WO1993008186A1 - Amides ou esters d'acide pyridine-3-carboxylique utilises comme antagonistes de 5-ht¿3? - Google Patents

Amides ou esters d'acide pyridine-3-carboxylique utilises comme antagonistes de 5-ht¿3? Download PDF

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Publication number
WO1993008186A1
WO1993008186A1 PCT/GB1992/001949 GB9201949W WO9308186A1 WO 1993008186 A1 WO1993008186 A1 WO 1993008186A1 GB 9201949 W GB9201949 W GB 9201949W WO 9308186 A1 WO9308186 A1 WO 9308186A1
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Prior art keywords
compound
compound according
pharmaceutically acceptable
formula
pyridine
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PCT/GB1992/001949
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English (en)
Inventor
Francis David King
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Smithkline Beecham 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
Priority claimed from GB919122641A external-priority patent/GB9122641D0/en
Priority claimed from GB929211072A external-priority patent/GB9211072D0/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to EP92922464A priority Critical patent/EP0611370A1/fr
Priority to JP5507574A priority patent/JPH07500590A/ja
Publication of WO1993008186A1 publication Critical patent/WO1993008186A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems

Definitions

  • This invention relates to novel compounds having pharmacological activity, to a process for their preparation and their use as pharmaceuticals.
  • EP-A-220011 (Beecham Group p.l.c.) describes the use of a benzamide derivative as a 5-HT3 receptor antagonist.
  • GB 1555682 (Ciba-Geigy) describes a group of 2-methoxy-3-pyridylamides.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof:
  • R 1 is C 1 -6 alkoxy, C 3-8 cycloalkoxy or C 3-8 cycloalkyl C 1 -4 alkoxy;
  • R 2 is hydrogen, halo, C 1 -6 alkyl, C 1 -6 alkoxy or amino optionally
  • R 3 is hydrogen, halo or C 1 -6 alkyl
  • L is O or NH
  • Z is a di-azacyclic or azabicyclic side chain
  • Suitable examples of alkyl moieties in R 1 to R 3 include methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tert-butyl
  • halo moieties include fluoro, chloro and bromo.
  • R 1 is methoxy
  • R 2 is NH 2
  • R 3 is chloro.
  • Suitable examples of Z are described in the art relating to 5-HT 3 receptor antagonists, ie. as follows: i) GB 2125398A (Sandoz Limited)
  • EP-A-215545 (Beecham Group p.l.c.)
  • EP-A-214772 (Beecham Group p.l.c.)
  • R is hydrogen or methyl; and X is oxygen, sulphur or nitrogen optionally substituted by C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-4 alkyl, phenyl, naphthyl, phenyl C 1-4 alkyl or naphthyl C 1-4 alkyl wherein a phenyl or naphthyl moiety is optionally substituted by one or more of halo, C 1-6 alkoxy or C 1-6 alkyl.
  • Side chains Z of particular interest include tropane, granatane, oxagranatane and azagranatane, where R is methyl. Suitable values for N-substituents when X is N are as described in WO 91/05174, for example, iso-propyl or ethyl.
  • L is preferably NH.
  • COL in formula (I) may be replaced by a bioisostere therefor, for example, 1,2,4-oxadiazole and the other groups of structure h) described in EP-A-377967 (Beecham Group p.l.c).
  • the pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts with conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric acids and pharmaceutically acceptable organic acids such as acetic, tartaric, maletc, citric, succinic, benzole, ascorbic, methanesulphonic, ⁇ -keto glutaric, ⁇ -glycerophosphoric, and gIucose-1-phosphoric acids.
  • conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric acids
  • pharmaceutically acceptable organic acids such as acetic, tartaric, maletc, citric, succinic, benzole, ascorbic, methanesulphonic, ⁇ -keto glutaric, ⁇ -glycerophosphoric, and gIucose-1-phosphoric acids.
  • Examples of pharmaceutically acceptable salts include quaternary derivatives of the compounds of formula (I) such as the compounds quatemised by compounds R x -T wherein R x is C 1 -6 alkyl, phenyl- C 1 -6 alkyl or C 5 -7 cycloalkyl, and T is a radical corresponding to an anion of an acid.
  • R x include methyl, ethyl and n- and iso-propyl; and benzyl and phenethyl.
  • Suitable examples of T include halide such as chloride, bromide and iodide.
