EP0506813A1 - 5-ht-3-antagonisten für die behandlung von übelkeit, bradykardie von hypotension zusammen mit instabilität des myokards - Google Patents

5-ht-3-antagonisten für die behandlung von übelkeit, bradykardie von hypotension zusammen mit instabilität des myokards

Info

Publication number
EP0506813A1
EP0506813A1 EP91901843A EP91901843A EP0506813A1 EP 0506813 A1 EP0506813 A1 EP 0506813A1 EP 91901843 A EP91901843 A EP 91901843A EP 91901843 A EP91901843 A EP 91901843A EP 0506813 A1 EP0506813 A1 EP 0506813A1
Authority
EP
European Patent Office
Prior art keywords
hydrogen
composition according
alkyl
treatment
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP91901843A
Other languages
English (en)
French (fr)
Inventor
Edward Stewart Smithkline Johnson
Thomas Conway Smithkline Hamilton
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beecham Group PLC
Original Assignee
Beecham Group PLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beecham Group PLC filed Critical Beecham Group PLC
Publication of EP0506813A1 publication Critical patent/EP0506813A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the present invention relates to a method for the treatment and/or prophylaxis of nausea and bradycardia associated with myocardial instability .
  • EP-A-158532 and EP-A-237281 (A.H. Robins Company, Inc.), EP-A-67770 and EP-A-2666730 (Merrell Toraude et Compagnie), GB 2125398A, GB 2145416A and 2152049A (Sandoz Limited), EP-A-322016, 350129 and 350130 (Duphar international Research B.V.), EP-A-307172 and US 4921982 (Eli Lilly and Company), EP-A-323077, EP-A-306148 and GB 2208385A and EP-A-361629 (John Wyeth and Brother Limited), EP-A-234872 (Adria Laboratories Inc.), EP-A-294292 (Adir et Compagnie), EP-A-339950, US 4924010, 4920219, 4290227 and WO90/6309 (Rorer International (overseas), Inc.), EP-A-309423 and EP- A-
  • EP-A-358903 disclose classes of compounds containing a saturated azacyclic or azabicyclic moiety, such as tropanyl, granatyl or quinuclidinyl, and are 5-HT 3 receptor antagonists.
  • EP-A-242973 EP-A-276163, EP-A-291172, EP-A-307145,
  • EP-A-357414, EP-A-357415, EP-A-357416, EP-A-357417, EP-A-364274 and EP-A-385722 (Glaxo Group Limited), EP-A-315316 (Beecham Group p.l.c), EP-A-361317 (Fujisawa), EP-A-375045 and EP-A-377238 (Duphar), EP-A-376624 and EP-A-381422 (Yamanouchi Pharmaceutical Co. Ltd.), EP-A-392663 (Ono Pharmaceutical Co.
  • EP-A-373061 (Adir et Compagnie)
  • US 4914207 Pfizer
  • GB 2229182A Merck Sharp and Dohme Limited
  • EP-A-201165 (Beecham Group p.l.c.) discloses the use of 5-HTo receptor antagonists, in particular MDL 72222 (Example 1), ICS 205-930 (Example 2) and ondansetron (Example 5) as antiemetic agents.
  • EP-A-200444 (Example 6) discloses the 5-HT 3 receptor antagonist, granisetron, which is also disclosed as an antiemetic agent. Ondansetron and granisetron are under clinical evaluation as antiemetic agents in cytotoxic drug induced emesis.
  • Myocardial instability occurs as a result of myocardial infarction, myocardial reperfusion following thrombolysis, percutaneous transluminal coronary angioplasty (PTCA), coronary bypass grafts and coronary cardiac catheterisation. Nausea, bradycardia (slowing of the heart) and hypotension as a result of myocardial instability is well known (E. Braunwald, Heart Disease' publ. Saunders pp. 1197-8, 1236, 1253, 1264), and there is a need for a suitable treatment to overcome these problems.
  • PTCA percutaneous transluminal coronary angioplasty
  • 5-HT 3 receptor antagonists such as compounds of the above classes, are of potential use in the treatment or prophylaxis of nausea, bradycardia and/or hypotension associated with myocardial instability.
  • the present invention provides a method for the treatment and/or prophylaxis of nausea and bradycardia and/or hypotension associated with myocardial instability in mammals, such as humans, which method comprises administering to the mammal in need of such treatment and/or prophylaxis an effective and/or prophylactic amount of a 5-HT 3 receptor antagonist, such as a compound of formula (I), or a pharmaceutically acceptable salt thereof:
  • a 5-HT 3 receptor antagonist such as a compound of formula (I), or a pharmaceutically acceptable salt thereof:
  • X is a phenyl group or a monocyclic 5 or 6 membered heteroaryl group, either of which group is optionally fused to a saturated or unsaturated 5-7 membered carbocyclic or heterocyclic ring;
  • A is a linking moiety; and
  • R is a saturated azabicyclic moiety or an imidazolyl moiety.
