DOCSLIB.ORG

Concise Total Synthesis of (+)-Aphanorphine

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Concise Total Synthesis of (+)-Aphanorphine SYNLETT0936-52141437-2096 Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart 2021, 32, 913–916 letter 913 en Synlett C. Wang, Y. Guan Letter Concise Total Synthesis of (+)-Aphanorphine Cheng Wang Yukun Guan* ClCO2Me H TMS OAc Pd Co Me School of Pharmacy, Yantai University, Qingquan Road-30, N Yantai 264005, P. R. of China H HO Me [email protected] N tBu 6 steps MeO S (+)-aphanorphine O YukunSchooleMailCorresponding [email protected] Guanof Pharmacy, Author Yantai University, Qingquan Road-30, Yantai 264005, P. R. of China Received: 28.02.2021 tion of the 2-benzylpyrrolidine intermediate to construct Accepted after revision: 19.03.2021 the ring B,2 transannular enolate or radical cyclization of 3- Published online: 08.04.2021 3 DOI: 10.1055/s-0037-1610769; Art ID: st-2021-l0074-l benzazepine derivatives to form both rings B and C, or in- tramolecular nucleophilic cyclization of tetralin or dihy- Abstract A concise total synthesis of (+)-aphanorphine is described. dronaphthalene substrates to build ring C.4 Grainger devel- The key features of the strategy include a Pd-catalyzed intermolecular oped a unique approach including a carbamoyl-radical cy- trimethylenemethane [3+2]-cycloaddition to form ring C and a Co-cat- alyzed radical cyclization through a hydrogen-atom transfer to close clization to close ring C and a late-stage formation of ring B. The synthesis was completed in six steps. aromatic ring A through an inverse-electron-demand Diels– Alder reaction.5 Here, we report a concise total synthesis of Key words aphanorphine, total synthesis, alkaloids, tert-butanesulfin- (+)-aphanorphine (5) based on transition metal-catalyzed imine, cycloaddition, hydrogen-atom transfer cyclization reactions. The metal-catalyzed hydrogen-atom transfer (MHAT) In 1988, an alkaloid named aphanorphine (1) was iso- reaction has emerged as a powerful tool in organic synthe- lated by Shimizu and Clardy and their co-workers during sis.6,7 As shown in Scheme 1, we envisioned that the ring B their studies on the biosynthesis of the neurotoxic alkaloid and C1 quaternary carbon center of (+)-aphanorphine (5) neosaxitoxin in the freshwater blue-green alga Aphanizom- might be obtained by a radical cyclization initiated by enon flos-aquae.1 Aphanorphine has a tricyclic benzazepine MHAT of the 2-benzylpyrrolidine 6, which, in turn, could be core and is structurally similar to the natural and synthetic assembled by intermolecular trimethylenemethane (TMM) analgesic benzomorphan alkaloids morphine (2), pentazo- [3+2]-cycloaddition8 of the known chiral imine 7 with 2- cine (3), and eptazocine (4) (Figure 1). Its intriguing struc- [(trimethylsilyl)methyl]allyl acetate (8) (Scheme 1). ture and its potential analgesic biological activity made aphanorphine an attractive target for organic synthesis. H MHAT-based H radical reaction B Me Many elegant strategies have been developed to construct A CN N R HO MeO the tricyclic benzazepine motif, such as Lewis acid-promot- Me 1 ed Friedel–Crafts or tin hydride-mediated radical cycliza- (+)-aphanorphine (5) 6 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. TMM [3+2] H H Me cycloaddition N t H N Bu + H MeO S TMS OAc HO 7 O A B N Me 8 C O HO H Me OH Scheme 1 Retrosynthetic analysis of (+)-aphanorphine (5) (–)-aphanorphine (1) (–)-morphine (2) Me Our total synthesis of (+)-aphanorphine (5) commenced H H Me N with the TMM [3+2]-cycloaddition of 2-[(trimethylsi- N Me HO Me HO lyl)methyl]allyl acetate (8) with the chiral imine 7 (Scheme Me Me 2),9 which can be prepared