DOCSLIB.ORG

WO 2009/092713 Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
WO 2009/092713 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 30 July 2009 (30.07.2009) WO 2009/092713 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07C 311/08 (2006.01) A61K 31/18 (2006.01) kind of national protection available): AE, AG, AL, AM, C07C 311/09 (2006.01) A61K 31/277 (2006.01) AO, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, C07C 317/32 (2006.01) A61K 31/381 (2006.01) CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, C07D 333/20 (2006.01) A61P 25/18 (2006.01) EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, (21) International Application Number: LR, LS, LT, LU, LY,MA, MD, ME, MG, MK, MN, MW, PCT/EP2009/050608 MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY,TJ, (22) International Filing Date: 2 1 January 2009 (21.01.2009) TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (25) Filing Language: English ZW (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, 0801220.5 23 January 2008 (23.0 1.2008) GB ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, (71) Applicant (for all designated States except US): GLAXO FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, GROUP LIMITED [GB/GB]; Glaxo Wellcome House, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, Berkeley Avenue, Greenford, Middlesex UB 6 ONN (GB). CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, (72) Inventors; and TD, TG). (75) Inventors/Applicants (for US only): THEWLIS, Kevin, Michael [GB/GB]; GlaxoSmithKline, New Frontiers Declarations under Rule 4.17: Science Park South, Third Avenue, Harlow, Essex CM19 — as to applicant's entitlement to apply for and be granted a 5AW (GB). WARD, Simon, E. [GB/GB]; GlaxoSmithK patent (Rule 4.17(U)) line, New Frontiers Science Park South, Third Avenue, — as to the applicant's entitlement to claim the priority of the Harlow, Essex CM19 5AW (GB). earlier application (Rule 4.17(Hi)) — of inventorship (Rule 4.17(iv)) (74) Agent: KONDO, Rie; GlaxoSmithKline, Corporate Intel lectual Property (CN925.1), 980 Great West Road, Brent Published: ford, Middlesex TW8 9GS (GB). — with international search report (54) Title: COMPOUNDS WHICH POTENTIATE THE AMPA RECEPTOR AND USES THEREOF IN MEDICINE (57) Abstract: This invention relates to novel N-(2-methyl-phenyl-cy- clopentyl)sulphonamide derivatives of formula (I) and salts thereof: wherein R1, R2, R3, R4, R5, R6, R7, R8, p, R9 and R10 are as defined in the description. The invention also relates to the use of the derivatives in treating diseases and conditions mediated by potentiation of the glutamate receptor, compositions containing the derivatives and processes for their preparation. (I) Compounds which potentiate the AMPA receptor and uses thereof in medicine This invention relates to potentiation of the AMPA receptor by novel N-(2-methyl-phenyl- cyclopentyl)sulphonamide derivatives. Glutamate receptors, which mediate the majority of fast excitatory neurotransmission in the mammalian central nervous system (CNS), are activated by the excitatory amino acid, L-glutamate (for review see Watkins JC, Krogsgaard-Larsen P, Honore T (1990) Trends Pharmacol Sci 11: 25-33). Glutamate receptors can be divided into two distinct families. The G-protein or second messenger-linked "metabotropic" glutamate receptor family which can be subdivided into three groups (Group I, mGlui and mGlu5; Group II, mGlu2 and mGlu3; Group III, mGlu4, mGluθ, mGlu7, mGluδ) based on sequence homology and intracellular transduction mechanisms (for review see Conn PJ and Pinn JP (1997) Ann Rev Pharmacol Toxicol 