  • X may be unsubstituted or substituted, usually by one or more substituents selected from halogen, C 1-6 alkoxy, C1-6 alkylthio, C 1-6 alkyl, hydroxy, amino, C 1-6 alkylamino, C 1-7 alkanoylamino, or two substituents on X (when fused), may be linked to form a saturated or unsaturated optionally substituted carbocyclic ring.
  • Heteroatoms for heteroaryl and heterocyclic groups are selected from oxygen, nitrogen and sulphur.
  • X may be joined to A by an aromatic carbon atom, or (when X is fused), by a carbocyclic ring carbon atom, or by a heterocyclic ring carbon or nitrogen atom.
  • A is attached at an aromatic carbon atom, it is preferably attached at the aromatic carbon adjacent a 'fused' carbon atom, which is attached to the heteroatom of a heterocyclic ring in formula (I).
  • Suitable examples of X are as described in the aforementioned patent publications relating to 5-HT 3 receptor antagonists containing a saturated azabicyclic moiety, the subject matter of which is incorporated herein by reference.
  • Suitable examples of A include CONH (amide), COO (ester), NHCONH (ureide), CONHCONH (extended ureide), or a group of structure (h):
  • dotted circle represents two double bonds in any position in the 5 membered ring;
  • two of G, H and I are selected from oxygen, sulphur, nitrogen and carbon and the other is oxygen, sulphur or nitrogen;
  • E is a bond or C 1-5 alkylene optionally substituted by phenyl or hydroxy.
  • A may also be a keto - (methylene or ethylene) linkage, such as -CO-(CH 2 ) 2 -, or another of the linkages as described in the abovementioned patent publications relating to further classes of compounds having 5-HT 3 receptor antagonist activity containing an unsaturated N-heterocycle, in particular those in the name of Glaxo Group Limited.
  • the suitable X values in formula (I) which are described in the referenced patent publications, are that part of the structure remaining when the saturated azabicyclic moiety and A (where A is one of the suitable examples listed above), are disregarded.
  • Preferred examples of X include a group of sub-formula (a), (b), (c), (d), (e), (f) or (g):
  • R a to R e and R g are selected from hydrogen, halogen or hydroxy;
  • R 1 is hydrogen and R 2 is hydrogen or C 1- 4 alkyl; or R 1 and R 2 together are a bond;
  • R w are independently selected from hydrogen or C 1-6 alkyl;
  • R 12 is hydrogen, C 1-6 alkoxy or amino optionally substituted by a C 1-6 alkyl group, or R 12 is alkanoylamino; and
  • R 13 is halo, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylthio;
  • R 1 4 is hydrogen or C 1-6 alkyl; and L is CH or N.
  • moieties in alkyl or alkyl containing groups in R 1 to R 14 include methyl, ethyl, n- and iso-propvl, n-, iso-, sec- and tert-butyl, preferably methyl.
  • R 2 and R 4 or R 8 and R 9 when joined include C 2 , C 3 , C 4 , C 5 or C 6 polymethylene, preferably C 2 , C 3 , C 4 or C 5 polymethylene.
  • R a to R e and R g are preferably selected from hydrogen, fluoro, chloro and hydroxy, most preferably hydrogen.
  • - R b may be 5-, 6- or 7-chloro or fluoro.
  • X is of sub-formula (a)
  • one of R 1 and R 3 is preferably hydrogen and one or both of R 2 and R 4 (most preferably both) are alkyl groups, such as methyl, or are joined to form C 2-7 polymethylene; or when one of R 2 and R 4 is hydrogen, the other is preferably ethyl or n- or iso- propyl.
  • R 5 is preferably hydrogen or a methyl or ethyl group.
  • R 7 is preferably methyl.
  • R 8 and R 9 are preferably both methyl groups.
  • R 12 is preferably amino and R 13 is preferably chloro or bromo, most preferably chloro.
  • R 10 is preferably methoxy when C 1- 6 alkoxy.
  • R 9 and R 11 are preferably chloro or methyl and R 10 is preferably hydrogen.
  • R 14 is preferably hydrogen or methyl.
  • X is preferably a group of sub-formula (e).
  • R Suitable examples of R are as described in the aforementioned patent publications relating to 5-HT 3 receptor antagonists containing a saturated azabicyclic moiety.
  • R then include the groups of sub-formula (i), (j) and (k):
  • Z is (CH 2 ) n wherein n is 2 or 3, or Z is CH 2 -O-CH 2 ; p and q are independently 1 to 3; and R 15 or R 16 is methyl or ethyl, preferably methyl.
  • R is most preferably endo-9-azabicyclo [3.2.1] non-3-yl, endo-8-azabicyclo [3.2.1] oct-3-yl, 9-aza-3-oxabicyclo- [3.2.1]non-7-yl or 3-quinuclidinyl.
  • R may also be an imidazolyl group, in particular, 5-methyl-4-imidazolyl.
  • Examples of the compounds of formula (I) include the examples described in the aforementioned Patent Publications/References disclosing compounds containing a saturated azabicyclic moiety. Particular examples include MDL 72222, ICS 205-930 (tropisetron) and PU 46470A, described in Example 5 of EP-A-247266, and granisetron.