  • Examples of pharmaceutically acceptable salts also include internal salts such as N-oxides.
  • the compounds of the formula (I), their pharmaceutically acceptable salts, (including quaternary derivatives and N-oxides) may also form
  • the invention also provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of formula (II): .
  • Examples of leaving groups Q 1 displaceable by a nucleophile, include halogen such as chloro and bromo, hydroxy, C 1 -4 alkoxy, such as CH 3 O and C 2 H 5 O-, PhO-, activated hydrocarbyloxy, such as Cl 5 C 6 O- or Cl 3 CO-; or COQ 1 , forms a mixed anhydride, so that Q 1 is carboxylic acyloxy; or an N-linked heterocycle, such as imidazoie.
  • halogen such as chloro and bromo
  • hydroxy, C 1 -4 alkoxy such as CH 3 O and C 2 H 5 O-, PhO-
  • activated hydrocarbyloxy such as Cl 5 C 6 O- or Cl 3 CO-
  • COQ 1 forms a mixed anhydride, so that Q 1 is carboxylic acyloxy; or an N-linked heterocycle, such as imidazoie.
  • a group Q 1 is a halide, or COQ 1 forms a mixed anhydride
  • the reaction is preferably carried out at non-extreme temperatures in an inert non-hydroxylic solvent, such as benzene, dichloromethane, toluene, diethyl ether, acetonitrile, tetrahydrofuran (THF) ordimethylformamide (DMF). It is also preferably carried out in the presence of an acid acceptor, such as an organic base, in particular a tertiary amine, such as triethylamine,
  • the acid acceptor can be inorganic, such as calcium carbonate, sodium carbonate or potassium carbonate. Temperatures of 0°-100°C, in particular 10-80°C are suitable.
  • a group Q 1 is C 1 -4 alkoxy, phenoxy or activated hydrocarbyloxy then the reaction is preferably carried out in an inert polar solvent, such as toluene or dimethylformamide. It is also preferred that the group Q 1 is CI 3 CO- and that the reaction is carried out in toluene at reflux temperature.
  • reaction is generally carried out in an inert non-hydroxyiic solvent, such as dichloromethane, THF or DMF optionally in the presence of a dehydrating agent such as a carbodiimide, for example dicyclohexylcarbodiimide.
  • a dehydrating agent such as a carbodiimide, for example dicyclohexylcarbodiimide.
  • non-extreme temperature such as -10 to 100°C, for example, 0 to 80°C.
  • higher reaction temperatures are employed with less active compounds whereas lower temperatures are employed with the more active compounds.
  • acyloxy leaving groups include C 1 -4 alkanoyloxy and C 1 -4 alkoxycarbonyloxy, in which case the reaction is preferably carried out in an inert solvent, such as dichloromethane, at a non-extreme temperature for example ambient temperatures in the presence of an acid acceptor, such as triethylamine.
  • C 1 -4 alkoxycarbonyloxy leaving groups may be generated in situ by treatment of the correspondfng compound wherein Q 1 is hydroxy with a C 1 -4 alkyl chloroformate.
  • a group Q 1 is activated hydrocarbyloxy then the reaction is preferably carried out in an inert polar solvent, such as dimethylformamide. It is also preferred that the activated hydrocarbyloxy group is a pentachlorophenyl ester and that the reaction is carried out at ambient temperature.
  • the compound of formula (III) may be in the form of a reactive derivative thereof, which is often a salt, such as the lithium, sodium or potassium salt.
  • An R 2 ' or R 3 ' group which is convertible R 2 or R 3 include a hydrogen substituent which is convertible to a halogen substituent by halogenation using conventional halogenating agents.
  • Z when other than Z may be wherein R is replaced by R' which is a hydrogenolysable protecting group which is benzyl optionally substituted by one or two groups selected from halo, C 1 -4 alkoxy and C 1 -4 alkyl.
  • R' which is a hydrogenolysable protecting group which is benzyl optionally substituted by one or two groups selected from halo, C 1 -4 alkoxy and C 1 -4 alkyl.
  • Such benzyl groups may, for example, be removed, when R 1 /R 2 is not halogen, by conventional transition metal catalysed hydrogenolysis to give compounds of the formula (I) wherein R is hydrogen.
  • This invention also provides a further process for the preparation of a compound of the formula (I) wherein R is methyl or a pharmaceutically acceptable salt thereof, which comprises N-methylating a compound of formula (I) wherein R is hydrogen, and optionally forming a pharmaceutically acceptable salt of the resulting compound of the formula (I).
