EP1023286A1 - Benzimidazole derivate, pharmazeutische zusammensetzungen die sie enthalten und ihre verwendung - Google Patents

Benzimidazole derivate, pharmazeutische zusammensetzungen die sie enthalten und ihre verwendung

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Publication number
EP1023286A1
EP1023286A1 EP98947406A EP98947406A EP1023286A1 EP 1023286 A1 EP1023286 A1 EP 1023286A1 EP 98947406 A EP98947406 A EP 98947406A EP 98947406 A EP98947406 A EP 98947406A EP 1023286 A1 EP1023286 A1 EP 1023286A1
Authority
EP
European Patent Office
Prior art keywords
substituted
compound
disorder
disease
phenyl
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Withdrawn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
EP98947406A
Other languages
English (en)
French (fr)
Inventor
Lene Teuber
Frank Wätjen
Yoshimasa Meiji Seika Kaisha Ltd. FUKUDA
Yasuyuki Meiji Seika Kaisha Ltd. ICHIMARU
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.)
NTG Nordic Transport Group AS
Original Assignee
Neurosearch AS
Meiji Seika Kaisha Ltd
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 Neurosearch AS, Meiji Seika Kaisha Ltd filed Critical Neurosearch AS
Publication of EP1023286A1 publication Critical patent/EP1023286A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
    • C07C239/08—Hydroxylamino compounds or their ethers or esters
    • C07C239/20—Hydroxylamino compounds or their ethers or esters having oxygen atoms of hydroxylamino groups etherified

Definitions

  • Benzimidazole compounds pharmaceutical compositions containing the compounds and their use.
  • This invention relates to novel benzimidazole compounds, pharmaceutical compositions containing these compounds, methods of treating therewith, and to method of preparing such benzimidazole compounds.
  • the novel compounds are useful in the treatment of central nervous system diseases and disorders, which are responsive to modulation of the GABA A receptor complex, such as for example anxiety, sleep disorders, memory disorders, and epilepsia or other convulsive disorders.
  • GABA A receptors are the most abundant inhibitory receptors in mammalian brain
  • the GABA A receptor are structurally constituted as macromolecuiar heteropentame ⁇ c assemblies (combinations of ⁇ , ⁇ , and ⁇ / ⁇ protein subunits).
  • Several subtypes of such GABA A receptors have been described by techniques of modern molecular biology.
  • Each GABA A receptor complex comprises a chloride ion channel that controls chloride flux across the neuronal membrane, and multiple recognition sites for small modulatory molecules such as benzodiazepines, barbiturates, picrotoxin, and certain steroids.
  • GABA interacts with its receptor, the ion channel is opened, chloride influx is enhanced, the membrane is hyperpolanzed and the cell becomes less responsive to excitatory stimuli.
  • This GABA induced ion current can be regulated by diverse agents, including agents that interact with the benzodiazepine receptor or recognition site.
  • Agents that bind or interact with the modulatory sites on the GABA A receptor complex can have either enhancing effect on the action of GABA, i.e. a positive modulatory effect of the receptor (agonists, partial agonists), an attenuating effect on the action of GABA, i.e. negative modulation of the receptor (inverse agonists, partial inverse agonists), or they can block the effect of both agonists and inverse agonists by competitive block (antagonists or ligands without intrinsic activity).
  • Agonists generally produce muscle relaxant, hypnotic, sedative, anxiolytic, and/or anticonvulsant effects, while inverse agonists produce proconvuisant, anti-inebriant, and anxiogenic effects.
  • Partial agonists are characterized as compounds with anxiolytic effects but without or with reduced muscle relaxant, hypnotic and sedative effects, whereas partial inverse agonists are considered to be useful as cognition enhancers.
  • WO 96/33191 describes oxime-substituted benzimidazoles having GABA-receptor activity.
  • the present invention provides novel benzimidazole compounds that interact with the benzodiazepine receptor of the GABA A receptor complex
  • the compounds of the present invention are valuable modulators of the GABA A receptor complex with a favorable pharmacodynamic
  • a further object of the present invention is to provide a method of preparing the novel pharmaceutical compositions.
  • the invention then, inter alia, comprises the following, alone or in combination:
  • R 11 represents a 5- or 6-membered monocyclic heteroaryl containing at least one nitrogen as the N-oxide; or a pharmaceutically acceptable salt thereof.
  • R" represents C ⁇ . 6 -alkyl substituted with one hydroxy-group.