  • Examples of compounds of formula (I) also include the examples described in the aforementioned Patent Publications/References disclosing compounds containing an imidazolyl moiety, in particular, ondansetron and Examples 1, 2, 3, 4 and 5 in EP-A-315316 (Beecham Group p.l.c.).
  • 5-HT 3 receptor antagonists are as described and claimed in the aforementioned patent publications, in particular, those in the name of Glaxo Group Limited.
  • references to a5-HT 3 receptor antagonist including compounds of formula (I) and the specific compounds mentioned hereinbefore and salts thereof, include solvates such as hydrates.
  • 5-HT 3 receptor antagonists may be identified by standard methods, such as tests involving antagonism of the von Bezold Jarisch reflex, as described by Fozard J.R. et. al., J. Cardiovasc. Pharmacol. 2, 229-245 (1980).
  • the compounds of formula (I), including the specific compounds mentioned hereinbefore and salts thereof may be prepared as described in the aforementioned Patent Publications/References.
  • the 5-HT 3 receptor antagonist is in substantially pure pharmaceutically acceptable form.
  • the administration of the 5-HT 3 receptor antagonist may be by way of oral, sublingual, transdermal or parenteral administration.
  • Parenteral administration will generally be preferred, and the 5-HT 3 receptor antagonist administered during or after cardiac treatment (thrombolysis, PTCA, coronary bypass grafts, coronary and cardiac catheterisation).
  • cardiac treatment thrombolysis, PTCA, coronary bypass grafts, coronary and cardiac catheterisation.
  • the preferred administration may be pretreatment by way of oral, sublingual or transdermal administration.
  • a unit dose will normally contain 0.1 to 50 mg for example 0.5 to 10 mg, of the 5-HT 3 receptor antagonist, such as a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • Unit doses will normally be administered once or more than once a day, for example 2, 3, or 4 times a day, more usually 1 to 3 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 0.1 to 50 mg, for example 0.1 to 5 mg, that is in the range of approximately 0.001 to 1 mg/kg/day, more usually 0.005 to 0.2 mg/kg/day.
  • the 5-HT 3 receptor antagonist is administered in the form of a unit-dose composition, such as a unit dose oral or parenteral composition.
  • compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories.
  • Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents.
  • the tablets may be coated according to well known methods in the art.
  • Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
  • Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
  • compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate
  • Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.
  • fluid unit dose forms are prepared containing the 5-HT 3 receptor antagonist and a sterile vehicle.
  • the compound depending on the vehicle and the concentration, can be either suspended or dissolved.
  • Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
  • compositions will usually be accompanied by written or printed directions for use in the treatment concerned.
  • the present invention also provides the use of a5-HT 3 receptor antagonist, such as a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of nausea, bradycardia and/or hypotension associated with myocardial instability.
  • a5-HT 3 receptor antagonist such as a compound of formula (I) or a pharmaceutically acceptable salt thereof
  • Such treatment and/or prophylaxis may be carried out as hereinbefore described.
  • the present invention further provides a pharmaceutical composition for use in the treatment and/or prophylaxis of nausea, bradycardia and/or hypotension associated with myocardial instability, which comprises a5-HT 3 receptor antagonist, such as a compound of formula (I) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  • a5-HT 3 receptor antagonist such as a compound of formula (I) or a pharmaceutically acceptable salt thereof
  • a pharmaceutically acceptable carrier may be prepared in the manner as hereinbefore described.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Epidemiology (AREA)
  • Otolaryngology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Indole Compounds (AREA)
EP91901843A 1989-12-21 1990-12-20 5-ht-3-antagonisten für die behandlung von übelkeit, bradykardie von hypotension zusammen mit instabilität des myokards Withdrawn EP0506813A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8928837 1989-12-21
GB898928837A GB8928837D0 (en) 1989-12-21 1989-12-21 Pharmaceuticals