from (4-methoxyphenyl)acetal- (–)-pentazocine (3) (–)-eptazocine (4) dehyde (9) and (R)-(+)-tert-butylsulfinamide (10) in 66% Figure 1 Representative benzomorphan alkaloids yield by a known procedure.10 Stockman and co-workers © 2021. Thieme. All rights reserved. Synlett 2021, 32, 913–916 Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany 914 Synlett C. Wang, Y. Guan Letter previously investigated the TMM [3+2]-cycloadditions of chiral aryl and alkyl tert-butanesulfinimines to yield enan- Me H 8, Pd(PPh3)4 tiopure pyrrolidine products.11 Unfortunately, when we fol- THF, reflux, 19 h H N tBu lowed Stockman’s method, none of the desired cycloaddi- MeO S N tBu 11 (9%), 16 (19%) MeO S O 15a (13%), 15b (39%) tion product was detected when 7 and 8 were stirred with 7 11 O Pd(PPh3)4 in THF for 18 hours at 25 °C. Instead, the unex- Me pected alkylation product 11 was isolated in 42% yield Me (Scheme 2a). We surmised that 11 might be formed by pro- H tBu H N S ton transfer from the C5 atom of 7 to the Pd–TMM interme- + + O + MeO diate 12. The C5 position of 7 is activated by both an elec- N tBu MeO S 15a tron-withdrawing inductive effect of the imine group and 16 O by the conjugate effect of the phenyl group; consequently, H tBu H instead of the expected cycloaddition of the TMM interme- 1) HCl, MeOH, 0 °C CO2Me N S N diate 12 with the imine, proton transfer from the C5 atom O MeO 2) ClCO2Me, Et3N MeO of 7 to the Pd-TMM intermediate 12 becomes the favored DCM, 25 °C 17 pathway to give methallyl complex 13, which is attacked by 15b 80% 12 the resulting anion 14 to deliver the alkylation product 11. Scheme 3 Synthesis of benzylpyrrolidine 17 a: attempted [3+2]-cycloaddition H H tBu Ti(iPrO) According to our synthetic plan, the next work was to H2N 4 S + N tBu construct the tricyclic benzazepine core of (+)-aphanor- O THF, 25 °C MeO S MeO O 66% phine (5) through MHAT-based radical cycloaddition. We 910 7O began our study by evaluating a catalytic system previously used by Shigehisa et al. for the hydroarylation of nonacti- Me vated alkenes (Table 1).13 Treatment of 17 with 1,1,3,3-te- H 8, Pd(PPh3)4 tramethyldisiloxane (TMDSO), N-fluoro-2,4,6-trimeth- N tBu ylpyridinium triflate (O1, Figure 2), and the ethylenedi- THF, 25 °C, 18 h MeO S 42% 11 O amine-containing salen Co-catalyst C1 in PhCF3 gave the desired tricyclic benzazepine 18 in only 6% yield (Table 1, b: proposed mechanism for the formation of 11 entry 1). To our delight, the use of the 1,3-diaminopropane- Ph P 3 PPh3 Ph3P PPh containing catalyst C2 (Figure 2) improved the yield to 72% Pd 3 Pd(PPh3)4 Pd (entry 2). The longer 1,4-butanediamine gave a much lower 12 13 TMS OAc yield (entry 3). Replacing the tert-butyl group on the 5-po- 8 Me H H sition of the aromatic ring of C2 with H, Me, or OMe (C4– H H C6) led to no conversion (entries 4–6). Further catalyst 5 5 N tBu N tBu screening showed that C7 was the best catalyst, affording a MeO S MeO S 7 O 14 O 76% yield of the desired product (entries 7 and 8). Next, a series of oxidants including N-fluoro-2,4,6-trimethylpyri- 11 dinium tetrafluoroborate (O2), N-fluoropyridinium triflate Scheme 2 Investigation of the [3+2]-cycloaddition (O3), N-fluoropyridinium tetrafluoroborate (O4), and (diac- etoxyiodo)benzene (O5) were evaluated, but all proved in- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. ferior to N-fluoro-2,4,6-trimethylpyridinium triflate (O1) Reports by Trost and co-workers12a,c suggested that in- (entries 9–12). Finally, we examined various silanes and we creasing the temperature might enhance the nucleophilici- found that poly(methylhydrosiloxane) (PMHS) was superior 14 ty of TMM. Pleasingly, when the reaction