37: 205-237). The "ionotropic" glutamate receptor family, which directly couple to ligand-gated cation channels, can be subdivided into at least three subtypes based on depolarizing activation by selective agonists, N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5- methylisoxazole-4-propionic acid (AMPA) and kainic acid (KA) (for review see Dingledine R, Borges K, Bowie D and Traynelis S (1999) Pharmacol. Rev. 5 1: 7-61 ). Native AMPA receptors (AMPAR) exist as heterotetramers consisting of combinations of four different protein subunits (GluR1-4) (for review see Bettler B and Muller C (1995) Neuropharmacology 34: 123-139.). Receptor subunit diversity is increased further as each subunit can undergo alternative splicing of a 38 amino acid sequence in the extracellular region just before the fourth membrane spanning domain M4. Such editing results in so- called 'flip' and 'flop' receptor isoforms which differ in kinetic and pharmacological properties (Sommer B, Keinanen K, Verdoon TA, Wisden W , Burnashev N, Herb A , Kohler M, Takagi T, Sakmann B, Seeburg PH (1990) Science 249: 1580-1585). Additionally, post-transcriptional editing of GluR2 mRNA changes a neutral glutamine to a positively charged arginine within M2. In normal humans >99% GluR2 is edited in this way. AMPAR containing such edited GluR2 subunit exhibit low calcium permeability (Burnachev N, Monyer H, Seeburg PH, Sakmann B (1992) Neuron 8: 189-198). There is a suggestion, however, that the number of AMPAR with high calcium permeability is elevated in certain disease-associated conditions (Weiss JH, and Sensi SL (2000) Trends in Neurosci 23: 365-371). AMPAR depolarization removes voltage dependent Mg 2+ block of NMDA receptors which in turn leads to NMDA receptor activation, an integral stage in the induction of Long Term Potentiation ("LTP") (Bliss TVP, Collingridge GL (1993) Nature 361 : 31-9). LTP is a physiological measure of increased synaptic strength following a repetitive stimulus or activity, such as occurs during learning. It has been reported that direct activation of glutamate receptors by agonists, in conditions where glutamate receptor function is reduced, increases the risk of excitotoxicity and additional neuronal damage. AMPAR positive allosteric modulators do not activate the receptor directly. However, when the ligand (L-glutamate or AMPA) is present AMPAR modulators increase receptor activity. Thus, AMPA receptor modulators enhance synaptic function when glutamate is released and is able to bind at post-synaptic receptor sites. Compounds which act as AMPAR positive allosteric modulators have been shown to increase ligand affinity for the receptor (Arai A , Guidotti A , Costa E, Lynch G (1996) Neuroreport. 7: 221 1-5.); reduce receptor desensitization and reduce receptor deactivation (Arai AC, Kessler M, Rogers G , Lynch G (2000) 58: 802-813) and facilitate the induction of LTP both in vitro (Arai A , Guidotti A , Costa E, Lynch G (1996) 7: 221 1-5.) and in vivo (Staubli U, Perez Y , Xu F, Rogers G , Ingvar M, Stone-Elander S, Lynch G ( 1994) Proc Natl Acad Sci 9 1: 11158-1 1162). Such compounds also enhance the learning and performance of various cognitive tasks in rodent (Zivkovic I, Thompson DM, Bertolino M, Uzunov D, DiBeIIa M, Costa E, Guidotti A (1995) JPET 272: 300-309, Lebrun C, Pilliere E, Lestage P (2000) Eu J Pharmacol 401 : 205-212), sub-human primate (Thompson DM, Guidotti A , DiBeIIa M, Costa E (1995) Proc Natl Acad Sci 92: 7667-7671) and man (Ingvar M, Ambros-lngerson J, Davis M, Granger R, Kessler M, Rogers GA, Schehr RS, Lynch G (1997) Exp Neurol 146: 