  • R" represents hydrogen, C ⁇ . 8 -alkyl which may be substituted one or more times with OH, C 2 ._- alkenyl which may be substituted one or more times with OH, C 2 . 6 -alkynyl which may be substituted one or more times with OH, or phenyl which may be substituted one or more times with OH; or
  • R 9 and R 8 independently may be hydrogen, Ci-a-alkyl, C 2 . 6 -alkenyl, C 2 . 6 - aii ⁇ /nvi r,. ,-r.vr:loalkvl C-oycloalkyl-d- ⁇ -alkyl, or R 9 and R 8 to ⁇ ether form a C ⁇ rinq, to form a compound of the formula
  • R 9 and R 8 has the meaning set forth above
  • composition comprising an effective amount of a compound as any above or a pharmaceutically acceptable salt thereof or an oxide thereof together with at least one pharmaceutically acceptable carrier or diluent,
  • a compound as any above for the preparation of a medicament for the treatment of a disorder or disease of a living animal body, including a human, which disorder or disease is responsive to the modulation of the GABA A receptor complex of the central nervous system;
  • a compound as any above for the preparation of a medicament for the treatment of a disorder or disease of a living animal body, including a human, which disorder or disease is responsive to positive modulation of the GABA A receptor complex of the central nervous system,
  • a compound as any above for the preparation of a medicament for the treatment of a disorder or disease selected from anxiety, sleep disorders, memory disorders, epilepsy or any other convulsive disorder,
  • a method of treating a disorder or disease of a living animal body, including a human, which disorder or disease is responsive to modulation of the GABA A receptor complex of the central nervous system comprising administering to such a living animal body, including a human, in need thereof a therapeutically effective amount of a compound as any above;
  • the active ingredient is administered in form of a pharmaceutical composition thereof, in which it is present together with a pharmaceutically acceptable carrier or diluent
  • Alkyl means a straight chain or branched chain of from one to eight carbon atoms or cyclic alkyl of from three to seven carbon atoms, including but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; methyl, ethyl, propyl, isopropyl and t-butyl are preferred groups.
  • Alkenyl means a straight chain or branched chain of from two to six carbon atoms containing one double bond, including but not limited to ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2- butenyl, and 3-butenyl
  • Alkynyl means a straight chain or branched chain of from two to six carbon atoms containing one triple bond, including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, ana 3-butynyl
  • a 5- or 6-membered monocyclic heteroaryl group includes, for example, oxazol-2-yl, oxazol-4- yl, oxazol-5-yl, ⁇ soxazoi-3-yl, ⁇ soxazol-4-yl, ⁇ soxazoi-5-yl, th ⁇ azol-2-yl, th ⁇ azol-4-yl, th ⁇ azol-5-yl, ⁇ soth ⁇ azol-3-yl, ⁇ soth ⁇ azol-4-yl, ⁇ soth ⁇ azol-5-yl, 1 ,2,4-oxad ⁇ azol-3-yl, 1 ,2,4-oxad ⁇ azol-5-yl, 1,2,4- th ⁇ ad ⁇ azol-3-yl, 1 ,2,4-th ⁇ ad ⁇ azol-5-yl, 1 ,2,5-oxad ⁇ azol-5-yl, 1 ,2,5-oxad
  • Examples of pharmaceutically-acceptable addition salts include inorganic and organic acid addition salts such as the hydrochlonde, hydrobromide, phosphate, nitrate, perchlorate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate, benzoate, ascorbate, cinnamate, benzenesulfonate, methanesulfonate, stearate, succinate, glutamate, glycollate, toluene-p-sulphonate, formate, malonate, naphthalene-2-sulphonate, salicylate and the acetate for example.
  • inorganic and organic acid addition salts such as the hydrochlonde, hydrobromide, phosphate, nitrate, perchlorate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate, benzoate, ascorbate, cinnamate, benzenesulfon
  • the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like.
  • pharmaceutically acceptable solvents such as water, ethanol and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention
  • Racemic forms can be resolved into the optical antipodes by known methods, for example, by separation of diastereomenc salts thereof, with an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optical active matrix.
  • Racemic compounds of the present invention can thus be resolved into their optical antipodes, e.g., by fractional crystallization of d- or I- (tartrates, mandelates, or camphorsulphonate) salts for example
  • the compounds of the instant invention may also be resolved by the formation of diastereomenc amides by reaction of the compounds of the present invention with an optically active activated carboxy c acid such as that derived from
  • the present invention includes both the Z- and E-form of the compounds of the invention as well as mixtures thereof.
  • the compounds of the invention may be prepared in numerous ways.