Publications (1)

Publication Number Publication Date
EP0506813A1 true EP0506813A1 (de) 1992-10-07

Family

ID=10668280

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91901843A Withdrawn EP0506813A1 (de) 1989-12-21 1990-12-20 5-ht-3-antagonisten für die behandlung von übelkeit, bradykardie von hypotension zusammen mit instabilität des myokards

Country Status (9)

Country Link
EP (1) EP0506813A1 (de)
JP (1) JPH05502872A (de)
KR (1) KR920703037A (de)
AU (1) AU7051691A (de)
CA (1) CA2071994A1 (de)
GB (1) GB8928837D0 (de)
IE (1) IE904603A1 (de)
WO (1) WO1991009593A2 (de)
ZA (1) ZA9010219B (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU676032B2 (en) * 1993-03-18 1997-02-27 F. Hoffmann-La Roche Ag Use of granisetron for the treatment of post-operative nausea and vomiting

Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2699794B2 (ja) * 1992-03-12 1998-01-19 三菱化学株式会社 チエノ〔３，２−ｂ〕ピリジン誘導体
PE20021019A1 (es) 2001-04-19 2002-11-13 Upjohn Co Grupos azabiciclicos sustituidos
AR036040A1 (es) 2001-06-12 2004-08-04 Upjohn Co Compuestos de heteroarilo multiciclicos sustituidos con quinuclidinas y composiciones farmaceuticas que los contienen
AR036041A1 (es) 2001-06-12 2004-08-04 Upjohn Co Compuestos aromaticos heterociclicos sustituidos con quinuclidina y composiciones farmaceuticas que los contienen
EP1432707B1 (de) 2001-10-02 2012-03-28 Pharmacia & Upjohn Company LLC Azabicyclisch- substituierte annelierte heteroaryl-verbinungen für die behandlung von krankheiten
US6849620B2 (en) 2001-10-26 2005-02-01 Pfizer Inc N-(azabicyclo moieties)-substituted hetero-bicyclic aromatic compounds for the treatment of disease
US6951868B2 (en) 2001-11-09 2005-10-04 Pfizer Inc. Azabicyclic-phenyl-fused-heterocyclic compounds for treatment of disease
DE10164139A1 (de) 2001-12-27 2003-07-10 Bayer Ag 2-Heteroarylcarbonsäureamide
JP2005522456A (ja) 2002-02-15 2005-07-28 ファルマシア・アンド・アップジョン・カンパニー・エルエルシー Ｃｎｓ関連障害治療のためのアザビシクロ置換ベンゾイルアミドおよびチオアミド
BR0307782A (pt) 2002-02-19 2005-01-04 Upjohn Co Compostos azabiciclo para o tratamento de doença
US6858613B2 (en) 2002-02-19 2005-02-22 Pfizer Inc. Fused bicyclic-N-bridged-heteroaromatic carboxamides for the treatment of disease
AU2003276919B2 (en) 2002-09-25 2013-05-16 Memory Pharmaceuticals Corporation Indazoles, benzothiazoles, and benzoisothiazoles, and preparation and uses thereof
DE602004010299T2 (de) 2003-12-22 2008-09-18 Memory Pharmaceuticals Corp. Indole, 1h-indazole, 1,2-benzisoxazole und 1,2-benzisothiazole und deren herstellung und anwendungen
RU2417225C2 (ru) 2004-03-25 2011-04-27 Мемори Фармасьютиклз Корпорейшн Индазолы, бензотиазолы, бензоизотиазолы, бензизоксазолы и их получение и применение
JP2007534692A (ja) 2004-04-22 2007-11-29 メモリー・ファーマシューティカルズ・コーポレイション インドール、１ｈ−インダゾール、１，２−ベンズイソキサゾール、１，２−ベンゾイソチアゾール、ならびにその調製および使用
JP2007538011A (ja) 2004-05-07 2007-12-27 メモリー・ファーマシューティカルズ・コーポレイション １ｈ−インダゾール、ベンゾチアゾール、１，２−ベンゾイソキサゾール、１，２−ベンゾイソチアゾール、およびクロモン、ならびにそれらの調製および使用
US7576094B2 (en) 2004-12-13 2009-08-18 Eli Lilly And Company Spiro derivatives as lipoxygenase inhibitors