553-559). The efficacy of various AMPAR positive allosteric modulators in pre-clinical and clinical models of psychiatric disorders, such as schizophrenia, have been investigated (Morrow J A , Maclean J KF, Jamieson C (2006) Current Opinion in Drug Discovery and Development 9(5) 571-579). Compounds which act as AMPA receptor positive allosteric modulators are known, for example in international patent application WO2006/015828. We have discovered a class of novel N-(2- methyl-phenyl-cyclopentyl)sulphonamide derivatives that potentiate the AMPA receptor. According to a first aspect, the invention provides a compound of formula (I), or a salt thereof: (I) wherein µ R is C-|.galkyl, haloC- galkyl, C2 _galkenyl, amino, monoC-|_4alkylamino or diC-|_4alkylamino; R , R3, R4, R5, R6, R7, anc | RiO which may be the same or different, are selected from hydrogen, halogen, C -µgalkyl, haloC-µgalkyl and C-|_4alkoxy; each R , which may be the same or different, is C -µgalkyl, halogen, haloC-|.galkyl, C-|. 4alkoxy, haloC-|.4alkoxy or cyano; p is O, 1 or 2 ; R9 is halo; or phenyl or aromatic heterocyclyl, either of which is optionally substituted by one or more groups independently selected from the group consisting of: halogen, µ 9 a 9 b haloC- galkyl, C-|_4alkoxy, haloC-|_4alkoxy, cyano, -(CH2) q NR SC>2R , 9 a 9 d 9 a 9 c 9 d -(CH 2 )q NR (C=O)R , -(CH 2 )q NR (C=O)N(R )2 -(CH 2 )q (C=O)R and 9 b 9 a 9 c -(CH 2 )qSO 2 R ; where R and each R , which may be the same or different, is hydrogen or C-|.galkyl; R9 b is C-|.galkyl or haloC-|.galkyl; R9 d is C-|.galkyl, 9 a 9 b 9 a 9 c 9 a 9 d C-|. 4 alkoxy or haloC-|.galkyl; or R and R , R and R , or R and R together with the interconnecting atoms, may form a 5- or 6-membered ring; and q is O, 1, or 2 .
Load more

Recommended publications
  • 986 Anxiolytic Sedatives Hypnotics and Antipsychotics
    986 Anxiolytic Sedatives Hypnotics and Antipsychotics Cyclobarbital (BAN, rINN) Detomidine Hydrochloride (BANM, USAN, rINNM) for the sedation of mechanically ventilated patients in intensive care. Dexmedetomidine is given as the hydrochloride, but doses Ciclobarbital; Cyclobarbitalum; Cyclobarbitone; Cyklobarbital; Demotidini Hydrochloridum; Detomidiinihydrokloridi; Detomi- are expressed in terms of the base. Dexmedetomidine hydrochlo- din hydrochlorid; Détomidine, chlorhydrate de; Detomidin-hid- Ethylhexabital; Hexemalum; Syklobarbitaali. 5-(Cyclohex-1-enyl)- ride 118 micrograms is equivalent to about 100 micrograms of 5-ethylbarbituric acid. roklorid; Detomidinhydroklorid; Detomidini hydrochloridum; dexmedetomidine. Hidrocloruro de detomidina; MPV-253-AII. 4-(2,3-Dimethylben- Циклобарбитал It is given in sodium chloride 0.9% by intravenous infusion in a zyl)imidazole hydrochloride. C12H16N2O3 = 236.3. loading dose equivalent to 1 microgram/kg of dexmedetomidine CAS — 52-31-3. Детомидина Гидрохлорид over 10 minutes, followed by a maintenance infusion of 0.2 to ATC — N05C A10. C12H14N2,HCl = 222.7. 0.7 micrograms/kg per hour for up to 24 hours. Reduced doses ATC Vet — QN05C A10. CAS — 76631-46-4 (detomidine); 90038-01-0 (detomi- may be necessary in patients with hepatic or renal impairment, or dine hydrochloride). in the elderly. The racemate, medetomidine (p.1006), is used as the hydrochlo- H ride in veterinary medicine. O N O CH3 ◊ References. N CH3 H3C 1. Venn RM, et al. Preliminary UK experience of dexmedetomi- NH dine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia 1999; 54: 1136–42. HN 2. Bhana N, et al. Dexmedetomidine. Drugs 2000; 59: 263–8. O 3. Coursin DB, et al. Dexmedetomidine. Curr Opin Crit Care (detomidine) 2001; 7: 221–6.