mixture was to TMDSO, PhSiH3, or Ph(i-PrO)SiH2, giving an improved stirred under reflux for 19 hours, our desired cycloaddition yield of 83%15 (entries 13–15). products 15a and 15b were obtained in 1:3 dr with a com- With 18 in hand, the remaining transformations of the bined yield of 52%, along with the mono- and dialkylation synthesis were N-methylation and O-demethylation. Re- products 11 and 16, respectively, in yields of 9 and 19%. For duction of 18 with excess LiAlH4 afforded (–)-8-O-meth- the synthesis of (+)-aphanorphine (5), the tert-butylsulfinyl ylaphanorphine (19) in 88% yield. On following the proce- 3a group of 15b was removed by treatment with 2 M HCl in dure of Fuchs and Funk, treatment of 19 with BBr3 in DCM MeOH, and the resulting secondary amine was treated with at a low temperature effected the expected O-demethyla- ClCO2Me in the presence of NEt3 to give the methyl carba- tion, giving (+)-aphanorphine (5) in 50% yield (Scheme 4). mate 17 in 80% yield over the two steps (Scheme 3). © 2021. Thieme. All rights reserved. Synlett 2021, 32, 913–916 915 Synlett C. Wang, Y. Guan Letter The physical and spectroscopic data of the synthetic (+)- H H 25 CO Me LiAlH4, THF Me aphanorphine (5) {[]D +20.8 (c 0.4, MeOH)} agreed with N 2 N those reported previously.1,2l MeO 25 °C MeO Me 88% Me 18 19 H BBr , DCM Table 1 Optimization of the MHAT-Based Radical Cycloaddition 3 N Me –30 °C to 0 °C HO Me H H 50% catalyst, oxidant (+)-aphanorphine (5) N CO2Me N CO2Me MeO silane, PhCF3 MeO Scheme 4 Completion of the total synthesis of (+)-aphanorphine (5) 25 °C Me 17 18 In summary, a concise total synthesis of (+)-aphanor- Entry Catalysta Silane Oxidanta Yieldb (%) phine (5) was achieved, starting from the known chiral tert- 1 C1 TMDSO O1 6 butanesulfinimine 7, in six steps and 11% overall yield.
Load more

Recommended publications
  • Updates Clinical
    Clinical ® PAIN Updates INTERNATIONAL ASSOCIATION FOR THE STUDY OF PAIN® Volume XIII, No.2 June 2005 EDITORIAL BOARD Editor-in-Chief Daniel B. Carr, MD The Challenge of Preemptive Analgesia Internal Medicine, Endocrinology, Anesthesiology USA Advisory Board 1 Elon Eisenberg, MD n 1988, Wall reviewed emerging data showing that analgesia before surgical Neurology I incision or amputation decreased postsurgical pain or reduced the incidence of Israel phantom pain, respectively, and decreased the amount of postoperative analgesic James R. Fricton, DDS, MS Dentistry, Orofacial Pain needed. Wall’s publication may be the first review of “preemptive analgesia,” USA which is defined as intervention preceding surgery for the purpose of preventing Maria Adele Giamberardino, MD or decreasing postsurgical pain by preventing central sensitization. To attain Internal Medicine, Physiology Italy preemptive analgesia, however, several critical principles must be applied suc- Cynthia R. Goh, MB BS, FRCP, PhD cessfully. Failure to apply all of these principles may lead to inadequate postsur- Palliative Medicine Singapore gical analgesia. In addition, in patients with pre-existing pain before surgery, Alejandro R. Jadad, MD, PhD preemptive analgesia is unfeasible because central sensitization has already oc- Anesthesiology, Evidence-Based curred due to presurgical pain. This issue of Pain: Clinical Updates surveys the Medicine and Consumer Issues Canada basis for, and challenges facing, preemptive analgesia and presents a practical Andrzej W. Lipkowski, PhD, DSc method for its successful practice. Neuropharmacology and Peptide Chemistry Poland Central Sensitization and Wind-up Patricia A. McGrath, PhD Psychology, Pediatric Pain Canada In response to nociceptive impulses, c-fos, a gene expressed rapidly in many Mohammad Sharify, MD types of cells in response to various stimuli, is expressed in spinal dorsal horn Family Medicine, Rheumatology and supraspinal neurons.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2004/0024006 A1 Simon (43) Pub
