUS—Continued
    20558 Federal Register / Vol. 60, No. 80 / Wednesday, April 26, 1995 / Notices DEPARMENT OF THE TREASURY Services, U.S. Customs Service, 1301 TABLE 1.ÐPHARMACEUTICAL APPEN- Constitution Avenue NW, Washington, DIX TO THE HTSUSÐContinued Customs Service D.C. 20229 at (202) 927±1060. CAS No. Pharmaceutical [T.D. 95±33] Dated: April 14, 1995. 52±78±8 ..................... NORETHANDROLONE. A. W. Tennant, 52±86±8 ..................... HALOPERIDOL. Pharmaceutical Tables 1 and 3 of the Director, Office of Laboratories and Scientific 52±88±0 ..................... ATROPINE METHONITRATE. HTSUS 52±90±4 ..................... CYSTEINE. Services. 53±03±2 ..................... PREDNISONE. 53±06±5 ..................... CORTISONE. AGENCY: Customs Service, Department TABLE 1.ÐPHARMACEUTICAL 53±10±1 ..................... HYDROXYDIONE SODIUM SUCCI- of the Treasury. NATE. APPENDIX TO THE HTSUS 53±16±7 ..................... ESTRONE. ACTION: Listing of the products found in 53±18±9 ..................... BIETASERPINE. Table 1 and Table 3 of the CAS No. Pharmaceutical 53±19±0 ..................... MITOTANE. 53±31±6 ..................... MEDIBAZINE. Pharmaceutical Appendix to the N/A ............................. ACTAGARDIN. 53±33±8 ..................... PARAMETHASONE. Harmonized Tariff Schedule of the N/A ............................. ARDACIN. 53±34±9 ..................... FLUPREDNISOLONE. N/A ............................. BICIROMAB. 53±39±4 ..................... OXANDROLONE. United States of America in Chemical N/A ............................. CELUCLORAL. 53±43±0
    [Show full text]
  • Stembook 2018.Pdf
    The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.
    [Show full text]
  • Anti-Androgenic Activity of Myricae Cortex—Isolation of Active Constituents from Bark of Myrica Rubra
    March 2001 Biol. Pharm. Bull. 24(3) 259—263 (2001) 259 Anti-androgenic Activity of Myricae Cortex—Isolation of Active Constituents from Bark of Myrica rubra ,a a a b a Hideaki MATSUDA,* Miho YAMAZAKI, Keizo MATSUO, Yusuke ASANUMA, and Michinori KUBO Faculty of Pharmaceutical Sciences, Kinki University,a 3–4–1 Kowakae, Higashiosaka, Osaka 577–8502, Japan and Daiichi Pharmaceutical Co., Ltd.,b 3–14–10, Nihonbashi, Chuo-ku, Tokyo 103–8234, Japan. Received October 16, 2000; accepted November 27, 2000 The aqueous ethanol extract of Myricae Cortex (bark of Myrica rubra SIEB. et ZUCC., Myricaceae) showed in vitro testosterone 5a-reductase inhibitory activity and in vivo anti-androgenic activity using growth of flank organ in castrated Syrian hamsters and/or hair regrowth after shaving in testosterone-treated C57Black/6CrSlc mice. Three constituents, myricanone, myricanol, and myricetin were identified as the main active principles. Key words Myrica rubra; testosterone 5a-reductase; anti-androgenic activity; hair regrowth Androgens have been indicated to be factors inciting com- tracted with 50% ethanol (5 ml) at room temperature for 24 mon baldness and both androgenic action and a genetic pre- h. After filtration, the fresh filtrates were used for in vitro disposition to be prerequisite to development of alopecia.1) assay of inhibition of testosterone 5a-reductase activity and Testosterone is metabolized intracellularly by the enzyme for an in vivo anti-androgenic experiment using testosterone- testosterone 5a-reductase to an active androgen, dihy- treated C57Black/6CrSlc mice. Myricae Cortex (100 g) and drotestosterone, which binds to androgen receptors and Rosae Rugosae Flos (100 g) were crushed and extracted with shows various hormonal actions.2) Thus the anti-androgenic 50% ethanol (500 ml, each) at room temperature for 24 h.