  • N-methylating a compound of formula (I) wherein R is hydrogen and optionally forming a pharmaceutically acceptable salt of the resulting compound of the formula (I).
  • N-methylating a compound of formula (I) wherein R is hydrogen
  • optionally forming a pharmaceutically acceptable salt of the resulting compound of the formula (I) optionally forming a pharmaceutically acceptable salt of the resulting compound of the formula (I).
  • N-methylating a compound of formula (I) wherein R is hydrogen
  • optionally forming a pharmaceutically acceptable salt of the resulting compound of the formula (I) may be achieved by reaction with a compound CH 3 Q 2 wherein Q 2 is a leaving group.
  • Suitable values for Q2 include groups displaced by nucleophiles such as Cl , Br, I, OSO 2 CH 3 or OSO 2 C 6 H 4 PCH 3 , preferably Cl , Br or I.
  • the reaction may be carried out under conventional alkylation conditions for example in an inert solvent such as dimethylformamide in the presence of an acid acceptor such as potassium carbonate. Generally the reaction is carried out at non-extreme temperature such as at ambient or slightly above.
  • 'N-methylation' may be effected under conventional reductive alkylation conditions.
  • Interconverting R in the compound of the formula (III) before coupling with the compound of the formula (II) is also possible. Such interconversions are effected conveniently under the above conditions. It is desirable to protect any amine function with a group readily removable by acidolysis such as a C 2-7 alkanoyl group, before R/Z intercon version. It is often convenient in the preparation of such a compound of formula (III) to prepare the corresponding compound wherein the methyl group is replaced by alkoxycarbonyl. Such compounds may then be reduced using a strong reductant such as lithium aluminium hydride to the corresponding compound of formula (II).
  • a strong reductant such as lithium aluminium hydride
  • pyridine carboxylic acid derivative intermediates of formula (II) are known or may be prepared from substituted pyridines, for example as described in the Description hereinafter.
  • corresponding exocyclic keto derivative of the azabicyclic side chain prepared by condensation methods, often using a substituted piperidine. They may be prepared by processes described in the aforementioned Patent Publications relating to values of the side chain Z.
  • the -COL- linkage has an endo orientation with respect to the ring of the bicyclic moiety to which it is attached.
  • a mixture of endo and exo isomers of the compound of the formula (I) may be synthesised non-stereospecificafly and the desired isomer separated conventionally therefrom e.g. by chromatography; or alternatively the endo isomer may if desired by synthesised from the corresponding endo form of the compound of the formula (II).
  • Corresponding geometric isomeric pairs are possible for the isoquinuclidine, isogranatane, oxa/thia-isogranatane and isotropane side chains.
  • compositions of this invention may be formed conventionally.
  • the salts may be formed for example by reaction of the base compound of formula (l) with a pharmaceutically acceptable organic or inorganic acid.
  • the compounds of the present invention are 5-HT 3 receptor antagonists and it is thus believed may generally be used In the treatment or prophylaxis of pain, emesis, CNS disorders and gastrointestinal disorders. Pain includes migraine, cluster headache, trigeminal neuralgia and visceral pain; emesis includes, in particular, that of preventing vomiting and nausea associated with cancer therapy, post-operative emesis and nausea associated with migraine. Examples of cancer therapy include that using cytotoxic agents, such as platinum complexes including cisplatin, and also doxorubicin and
  • CNS disorders include anxiety, psychosis including schizophrenia, cognitive disorders such as senile dementia and age associated memory impairment (AAMI), and drug dependence/withdrawal syndrome.
  • Gastrointestinal disorders include irritable bowel syndrome and diarrohea.