    US 2004.0024006A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0024006 A1 Simon (43) Pub. Date: Feb. 5, 2004 (54) OPIOID PHARMACEUTICAL May 30, 1997, now abandoned, and which is a COMPOSITIONS continuation-in-part of application No. 08/643,775, filed on May 6, 1996, now abandoned. (76) Inventor: David Lew Simon, Mansfield Center, CT (US) Publication Classification Correspondence Address: (51) Int. Cl. ................................................ A61K 31/485 David L. Simon (52) U.S. Cl. .............................................................. 514/282 P.O. Box 618 100 Cemetery Road (57) ABSTRACT Mansfield Center, CT 06250 (US) The invention is directed in part to dosage forms comprising a combination of an analgesically effective amount of an (21) Appl. No.: 10/628,089 opioid agonist analgesic and a neutral receptor binding agent or a partial mu-opioid agonist, the neutral receptor binding (22) Filed: Jul. 25, 2003 agent or partial mu-opioid agonist being included in a ratio Related U.S. Application Data to the opioid agonist analgesic to provide a combination product which is analgesically effective when the combina (63) Continuation-in-part of application No. 10/306,657, tion is administered as prescribed, but which is leSS analge filed on Nov. 27, 2002, which is a continuation-in-part Sically effective or less rewarding when administered in of application No. 09/922,873, filed on Aug. 6, 2001, excess of prescription. Preferably, the combination product now Pat. No. 6,569,866, which is a continuation-in affects an opioid dependent individual differently from an part of application No. 09/152,834, filed on Sep.
    [Show full text]
  • Bispectral Index Monitoring Prevent Awareness During Total Intravenous Anesthesia: a Prospective, Randomized, Double-Blinded, Multi-Center Controlled Trial
    Awareness under TIVA Joseph Eldor, MD Chin Med J (Engl). 2011 Nov;124(22):3664-9. Bispectral index monitoring prevent awareness during total intravenous anesthesia: a prospective, randomized, double-blinded, multi-center controlled trial. Zhang C, Xu L, Ma YQ, Sun YX, Li YH, Zhang L, Feng CS, Luo B, Zhao ZL, Guo JR, Jin YJ, Wu G, Yuan W,Yuan ZG, Yue Y. Source Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China. Abstract BACKGROUND: Awareness is a serious complication of general anesthesia. In China, the incidence of intraoperative awareness was 1% in patients undergoing total intravenous anesthesia (TIVA). In this study, we compared the incidence of awareness between Bispectral index (BIS)- guided and routine TIVA protocol and evaluated the effect of BIS on preventing awareness. METHODS: A prospective, randomized, double-blinded, multicenter controlled trial was performed. Patients (≥ 18 years of age) undergoing TIVA were randomly divided into BIS-guided group (Group A, BIS was monitored and recommended to maintain between 40 - 60) and control group (Group B, BIS was monitored but the screen was covered). The intraoperative BIS values were downloaded and the BIS trends of confirmed awareness cases were analyzed to determine whether light anesthesia existed. RESULTS: Of the total 5228 patients, 2919 patients were assigned to Group A and 2309 to Group B. Four cases of confirmed awareness (0.14%) were reported in the BIS-guided group and 15 (0.65%) in the control group (P = 0.002, OR = 0.21, 95% confidence intervals: 0.07 - 0.63). The incidence of possible awareness (0.14% vs.