    [Show full text]
  • Behandling Av Ångestsyndrom
    Behandling av ångestsyndrom En systematisk litteraturöversikt Volym 2 September 2005 SBU • Statens beredning för medicinsk utvärdering The Swedish Council on Technology Assessment in Health Care SBU utvärderar sjukvårdens metoder SBU (Statens beredning för medicinsk utvärdering) är en statlig myn- Behandling av ångestsyndrom dighet som utvärderar sjukvårdens metoder. SBU analyserar nytta och kostnader för olika medicinska metoder och jämför vetenskapens stånd- punkt med svensk vårdpraxis. Målet är ett bättre beslutsunderlag för En systematisk litteraturöversikt alla som avgör vilken sjukvård som ska bedrivas. Välkommen att besöka SBU:s hemsida, www.sbu.se Volym 2 SBU ger ut tre serier av rapporter. I den första serien presenteras utvär- deringar som utförts av SBU:s projektgrupper. Dessa utvärderingar Projektgrupp åtföljs alltid av en sammanfattning och slutsatser fastställda av SBU:s Lars von Knorring Ingrid Håkanson styrelse och råd. Denna rapportserie ges ut med gula omslag. I den andra (ordförande) (projektassistent) serien, med vita omslag, presenteras aktuella kunskaper inom något Viveka Alton Lundberg Agneta Pettersson område av sjukvården där behov av utvärdering kan föreligga. Den tredje Vanna Beckman (projektledare under serien, Alert-rapporterna, avser tidiga bedömningar av nya metoder inom (deltog 1995–2002) perioden 2004–2005) hälso- och sjukvården. Susanne Bejerot Per-Anders Rydelius Roland Berg Sten Thelander (deltog 1995–2002) (projektledare under Cecilia Björkelund perioden 1995–2004) Per Carlsson Helene Törnqvist (deltog 1995–1999) (deltog 1999–2005) Elias Eriksson Kristian Wahlbeck (deltog 1995–2001) (deltog 2002–2005) Tom Fahlén Hans Ågren Mats Fredrikson Rapporten ”Behandling av ångestsyndrom” består av två volymer (nr 171/1+2) och kan beställas från: Externa granskare SBU, Box 5650, 114 86 Stockholm Fredrik Almqvist Per Høglend Besöksadress: Tyrgatan 7 Alv A.
    [Show full text]
  • Acamprosate Pharmaceutical Form(S)/Strength: Gastro-Resistant Tablet P-RMS: IE/H/PSUR/0011/002 Date of FAR: 09.02.2012 4.3 Contraindications
    Core Safety Profile Active substance: Acamprosate Pharmaceutical form(s)/strength: Gastro-resistant tablet P-RMS: IE/H/PSUR/0011/002 Date of FAR: 09.02.2012 4.3 Contraindications {Tradename} is contraindicated in patients with hypersensitivity to acamprosate or to any of the excipients. Acamprosate is contraindicated in patients with renal impairment (serum creatinine >120 micromol/l), breastfeeding women (see section 4.6) 4.4 Special warnings and precautions for use The safety and efficacy of {Tradename} has not been established in patients younger than 18 years or older than 65 years. {Tradename} is therefore not recommended for use in these populations. The safety and efficacy of {Tradename} has not been established in patients with severe liver insufficiency (Childs-Pugh Classification C). Because the interrelationship between alcohol dependence, depression and suicidality is well recognised and complex, it is recommended that alcohol-dependent patients, including those treated with acamprosate, be monitored for respective symptoms. Abuse and dependence Non-clinical studies suggest that acamprosate has little or no abuse potential. No evidence of dependence on acamprosate was found in any clinical study thus demonstrating that acamprosate has no significant dependence potential. 4.5 Interaction with other medicinal products and other forms of interaction No change in the frequency of clinical and/or biological adverse reactions has been shown when acamprosate is used concomitantly with disulfiram, oxazepam, tetrabamate or meprobamate. In clinical trials, acamprosate has been safely administered in combination with antidepressants, anxiolytics, hypnotics and sedatives, and non-opioid analgesics. The concomitant intake of alcohol and {Tradename} does not affect the pharmacokinetics of either alcohol or acamprosate.