BRPI0517494A (pt) 2004-12-22 2008-10-14 Memory Pharm Corp composto, composição farmacêutica, método de ativação/estimulação seletiva de receptores nicotìnicos de a-7 em um paciente em que tal ativação/estimulação tem um efeito terapêutico, método de tratamento de um paciente que sofre de uma doença psicótica, uma doença neurodegenerativa que envolve uma disfunção do sistema colinérgico, e/ou uma condição de debilitação da memória e/ou da cognição, método de tratamento de um paciente que sofre de demência e/ou uma outra condição com perda da memória, método de tratamento de um paciente que sofre de debilitação da memória devido à debilitação cognitiva suave devido ao envelhecimento, mal de alzheimer, esquizofrenia, mal de parkinson, mal de huntington, mal de pick, mal de creutzfeldt-jakob, depressão, envelhecimento, trauma na cabeça, acidente vascular cerebral, hipoxia do snc, senilidade cerebral, demência de multiinfarto, hiv e/ou doença cardiovascular, método de tratamento e/ou prevenção da demência em um paciente com o mal de alzheimer, método de tratamento de um paciente para cortar o vìcio do álcool ou o tratamento de um paciente com a terapia anti-intoxicação, método de tratamento de um paciente para propiciar neuroproteção contra os danos associados com acidentes vasculares cerebrais e isquemia e excitotoxicidade induzida por glutamatos, método de tratamento de um paciente que sofre do vìcio da nicotina, dor, tontura do fuso horário, obesidade e/ou diabetes, método de indução do ato de parar fumar em um paciente, método de tratamento de um paciente que sofre de debilitação cognitiva suave (mci), demência vascular (vad), declìnio cognitivo associado com a idade (aacd), amnésia associada com a cirurgia com o coração aberto, parada cardìaca, anestesia geral, deficiências da memória devido à exposição a agentes anestésicos, debilitação cognitiva induzida pela privação do sono, sìndrome de fadiga crÈnica, narcolepsia, demência relacionada com a aids, debilitação cognitiva relacionada com a epilepsia, sìndrome de down, demência relacionada ao alcoolismo, debilitações da memória induzidas por drogas/substáncias, demência pugilìstica (sìndrome do boxeador), ou demência animal, método para o tratamento da perda da memória, método para o tratamento de um paciente que sofre de debilitação da memória, método para o tratamento ou a profilaxia de uma doença ou de uma condição resultante da disfunção da transmissão do receptor nicotìnico de acetilcolina em um paciente, método para o tratamento ou a profilaxia de uma doença ou de uma condição resultante de receptores nicotìnicos de acetilcolina defeituosos ou funcionando mal em um paciente, método para o tratamento ou a profilaxia de uma doença ou de uma condição resultante da transmissão suprimida do receptor nicotìnico de acetilcolina em um paciente, método para o tratamento ou a profilaxia de uma doença ou de uma condição resultante da perda de sinapses colinérgicas em um paciente, método para a proteção dos neurÈnios em um paciente com neurotoxicidade induzi
US8106066B2 (en) 2005-09-23 2012-01-31 Memory Pharmaceuticals Corporation Indazoles, benzothiazoles, benzoisothiazoles, benzisoxazoles, pyrazolopyridines, isothiazolopyridines, and preparation and uses thereof
MX357676B (es) 2010-05-17 2018-07-18 Forum Pharmaceuticals Inc Una forma cristalina de clorhidrato de (r)-7-cloro-n-(quinuclidin- 3-il)benzo[b]tiofeno-2-carboxamida monohidratado.
EP3666272A1 (de) 2012-05-08 2020-06-17 Forum Pharmaceuticals Inc. Verwendung von encenicline bei der behandlung von kognitiver behinderung, alzheimer-krankheit, speicherdefizit