    [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]
  • Types of Opioid Harms in Canadian Hospitals: Comparing Canada And
    Types of Opioid Harms in Canadian Hospitals: Comparing Canada and Australia Production of this document is made possible by financial contributions from Health Canada and provincial and territorial governments. The views expressed herein do not necessarily represent the views of Health Canada or any provincial or territorial government. Unless otherwise indicated, this product uses data provided by Canada’s provinces and territories. All rights reserved. The contents of this publication may be reproduced unaltered, in whole or in part and by any means, solely for non-commercial purposes, provided that the Canadian Institute for Health Information is properly and fully acknowledged as the copyright owner. Any reproduction or use of this publication or its contents for any commercial purpose requires the prior written authorization of the Canadian Institute for Health Information. Reproduction or use that suggests endorsement by, or affiliation with, the Canadian Institute for Health Information is prohibited. For permission or information, please contact CIHI: Canadian Institute for Health Information 495 Richmond Road, Suite 600 Ottawa, Ontario K2A 4H6 Phone: 613-241-7860 Fax: 613-241-8120 www.cihi.ca [email protected] ISBN 978-1-77109-743-7 (PDF) © 2018 Canadian Institute for Health Information How to cite this document: Canadian Institute for Health Information. Types of Opioid Harms in Canadian Hospitals: Comparing Canada and Australia. Ottawa, ON: CIHI; 2018. Cette publication est aussi disponible en français sous le titre Types de
    [Show full text]
  • Disposal Systems of Transdermal Delivery Devices to Prevent Misuse of the Active Agents Contained Therein
    (19) & (11) EP 1 837 023 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 26.09.2007 Bulletin 2007/39 A61K 31/485 (2006.01) A61K 9/70 (2006.01) A61K 31/445 (2006.01) B09B 3/00 (2006.01) (2006.01) (21) Application number: 07003694.2 A61F 13/00 (22) Date of filing: 10.06.2003 (84) Designated Contracting States: (72) Inventors: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR • Baker, Carl J. HU IE IT LI LU MC NL PT RO SE SI SK TR Middletown, NY 10941-5004 (US) Designated Extension States: • Shevchuck, Ihor AL LT LV MK Yonkers, NY 10710 (US) (30) Priority: 10.06.2002 US 387800 P (74) Representative: Maiwald Patentanwalts GmbH Elisenhof, (62) Document number(s) of the earlier application(s) in Elisenstrasse 3 accordance with Art. 76 EPC: 80335 München (DE) 03757468.8 / 1 513 532 Remarks: (71) Applicant: EURO-CELTIQUE S.A. This application was filed on 22 - 02 - 2007 as a 2330 Luxembourg (LU) divisional application to the application mentioned under INID code 62. (54) Disposal systems of transdermal delivery devices to prevent misuse of the active agents contained therein (57) The present invention relates to a transdermal at least one deactivating agent to chemically alter, to de- delivery device disposal system for disposing of a grade, and/or to deactivate the active component (s) con- transdermal delivery device containing at least one phar- tained in the transdermal delivery device, such as an opi- maceutically active component. The disposal system oid antagonist or an opioid agonist deactivating agent so contains
    [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]
  • Percutaneously Absorbable Composition of Narcotic and Nonnarcotic Analgesics
    Europaisches Patentamt J European Patent Office © Publication number: 0 480 054 A1 Office europeen des brevets © EUROPEAN PATENT APPLICATION published in accordance with Art. 158(3) EPC © Application number: 91906584.7 © Int. CI.5: A61K 45/08, A61 K 31/485, A61K 9/08, A61K 47/10, © Date of filing: 29.03.91 A61 K 47/46) A61 K 31 /55 © International application number: PCT/JP91/00413 © International publication number: WO 91/15241 (17.10.91 91/24) ® Priority: 30.03.90 JP 81180/90 © Applicant: Morimoto, Yasunori 7-22, Nishisakado 4-chome © Date of publication of application: Sakado-shi, Saitama-ken 350-02(JP) 15.04.92 Bulletin 92/16 © Inventor: MORIMOTO, Yasunori, 7-22, ® Designated Contracting States: Nishisakado 4-chome AT BE CH DE DK ES FR GB IT LI LU NL SE Sakado-shi Saitama-ken 350-02(JP) Inventor: SUGIBAYASHI, Kenji, 9-22, Nishisakado 4-chome Sakado-shi Saitama-ken 350-02(JP) Inventor: KOBAYASHI, Kouji, Toko Yakuhin Kogyo Kabushikikaisha 8-19, Shinden 3-chome Adachi-ku Tokyo 123(JP) Inventor: KUSANO, Hisashi, 19-304, Nishiageo No. 2 Danchi 2, 77-1 Oaza Koshikidani Ageo-shi Saitama-ken 362(JP) © Representative: Pearce, Anthony Richmond MARKS & CLERK Alpha Tower Suffolk Street Queensway Birmingham B1 1TT(GB) !£> © PERCUTANEOUSLY ABSORBABLE COMPOSITION OF NARCOTIC AND NONNARCOTIC ANALGESICS. o 00 © A percutaneously absorbable preparation comprising a narcotic analgesic of a low percutaneous absor- bability such as morphine hydrochloride or sulfate, a nonnarcotic analgesic such as eptazocine hydrobromide, a © percutaneous absorption promoter, and a percutaneous absorption promoter aid. Q_ UJ Rank Xerox (UK) Business Services EP 0 480 054 A1 Fig.