    [Show full text]
  • Summary of Product Characteristics, Labelling and Package Leaflet
    SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET 1 SUMMARY OF PRODUCT CHARACTERISTICS 2 1. NAME OF THE MEDICINAL PRODUCT Acamprosate 333 mg Gastro-resistant Tablets. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each gastro-resistant tablet contains acamprosate calcium 333.0 mg as the active ingredient. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Gastro-resistant tablet. White, round, biconvex coated tablet with “M” over “AC” printed in black ink on one side of the tablet and blank on the other side. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Acamprosate is indicated as therapy to maintain abstinence in alcohol-dependent patients. It should be combined with counselling. 4.2 Posology and method of administration Posology Adults within the age range 18-65 years - 2 tablets three times daily with meals (2 tablets in the morning, noon and night) in subjects weighing 60kg or more. - In subjects weighing less than 60kg, 4 tablets divided into three daily doses with meals (2 tablets in the morning, 1 at noon and 1 at night). Paediatric population and older people Acamprosate should not be administered to children, adolescents and the elderly. Duration of treatment The recommended treatment period is one year. Treatment with acamprosate should be initiated as soon as possible after the withdrawal period and should be maintained if the patient relapses. Acamprosate does not prevent the harmful effects of continuous alcohol abuse. Continued alcohol abuse negates the therapeutic benefit; therefore acamprosate treatment should only be initiated after weaning therapy, once the patient is abstinent from alcohol. Method of administration For oral use.
    [Show full text]
  • A Meta-Analysis of the Alcohol Treatment Outcome Literature: 1993 to 2000
    Utah State University DigitalCommons@USU All Graduate Theses and Dissertations Graduate Studies 5-2002 A Meta-analysis of the Alcohol Treatment Outcome Literature: 1993 to 2000 Anthony Phillip Tranchita Utah State University Follow this and additional works at: https://digitalcommons.usu.edu/etd Part of the Psychology Commons Recommended Citation Tranchita, Anthony Phillip, "A Meta-analysis of the Alcohol Treatment Outcome Literature: 1993 to 2000" (2002). All Graduate Theses and Dissertations. 6366. https://digitalcommons.usu.edu/etd/6366 This Thesis is brought to you for free and open access by the Graduate Studies at DigitalCommons@USU. It has been accepted for inclusion in All Graduate Theses and Dissertations by an authorized administrator of DigitalCommons@USU. For more information, please contact [email protected]. A META-ANALYSIS OF OF THE THE ALCOHOL ALCOHOL TREATMENT TREATMENT OUTCOME LITERATURE: 1993 TO 2000 by Anthony PhillipPhillip Tranchita A thesis submitted in partial fulfillment of the requirementsrequirements for for the degree oof f MASTER OF SCIENCE in Psychology Approved : ~,1v,,$ ca;; - ~~~ Oavid M: Stein. Ph.D~ - Carolyn if.Barcus. Ed.D. Major Professor Committee Member L1._&wf~ /2]~)µ- SusanL. Crowley, Ph.D. / ThqdlasL. Kent. Ph .D. ' Committee Member Dean of Graduate Studies UTUTAH AH STATE UNIVERSITYUNIVERSITY Logan.Logan, Utah 2002 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 face, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted.