  • 5-HT 3 receptor antagonists may also be of potential use in the treatment of obesity and/or arrhythmia.
  • Some of the compounds of formula (I), such as the compounds wherein Z is quinuclidine or an isogranatane, may also be 5-HT 4 receptor agonists, of potential use in the treatment of disorders relating to impaired gastrointestinal motility, such as those described in EP-A-94742 (Beecham Group p.l.c).
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • compositions are prepared by admixture and are usually 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.
  • Orally administrable compositions are preferred, since they are more convenient for general use.
  • 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, for example with an enteric coating.
  • Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
  • Suitable disintegrants include starch, polyvinylpolypyrrolidone and starch derivatives such as sodium starch glycollate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
  • 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, carboxymethylcellulose, 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;
  • suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia
  • non-aqueous vehicles which may include edible oils
  • almond oil fractionated coconut oil
  • oily esters such as esters of g
  • preservatives for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • Oral liquid preparations are usually in the form of aqueous or oily
  • suspensions, solutions, emulsions, syrups, or elixirs are 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, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and flavouring or colouring agents.
  • the oral compositions may be prepared by conventional methods of blending, filling ortabletti ⁇ g. 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.
  • fluid unit dose forms are prepared containing a compound of the present invention 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 anodide
  • compositions 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 of 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.
  • the invention further provides a method of treatment or prophylaxis of pain, emesis, CNS disorders and/or gastrointestinal disorders in mammals, such as humans, which comprises the administration of an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.
  • An amount effective to treat the disorders herein- before described depends on the relative efficacies of the compounds of the invention, the nature and severity of the disorder being treated and the weight of the mammal.
  • a unit dose for a 70kg adult will normally contain 0.05 to 1000mg for example 0.5 to 500mg, of the compound of the invention.
  • Unit doses may 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, that is in the range of approximately 0.0001 to 50mg/kg/day, more usually 0.0002 to 25 mg/kg/day.
  • the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance, in particular for use in the treatment of pain, emesis, CNS disorders and/or gastrointestinal disorders.
  • the following Examples illustrate the preparation of compounds of formula (I); the following Description relates to the preparation of an intermediate of formula (II).
  • the method is as described by Nelson & Thomas, Biochem. Pharmacol. 38. 1693-1695 (1989).
  • the compound E1 had a pKi of 10.4.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On décrit des composés de la formule (I) et des sels pharmaceutiquement acceptables de ceux-ci, formule dans laquelle R1 représente alcoxy C1-6, cycloalcoxy C3-8, ou cycloalkyle C3-8 alcoxy C1-6 ou amino éventuellement substitués par un ou deux groupes alkyle C1-6; R3 représente hydrogène, halo ou alkyle C1-6; L représente O ou NH; et Z représente une chaîne latérale di-azacyclique ou azabicyclique. Ces composés présentent une activité antagoniste par rapport au récepteur de 5-HT3.
PCT/GB1992/001949 1991-10-24 1992-10-23 Amides ou esters d'acide pyridine-3-carboxylique utilises comme antagonistes de 5-ht¿3? WO1993008186A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP92922464A EP0611370A1 (fr) 1991-10-24 1992-10-23 Amides ou esters d'acide pyridine-3-carboxylique utilises comme antagonistes de 5-ht 3?
JP5507574A JPH07500590A (ja) 1991-10-24 1992-10-23 ５−ｈｔ３アンタゴニストとして有用なピリジン−３−カルボン酸エステルまたはアミド