    [Show full text]
  • Customs Tariff - Schedule
    CUSTOMS TARIFF - SCHEDULE 99 - i Chapter 99 SPECIAL CLASSIFICATION PROVISIONS - COMMERCIAL Notes. 1. The provisions of this Chapter are not subject to the rule of specificity in General Interpretative Rule 3 (a). 2. Goods which may be classified under the provisions of Chapter 99, if also eligible for classification under the provisions of Chapter 98, shall be classified in Chapter 98. 3. Goods may be classified under a tariff item in this Chapter and be entitled to the Most-Favoured-Nation Tariff or a preferential tariff rate of customs duty under this Chapter that applies to those goods according to the tariff treatment applicable to their country of origin only after classification under a tariff item in Chapters 1 to 97 has been determined and the conditions of any Chapter 99 provision and any applicable regulations or orders in relation thereto have been met. 4. The words and expressions used in this Chapter have the same meaning as in Chapters 1 to 97. Issued January 1, 2020 99 - 1 CUSTOMS TARIFF - SCHEDULE Tariff Unit of MFN Applicable SS Description of Goods Item Meas. Tariff Preferential Tariffs 9901.00.00 Articles and materials for use in the manufacture or repair of the Free CCCT, LDCT, GPT, following to be employed in commercial fishing or the commercial UST, MXT, CIAT, CT, harvesting of marine plants: CRT, IT, NT, SLT, PT, COLT, JT, PAT, HNT, Artificial bait; KRT, CEUT, UAT, CPTPT: Free Carapace measures; Cordage, fishing lines (including marlines), rope and twine, of a circumference not exceeding 38 mm; Devices for keeping nets open; Fish hooks; Fishing nets and netting; Jiggers; Line floats; Lobster traps; Lures; Marker buoys of any material excluding wood; Net floats; Scallop drag nets; Spat collectors and collector holders; Swivels.
    [Show full text]
  • Thesis Introduction
    RESEARCH BACKGROUND: 1.1 HISTORY: Opioids have been used for centuries to produce euphoria, analgesia and sedation and prevent diarrhoea [Rang et al., 2003]. Opium extracted from the poppy plant, Papaver somniferum, was the first opioid isolated and used for medicinal purposes [Gutstein & Akil, 2001; Rang et al., 2003]. Assyrian medical references from 7000 B.C. refer to the use of this poppy juice while the Sumerians record usage from about 4000 B.C.. Egyptian papyri dating from 2000 B.C. report the use of opium for veterinary and gynaecological procedures and the use of the poppy is thought to have spread from here through Asia Minor and Greece. The use of this medicine then travelled with Arab traders through Persia, India and China and by the 10th and 11th centuries A.D., the opium trade was firmly established in Europe [Berridge & Edwards, 1981]. As availability increased, opium use became common and salves or elixirs containing opium were used as a sedative and anaesthetic throughout Europe in the 16th century. Even at this early time the potential for opium to cause “deepe deadly sleapes” was well known, as described by W.D. Bullein in his book “Bulwarke of defense against all sicknesse, soarnesse and woundes“ published in 1579 [Bullein, 1579]. The effectiveness of this compound, however, ensured its continued use. Over the following centuries, medicinal and recreational use continued, and despite the identification of the potential for opioid abuse and addiction, it was not openly discussed in the 1700s. While complications were known, opium was still readily available through grocer or druggist stores in England during the 1800s in the form of laudanum or tinctures, which are 1 Research Background: mixtures of opium, alcohol and various other ingredients.