    [Show full text]
  • Review of Existing Classification Efforts
    Project No. TREN-05-FP6TR-S07.61320-518404-DRUID DRUID Driving under the Influence of Drugs, Alcohol and Medicines Integrated Project 1.6. Sustainable Development, Global Change and Ecosystem 1.6.2: Sustainable Surface Transport 6th Framework Programme Deliverable 4.1.1 Review of existing classification efforts Due date of deliverable: (15.01.2008) Actual submission date: (07.02.2008) Start date of project: 15.10.2006 Duration: 48 months Organisation name of lead contractor for this deliverable: UGent Revision 1.0 Project co-funded by the European Commission within the Sixth Framework Programme (2002-2006) Dissemination Level PU Public X PP Restricted to other programme participants (including the Commission Services) RE Restricted to a group specified by the consortium (including the Commission Services) CO Confidential, only for members of the consortium (including the Commission Services) Task 4.1 : Review of existing classification efforts Authors: Kristof Pil, Elke Raes, Thomas Van den Neste, An-Sofie Goessaert, Jolien Veramme, Alain Verstraete (Ghent University, Belgium) Partners: - F. Javier Alvarez (work package leader), M. Trinidad Gómez-Talegón, Inmaculada Fierro (University of Valladolid, Spain) - Monica Colas, Juan Carlos Gonzalez-Luque (DGT, Spain) - Han de Gier, Sylvia Hummel, Sholeh Mobaser (University of Groningen, the Netherlands) - Martina Albrecht, Michael Heiβing (Bundesanstalt für Straßenwesen, Germany) - Michel Mallaret, Charles Mercier-Guyon (University of Grenoble, Centre Regional de Pharmacovigilance, France) - Vassilis Papakostopoulos, Villy Portouli, Andriani Mousadakou (Centre for Research and Technology Hellas, Greece) DRUID 6th Framework Programme Deliverable D.4.1.1. Revision 1.0 Review of Existing Classification Efforts Page 2 of 127 Introduction DRUID work package 4 focusses on the classification and labeling of medicinal drugs according to their influence on driving performance.
    [Show full text]
  • Pharmaceuticals (Monocomponent Products) ………………………..………… 31 Pharmaceuticals (Combination and Group Products) ………………….……
    DESA The Department of Economic and Social Affairs of the United Nations Secretariat is a vital interface between global and policies in the economic, social and environmental spheres and national action. The Department works in three main interlinked areas: (i) it compiles, generates and analyses a wide range of economic, social and environmental data and information on which States Members of the United Nations draw to review common problems and to take stock of policy options; (ii) it facilitates the negotiations of Member States in many intergovernmental bodies on joint courses of action to address ongoing or emerging global challenges; and (iii) it advises interested Governments on the ways and means of translating policy frameworks developed in United Nations conferences and summits into programmes at the country level and, through technical assistance, helps build national capacities. Note Symbols of United Nations documents are composed of the capital letters combined with figures. Mention of such a symbol indicates a reference to a United Nations document. Applications for the right to reproduce this work or parts thereof are welcomed and should be sent to the Secretary, United Nations Publications Board, United Nations Headquarters, New York, NY 10017, United States of America. Governments and governmental institutions may reproduce this work or parts thereof without permission, but are requested to inform the United Nations of such reproduction. UNITED NATIONS PUBLICATION Copyright @ United Nations, 2005 All rights reserved TABLE OF CONTENTS Introduction …………………………………………………………..……..……..….. 4 Alphabetical Listing of products ……..………………………………..….….…..….... 8 Classified Listing of products ………………………………………………………… 20 List of codes for countries, territories and areas ………………………...…….……… 30 PART I. REGULATORY INFORMATION Pharmaceuticals (monocomponent products) ………………………..………… 31 Pharmaceuticals (combination and group products) ………………….……........