    [Show full text]
  • (12) United States Patent (Lo) Patent No.: US 8,480,637 B2
    111111111111111111111111111111111111111111111111111111111111111111111111 (12) United States Patent (lo) Patent No.: US 8,480,637 B2 Ferrari et al. (45) Date of Patent : Jul. 9, 2013 (54) NANOCHANNELED DEVICE AND RELATED USPC .................. 604/264; 907/700, 902, 904, 906 METHODS See application file for complete search history. (75) Inventors: Mauro Ferrari, Houston, TX (US); (56) References Cited Xuewu Liu, Sugar Land, TX (US); Alessandro Grattoni, Houston, TX U.S. PATENT DOCUMENTS (US); Daniel Fine, Austin, TX (US); 5,651,900 A 7/1997 Keller et al . .................... 216/56 Randy Goodall, Austin, TX (US); 5,728,396 A 3/1998 Peery et al . ................... 424/422 Sharath Hosali, Austin, TX (US); Ryan 5,770,076 A 6/1998 Chu et al ....................... 210/490 5,798,042 A 8/1998 Chu et al ....................... 210/490 Medema, Pflugerville, TX (US); Lee 5,893,974 A 4/1999 Keller et al . .................. 510/483 Hudson, Elgin, TX (US) 5,938,923 A 8/1999 Tu et al . ........................ 210/490 5,948,255 A * 9/1999 Keller et al . ............. 210/321.84 (73) Assignees: The Board of Regents of the University 5,985,164 A 11/1999 Chu et al ......................... 516/41 of Texas System, Austin, TX (US); The 5,985,328 A 11/1999 Chu et al ....................... 424/489 Ohio State University Research (Continued) Foundation, Columbus, OH (US) FOREIGN PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this WO WO 2004/036623 4/2004 WO WO 2006/113860 10/2006 patent is extended or adjusted under 35 WO WO 2009/149362 12/2009 U.S.C. 154(b) by 612 days.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2002/0010208A1 Shashoua Et Al
    US 2002001 0208A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2002/0010208A1 Shashoua et al. (43) Pub. Date: Jan. 24, 2002 (54) DHA-PHARMACEUTICAL AGENT Related U.S. Application Data CONJUGATES OF TAXANES (63) Continuation of application No. 09/135,291, filed on (76) Inventors: Victor Shashoua, Brookline, MA (US); Aug. 17, 1998, now abandoned, which is a continu Charles Swindell, Merion, PA (US); ation of application No. 08/651,312, filed on May 22, Nigel Webb, Bryn Mawr, PA (US); 1996, now Pat. No. 5,795,909. Matthews Bradley, Layton, PA (US) Publication Classification Correspondence Address: Edward R. Gates, Esq. (51) Int. Cl." ............................................ A61K 31/337 Wolf, Greenfield & Sacks, P.C. (52) U.S. Cl. .............................................................. 514/449 600 Atlantic Avenue Boston, MA 02210 (US) (57) ABSTRACT The invention provides conjugates of cis-docosahexaenoic (21) Appl. No.: 09/846,838 acid and pharmaceutical agents useful in treating noncentral nervous System conditions. Methods for Selectively target 22) Filled: Mayy 1, 2001 ingg pharmaceuticalp agents9. to desired tissues are pprovided. Patent Application Publication Jan. 24, 2002 Sheet 1 of 14 US 2002/0010208A1 1 OO 5 O -5OO - 1 OO-9 -8 -7 -6 -5 -4 LOG-10 OF SAMPLE CONCENTRATION (MOLAR) CCRF-CEM-o- SR ----- RPM-8226----- K-562- - -A - - HL-60 (TB) -g- - MOLT4: ... O Fig. 1 1 OO 5 O -5OO -1 O O -8 -7 -6 -5 -4 -- 9 LOGo OF SAMPLE CONCENTRATION (MOLAR) A549/ATCC-o-NS326. NCEKVX 28. --Q-- NCI-H322M-...-a---Eidsf8::... NC-H522--O-- HOP-62---Fig. 2 a-- NC-H460.-------- Patent Application Publication Jan.
    [Show full text]
  • Information to Users
    INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter free, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand comer and continuing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book. Photographs included in the original manuscript have been reproduced xerographically in this copy. Higher quality 6” x 9” black and white photographic prints are available for any photographs or illustrations appearing in this copy for an additional charge. Contact UMI directly to order. UMI A Bell & Howell Information Company 300 North Zeeb Road, Ann Arbor MI 48106-1346 USA 313/761-4700 800/521-0600 DEVELOPMENT OF STEROIDAL INHIBITORS OF CYTOCHROME P450-DEPENDENT ANDROGEN AND ESTROGEN BIOSYNTHESIS DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Patrick John Ward, A.B.
    [Show full text]
  • Androgen Receptor: Structure, Role in Prostate Cancer and Drug Discovery
    Acta Pharmacologica Sinica 2014: 1–21 npg © 2014 CPS and SIMM All rights reserved 1671-4083/14 $32.00 www.nature.com/aps Review Androgen receptor: structure, role in prostate cancer and drug discovery MH Eileen TAN1, 2, *, Jun LI1, H Eric XU2, 3, Karsten MELCHER2, Eu-leong YONG1, * 1Department of Obstetrics & Gynecology, National University Hospital, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 2Laboratory of Structural Sciences, Center for Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, MI 49503, USA; 3VARI/SIMM Center, CAS-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China Androgens and androgen receptors (AR) play a pivotal role in expression of the male phenotype. Several diseases, such as androgen insensitivity syndrome (AIS) and prostate cancer, are associated with alterations in AR functions. Indeed, androgen blockade by drugs that prevent the production of androgens and/or block the action of the AR inhibits prostate cancer growth. However, resistance to these drugs often occurs after 2–3 years as the patients develop castration-resistant prostate cancer (CRPC). In CRPC, a functional AR remains a key regulator. Early studies focused on the functional domains of the AR and its crucial role in the pathology. The elucidation of the structures of the AR DNA binding domain (DBD) and ligand binding domain (LBD) provides a new framework for understanding the functions of this receptor and leads to the development of rational drug design for the treatment of prostate cancer. An overview of androgen receptor structure and activity, its actions in prostate cancer, and how structural information and high-throughput screening have been or can be used for drug discovery are provided herein.
    [Show full text]