Family Cites Families (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2531083B1 (fr) * 1982-06-29 1986-11-28 Sandoz Sa Nouveaux derives de la piperidine, leur preparation et leur utilisation comme medicaments
FR2557110B1 (fr) * 1983-12-23 1989-11-24 Sandoz Sa Nouveaux derives d'amines cycliques, leur preparation et leur utilisation comme medicaments
HU193592B (en) * 1984-01-25 1987-11-30 Glaxo Group Ltd Process for producing tetrahydro-carbazolone derivatives
DE3680123D1 (en) * 1985-01-23 1991-08-14 Glaxo Group Ltd Tetrahydrocarbazolonderivate.
DE3650772T2 (de) * 1985-04-27 2003-04-03 F. Hoffmann-La Roche Ag, Basel Derivate von Indazole-3-carboxamide und -3-carboxylsäure
GB8518743D0 (en) * 1985-07-24 1985-08-29 Glaxo Group Ltd Heterocyclic compounds
GB8518745D0 (en) * 1985-07-24 1985-08-29 Glaxo Group Ltd Heterocyclic compounds
DE3687980T2 (de) * 1986-01-07 1993-06-17 Beecham Group Plc Indolderivate mit einer azabicyclischen seitenkette, verfahren zu ihrer herstellung, zwischenprodukte und pharmazeutische zusammensetzungen.
GB8701494D0 (en) * 1987-01-23 1987-02-25 Glaxo Group Ltd Chemical compounds
ZA878096B (en) * 1986-11-03 1988-04-26 Merrell Dow Pharmaceuticals Inc. Esters of hexahydro-8-hydroxy-2,6-methano-2h-quinolizin-3(4h)-one and related compounds
GB8628475D0 (en) * 1986-11-28 1987-01-07 Glaxo Group Ltd Medicaments
FR2616149B1 (fr) * 1987-06-04 1990-10-19 Adir Nouveau derive de l'acide benzo (b) thiophene - 7 carboxylique, son procede de preparation et les compositions pharmaceutiques qui le contiennent
NZ226032A (en) * 1987-09-03 1991-12-23 Glaxo Group Ltd 2-(imidazolylmethyl)-pyrido or-azepino(4,3-b)indole-1(2h)-one derivatives; preparatory processes and pharmaceutical compositions
GB8723157D0 (en) * 1987-10-02 1987-11-04 Beecham Group Plc Compounds
EP0315390B1 (de) * 1987-11-04 1994-07-20 Beecham Group Plc Neue 4-Oxobenzotriazine und 4-Oxochinazoline
DE3740984A1 (de) * 1987-12-03 1989-06-15 Sandoz Ag N-oxide von heterocyclischen carbonsaeurederivaten bzw. verfahren zu deren herstellung und deren verwendung
US4985420A (en) * 1987-12-10 1991-01-15 Duphar International Research B.V. 1,7-annelated indolecarboxylic acid esters and -amides
DE3810552A1 (de) * 1988-03-29 1989-10-19 Sandoz Ag Ester und amide von indol-, benzo(b)thiopen-, benzo(b)furancarbonsaeuren oder 4-amino-2-methoxy-benzolsaeuren mit n-heterocyclischen oder n-heterobicyclischen alkoholen oder aminen, verfahren zu deren herstellung sie enthaltende pharmazeutische zusammensetzungen sowie applikator zur verabreichung derselben
US5116984A (en) * 1988-04-07 1992-05-26 Glaxo Group Limited Imidazole derivatives
US5049563A (en) * 1988-07-07 1991-09-17 Duphar International Research B.V. Annelated indoleketones with an imidazolylalkyl substituent
IT1226389B (it) * 1988-07-12 1991-01-15 Angeli Inst Spa Nuovi derivati ammidinici e guanidinici
FR2639944B1 (fr) * 1988-12-06 1991-01-18 Adir Nouveaux derives de l'indole, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
CA2004911A1 (en) * 1988-12-22 1990-06-22 Mitsuaki Ohta 4,5,6,7-tetrahydrobenzimidazole derivatives
IT1228288B (it) * 1989-01-09 1991-06-07 Zambon Spa Composti ad attivita' antiserotoninica