    [Show full text]
  • Alcohol's Effects on Sleep in Alcoholics
    Alcohol’s Effects on Sleep in Alcoholics Kirk J. Brower, M.D. Sleep problems, which can have significant clinical and economic consequences, are more common among alcoholics than among nonalcoholics. During both drinking periods and withdrawal, alcoholics commonly experience problems falling asleep and decreased total sleep time. Other measures of sleep are also disturbed. Even alcoholics who have been abstinent for short periods of time (i.e., several weeks) or extended periods of time (i.e., several years) may experience persistent sleep abnormalities. Researchers also found that alcoholics are more likely to suffer from certain sleep disorders, such as sleep apnea. Conversely, sleep problems may predispose some people to developing alcohol problems. Furthermore, sleep problems may increase the risk of relapse among abstinent alcoholics. KEY WORDS: sleep disorder; AOD (alcohol or other drug) dependence; physiological AODE (effects of AOD use, abuse, and dependence); REM (rapid eye movement) sleep; AOD withdrawal syndrome; AOD abstinence; self medication; AODD (AOD use disorder) relapse; melatonin; treatment and maintenance; literature review leep problems1 are more common All of these terms refer both to subjec­ alcoholics than in nonalcoholics—has among alcoholics than among non- tive complaints about sleep, such as been associated with increased mortality Salcoholics (Aldrich 1998; Ehlers insomnia, and to objectively measured from heart disease and stroke (Aldrich 2000; National Institute on Alcohol Abuse abnormalities in sleep, which
    [Show full text]
  • Drug/Substance Trade Name(S)
    A B C D E F G H I J K 1 Drug/Substance Trade Name(s) Drug Class Existing Penalty Class Special Notation T1:Doping/Endangerment Level T2: Mismanagement Level Comments Methylenedioxypyrovalerone is a stimulant of the cathinone class which acts as a 3,4-methylenedioxypyprovaleroneMDPV, “bath salts” norepinephrine-dopamine reuptake inhibitor. It was first developed in the 1960s by a team at 1 A Yes A A 2 Boehringer Ingelheim. No 3 Alfentanil Alfenta Narcotic used to control pain and keep patients asleep during surgery. 1 A Yes A No A Aminoxafen, Aminorex is a weight loss stimulant drug. It was withdrawn from the market after it was found Aminorex Aminoxaphen, Apiquel, to cause pulmonary hypertension. 1 A Yes A A 4 McN-742, Menocil No Amphetamine is a potent central nervous system stimulant that is used in the treatment of Amphetamine Speed, Upper 1 A Yes A A 5 attention deficit hyperactivity disorder, narcolepsy, and obesity. No Anileridine is a synthetic analgesic drug and is a member of the piperidine class of analgesic Anileridine Leritine 1 A Yes A A 6 agents developed by Merck & Co. in the 1950s. No Dopamine promoter used to treat loss of muscle movement control caused by Parkinson's Apomorphine Apokyn, Ixense 1 A Yes A A 7 disease. No Recreational drug with euphoriant and stimulant properties. The effects produced by BZP are comparable to those produced by amphetamine. It is often claimed that BZP was originally Benzylpiperazine BZP 1 A Yes A A synthesized as a potential antihelminthic (anti-parasitic) agent for use in farm animals.
    [Show full text]
  • WO 2009/053449 Al
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 30 April 2009 (30.04.2009) WO 2009/053449 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07D 277/42 (2006.01) A61K 31/44 (2006.01) kind of national protection available): AE, AG, AL, AM, C07D 417/12 (2006.01) A61P 25/18 (2006.01) AO, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, A61K 31/426 (2006.01) CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, (21) International Application Number: IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, PCT/EP2008/064408 LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, (22) International Filing Date: 24 October 2008 (24.10.2008) MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, (25) Filing Language: English TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (26) Publication Language: English ZW (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 0721092.5 26 October 2007 (26.10.2007) GB kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): GLAXO GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, GROUP LIMITED [GB/GB]; Glaxo Wellcome House, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), Berkeley Avenue, Greenford, Middlesex UB 6 ONN (GB).