    [Show full text]
  • List of Psychoactive Drug Spirits for MD A-Methylfentanyl, Abilify
    List of Psychoactive Drug Spirits for MD A-Methylfentanyl, Abilify, abnormal basal ganglia function, abuse of medicines, Aceperone, Acepromazine, Aceprometazine, Acetildenafil, Aceto phenazine, Acetoxy Dipt, Acetyl morphone, Acetyl propionyl morphine, Acetyl psilocin, Activation syndrome, acute anxiety, acute hypertension, acute panic attacks, Adderall, Addictions to drugs, Addictions to medicines, Addictions to substances, Adrenorphin, Adverse effects of psychoactive drugs, adverse reactions to medicines, aggression, aggressive, aggressiveness, agitated depression, Agitation and restlessness, Aildenafil, Akuammine, alcohol abuse, alcohol addiction, alcohol withdrawl, alcohol-related brain damage, alcohol- related liver damage, alcohol mix with medicines for adverse reaction, Alcoholism, Alfetamine, Alimemazine, Alizapride, Alkyl nitrites, allergic breathing reactions to meds, choking to anaphallectic shock, & death; allergic skin reactions to meds, rash, itchyness, hives, welts, etc, Alletorphine, Almorexant, Alnespirone, Alpha Ethyltryptamine, Alpha Neoendorphin, alterations in brain hormones, alterations in mental status, altered consciousness, altered mind, Altoqualine, Alvimopan, Ambien, Amidephrine, Amidorphin, Amiflamine, Amisulpride, Amphetamines, Amyl nitrite, Anafranil, Analeptic, Anastrozole, Anazocine, Anilopam, Antabuse, anti anxiety meds, anti dopaminergic activity, anti seizure meds, Anti convulsants, Anti depressants, Anti emetics, Anti histamines, anti manic meds, anti parkinsonics, Anti psychotics, Anxiety disorders,
    [Show full text]
  • FDA Briefing Document Joint Meeting of the Drug Safety and Risk Management (Dsarm) Advisory Committee and Anesthetic and Analges
    FDA Briefing Document Joint Meeting of the Drug Safety and Risk Management (DSaRM) Advisory Committee and Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC) June 11-12, 2019 1 The attached package contains background information prepared by the Food and Drug Administration (FDA) for the panel members of the advisory committee. The FDA background package often contains assessments and/or conclusions and recommendations written by individual FDA reviewers. Such conclusions and recommendations do not necessarily represent the final position of the individual reviewers, nor do they necessarily represent the final position of the Review Division or Office. We have brought the clinical utility and safety concerns associated with the higher range of opioid analgesic dosing (both in terms of higher strength products and higher daily doses) in the outpatient setting, to this Advisory Committee in order to gain the Committee’s insights and opinions, and the background package may not include all issues relevant to the final regulatory recommendation and instead is intended to focus on issues identified by the Agency for discussion by the advisory committee. The FDA will not issue a final determination on the issues at hand until input from the advisory committee process has been considered and all reviews have been finalized. The final determination may be affected by issues not discussed at the advisory committee meeting. 2 Table of Contents Page Office Director Memorandum 4 Division of Anesthesia, Analgesia, and Addiction Products (DAAAP) Memorandum: Opioids Regulatory Background 9 Division of Epidemiology (DEPI) Review: Prescribing Patterns, Clinical Use, and Risks Associated with Higher Dosage Strength Products and Higher Daily Dosing of Opioid Analgesics 29 3 OFFICE DIRECTOR MEMORANDUM Department of Health and Human Services Public Health Service Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) Office of Surveillance and Epidemiology (OSE) Date: May 22, 2019 From: Judy Staffa, Ph.D., R.Ph.
    [Show full text]