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9109593A2 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU676032B2 (en) * 1993-03-18 1997-02-27 F. Hoffmann-La Roche Ag Use of granisetron for the treatment of post-operative nausea and vomiting

Also Published As

Publication number Publication date
KR920703037A (ko) 1992-12-17
JPH05502872A (ja) 1993-05-20
WO1991009593A2 (en) 1991-07-11
WO1991009593A3 (en) 1991-09-05
GB8928837D0 (en) 1990-02-28
ZA9010219B (en) 1991-11-27
CA2071994A1 (en) 1991-06-22
AU7051691A (en) 1991-07-24
IE904603A1 (en) 1991-07-03

Similar Documents

Publication Publication Date Title
WO1991009593A2 (en) 5-ht3 antagonists for treatment of nausea, bradycardia of hypotension associated with myocardial instability
EP0200444B1 (de) Azabicyclononyl-indazol-carboxamid mit 5-HT-antagonistischer Wirkung
DE3689974T2 (de) Arzneimittel zur Behandlung von Emesis.
US4845092A (en) Novel treatment
US5418240A (en) Heterocyclic compounds and their preparation and use
KR880001291A (ko) 세로토닌 길항물질의 치료학적 사용방법
EP0340270B1 (de) 5-ht3-rezeptor-antagonisten zur behandlung von husten und bronchokonstriktion
US4786643A (en) Treatment of migraine, cluster headaches and trigeminal neuralgia
AU557463B2 (en) Dibenzodiazepinones
US4800225A (en) Pharmacologically active hydrated azabicyclo compound
EP0433043A1 (de) Medikamente
WO1994013284A1 (en) New use of 5-ht3 receptor antagonists
AU758936B2 (en) Method of treatment
US4956362A (en) Use of carpipramine for the treatment of anxiety and sleep disorders
EP0418327A1 (de) Eregolin abkoemmlinge mit anti-emesis wirkung.
Alhaider Antihistamine, anticholinergic and cardiovascular effects of 2-substituted-4-phenylquinoline derivatives
GB2132189A (en) Tropyl and pseudotropyl benzoates and their use in migraine treatment
MXPA01000466A (en) Method of treatment

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19920525

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19940701