    [Show full text]
  • Flunitrazepam
    996 Anxiolytic Sedatives Hypnotics and Antipsychotics Etifoxine Hydrochloride (BANM, rINNM) Profile Etifoxin Hydrochloride; Étifoxine, Chlorhydrate d’; Etifoxini Hy- Febarbamate is a barbiturate with general properties similar to those of amobarbital (p.961). It has been used in the management H C O drochloridum; Hidrocloruro de etifoxina; Hoe-36801. 6-Chloro- 3 of anxiety, insomnia, and alcohol withdrawal symptoms. How- N 4-methyl-4-phenyl-3,1-benzoxazin-2-yl(ethyl)amine hydrochlo- ever, barbiturates are no longer considered appropriate in the ride. management of these conditions. Этифоксина Гидрохлорид Tetrabamate, a complex of febarbamate, difebarbamate, and N C17H17ClN2O,HCl = 337.2. phenobarbital, has been used similarly but was associated with CAS — 21715-46-8 (etifoxine); 56776-32-0 (etifoxine hy- the development of hepatitis. O N drochloride). 2 F ATC — N05BX03. Preparations ATC Vet — QN05BX03. Proprietary Preparations (details are given in Part 3) Multi-ingredient: Hung.: Atrium†. NOTE. The following terms have been used as ‘street names’ (see (BAN, rINN) p.vi) or slang names for various forms of flunitrazepam: Fluanisone Benzo; Circles; Date rape drug; Forget me drug; Forget pill; For- H Fluanison; Fluanisona; Fluanisoni; Fluanisonum; Haloanisone; MD- get-me pill; Forget-Me-Pill; Getting roached; La Rocha; La Ro- O N CH3 2028; R-2028; R-2167. 4′-Fluoro-4-[4-(2-methoxyphenyl)piper- che; Lunch money drug; Mexican valium; Pingus; R2; R-2; Rey- H3C azin-1-yl]butyrophenone. nolds; Rib; Rick James Biatch; Roach 2; Roach-2; Roaches; N Roachies; Roapies; Robutal; Rochas dos; Roche; Roches; Флуанизон Rolpes; Roofie; Roofies; Roopies; Rope; Rophies; Rophy; Rop- C21H25FN2O2 = 356.4.
    [Show full text]
  • Meta-Analysis of Benzodiazepine Use in the Treatment of Acute Alcohol Withdrawal Evidence Études
    Meta-analysis of benzodiazepine use in the treatment of acute alcohol withdrawal Evidence Études From the Centre for Anne M. Holbrook, MD, PharmD, MSc; Renée Crowther, MSc; Evaluation of Medicines, Ann Lotter, BA; Chiachen Cheng, MD; Derek King, BMath St. Joseph’s Hospital and McMaster University, Abstract Hamilton, Ont. Objective: To analyse the evidence for the efficacy and potential harmful effects of This article has been peer reviewed. benzodiazepines compared with other therapies in the treatment of acute alco- hol withdrawal. CMAJ 1999;160:649-55. Data sources: MEDLINE and the Cochrane Controlled Trials Registry were searched for English-language articles published from 1966 to December 1997 ß An overview of the diagnosis and that described randomized controlled trials (RCTs) of benzodiazepines in the management of acute alcohol treatment of acute alcohol withdrawal. Key words included “benzodiazepines” withdrawal appears on page 675 (exploded) and “randomized controlled trial.” Bibliographies of relevant articles were reviewed for additional RCTs, and manufacturers of benzodiazepines were asked to submit additional RCT reports not in the literature. Study selection: Articles were considered for the meta-analysis if they were RCTs involving patients experiencing acute alcohol withdrawal and comparing a ben- zodiazepine available in Canada with placebo or an active control drug. Of the original 23 trials identified, 11 met these criteria, representing a total of 1286 patients. Data extraction: Data were extracted regarding the participants, the setting, details of the intervention, the outcomes (including adverse effects) and the method- ologic quality of the studies. Data synthesis: The meta-analysis of benefit (therapeutic success within 2 days) showed that benzodiazepines were superior to placebo (common odds ratio [OR] 3.28, 95% confidence interval [CI] 1.30–8.28).
    [Show full text]