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB919122641A GB9122641D0 (en) 1991-10-24 1991-10-24 Pharmaceuticals
GB9122641.5 1991-10-24
GB9211072.5 1992-05-23
GB929211072A GB9211072D0 (en) 1992-05-23 1992-05-23 Pharmaceuticals

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WO1993008186A1 true WO1993008186A1 (fr) 1993-04-29

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EP (1) EP0611370A1 (fr)
JP (1) JPH07500590A (fr)
AU (1) AU2797292A (fr)
MX (1) MX9206075A (fr)
PT (1) PT100990A (fr)
WO (1) WO1993008186A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0855397A1 (fr) * 1995-07-28 1998-07-29 Dainippon Pharmaceutical Co., Ltd. (r)-5-bromo-n-(1-ethyl-4-methylhexahydro-1h-1,4-diazepin-6-yl)-2-methoxy-6-methylamino-3-pyridine-carboxamide, son procede d'obtention et medicament le contenant
WO1998056397A1 (fr) * 1997-06-12 1998-12-17 Braswell A Glenn Composition utile pour une surveillance de poids renfermant de l'hypericum perforatum

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ATE169015T1 (de) * 1992-02-04 1998-08-15 Eisai Co Ltd Aminobenzoesäure derivate

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US4089960A (en) * 1975-09-25 1978-05-16 Ciba-Geigy Corporation Antiemetic, psychosomatic and antipsychotic heterocyclic pyridine carboxamides
EP0099194A2 (fr) * 1982-07-03 1984-01-25 Beecham Group Plc Benzamides
EP0255297A2 (fr) * 1986-07-31 1988-02-03 Beecham Group Plc Composés azabicycliques, procédé pour leur préparation et leur utilisation pharmaceutique
DE3740984A1 (de) * 1987-12-03 1989-06-15 Sandoz Ag N-oxide von heterocyclischen carbonsaeurederivaten bzw. verfahren zu deren herstellung und deren verwendung

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Publication number Priority date Publication date Assignee Title
US4089960A (en) * 1975-09-25 1978-05-16 Ciba-Geigy Corporation Antiemetic, psychosomatic and antipsychotic heterocyclic pyridine carboxamides
EP0099194A2 (fr) * 1982-07-03 1984-01-25 Beecham Group Plc Benzamides
EP0255297A2 (fr) * 1986-07-31 1988-02-03 Beecham Group Plc Composés azabicycliques, procédé pour leur préparation et leur utilisation pharmaceutique
DE3740984A1 (de) * 1987-12-03 1989-06-15 Sandoz Ag N-oxide von heterocyclischen carbonsaeurederivaten bzw. verfahren zu deren herstellung und deren verwendung

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Title
JOURNAL OF MEDICINAL CHEMISTRY. vol. 33, no. 6, 1990, WASHINGTON US pages 1594 - 1600 M.F. HIBERT ET AL. 'Conformation-activity relationship study of 5-HT3 receptor antagonists and a definition of a model for this receptor site.' *
JOURNAL OF MEDICINAL CHEMISTRY. vol. 33, no. 7, 1990, WASHINGTON US pages 1932 - 1935 J. BERMUDEZ ET AL. '5-Hydroxytryptamine (5-HT3) receptor antagonists. 3. Ortho-substituted phenylureas.' *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0855397A1 (fr) * 1995-07-28 1998-07-29 Dainippon Pharmaceutical Co., Ltd. (r)-5-bromo-n-(1-ethyl-4-methylhexahydro-1h-1,4-diazepin-6-yl)-2-methoxy-6-methylamino-3-pyridine-carboxamide, son procede d'obtention et medicament le contenant
EP0855397A4 (fr) * 1995-07-28 1998-12-02 Dainippon Pharmaceutical Co (r)-5-bromo-n-(1-ethyl-4-methylhexahydro-1h-1,4-diazepin-6-yl)-2-methoxy-6-methylamino-3-pyridine-carboxamide, son procede d'obtention et medicament le contenant
US5945415A (en) * 1995-07-28 1999-08-31 Dainippon Pharmaceutical Co., Ltd. (R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methylamino-3-pyridinecarboxamide, process for producing the same and medicinal composition containing the same
CN1096459C (zh) * 1995-07-28 2002-12-18 大日本制药株式会社 (r)－5－溴－n－(1－乙基－4－甲基六氢－1h－1,4－二氮杂䓬－6－基)－2－甲氧基－6－甲胺基－3－吡啶羧酰胺,其制备方法及含有该化合物的医药组合物
WO1998056397A1 (fr) * 1997-06-12 1998-12-17 Braswell A Glenn Composition utile pour une surveillance de poids renfermant de l'hypericum perforatum
US5911992A (en) * 1997-06-12 1999-06-15 A. Glenn Braswell Method for controlling weight with hypericum perforatum and garcinia cambogia

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PT100990A (pt) 1994-01-31
JPH07500590A (ja) 1995-01-19
MX9206075A (es) 1993-04-01
AU2797292A (en) 1993-05-21
EP0611370A1 (fr) 1994-08-24

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