  • the compounds of the invention and their pharmaceutically acceptable derivatives may thus be prepared by any method known in the art for the preparation of compounds of analogous structure and as shown in the representative examples which follows.
  • GABA 4-aminobytyric acid
  • GABA A 4-aminobytyric acid
  • GABA B receptors 4-aminobytyric acid
  • Recent molecular biology has demonstrated that the GABA A receptors can be subdivided into numerous subreceptors consistant with the selective and or partial pharmacological effects observed with certain benzodiazepine receptor ligands as opposed to the unselective effects observed for the classical benzodiazepine receptor ligands such as for example diazepam.
  • Activation of GABA receptors leads to alternations in membrane potential (hyperpolarization).
  • the GABA A receptors are associated with chloride influx through its associated and integrated chloride channel, whereas GABA B receptor activation indirectly alters potassium and calcium channels as well as modifies second messenger production.
  • the GABA A recognition sites can be activated by GABA, muscimol; and isoguvacine for example, but not by GABA B agonists such as for example baclofen.
  • the modulatory GABA A recognition site at the benzodiazepine receptor sites can be selectively radiolabelled with 3 H-flunitrazepam. The affinity of various potential ligands for the benzodiazepine receptor sites can thus be evaluated by estimating the ability of test compounds to displace 3 H-flunitrazepam.
  • the membrane preparation is thawed and centrifuged at 2°C for 10 mm at 27,000 x g.
  • the pellet is washed twice with 20 ml 50 mM Tns-citrate, pH 7 1 using an Ultra-Turrax homogenizer and centrifuged for 10 mm at 27,000 x g.
  • the final pellet is resuspended in 50 mM Tns-citrate, pH 7 1 (500 ml buffer per g of original tissue), and then used for binding assays.
  • the test value is calculated as the IC 50 (the concentration (nM) of the test substance which inhibits the specific binding of 3 H-FNM by 50%)
  • Test compound IC 50 (nM)
  • a compound of the invention may be administered as the raw chemical, then it is preferable to present the active ingredient as a pharmaceutical formulation.
  • the invention thus further provides a pharmaceutical formulation comprising a compound of the invention or a pharmaceutically acceptable salt or derivative thereof together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and/or prophylactic ingredients
  • a pharmaceutical formulation comprising a compound of the invention or a pharmaceutically acceptable salt or derivative thereof together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and/or prophylactic ingredients
  • the car ⁇ erfs must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • compositions and unit dosages thereof may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile mjectable solutions for parenteral (including subcutaneous) use.
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • Formulations containing one (1) milligram of active ingredient or, more broadly, 0.01 to one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
  • compositions from the compounds of the present invention can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from one to about seventy percent of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcelluiose, sodium carboxymethylcellulose, a low melting vax, cocoa butter, and the like.
  • the term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
  • a low melting vax such as a mixture of fatty acid glyce ⁇ des or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions.
  • parenteral injection liquid preparations can be formulated in solutions in aqueous polyethylene glycol solution.
  • the compounds according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophiiisation from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilizing and thickening agents, as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcelluiose, sodium carboxymethylcellulose, and other well known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcelluiose, sodium carboxymethylcellulose, and other well known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavours, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
  • Formulations suitable for topical administration in the mouth include lozenges comprising active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Solutions or suspensions are applied directly to the nasel cavity by conventional means, for example with a dropper, pipette or spray.
  • the formulations may be provided in single or multidose form. In the latter case of a dropper or pipette this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray this may be achieved for example by means of a metering atomising spray pump.
  • Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, tnchlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, tnchlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • CFC chlorofluorocarbon
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by provision of a metered valve.
  • the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvmylpyrrolidine (PVP).
  • a powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvmylpyrrolidine (PVP).
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of e.g. gelatin or blister packs from which the powder may be administered by means of an inhaler.
  • the compound In formulations intended for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
  • formulations adapted to give sustained release of the active ingredient may be employed.
  • the pharmaceutical preparations are preferably in unit dosage forms.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form
  • Tablets or capsules for oral administration and liquids for intravenous administration are preferred compositions.
  • the compounds of this invention are extremely useful in the treatment of disorders or diseases of a living animal body due to their affinity for the benzodiazepine binding site of the GABA A receptor These properties make the compounds of this invention extremely useful in the treatment of convulsions, anxiety sleep disorders, memory disorders as well as other disorders sensitive to modulation of the GABA A receptor
  • the compounds of this invention may accordingly be administered to a subject, including a human, in need of treatment, alleviation, or elimination of a disorder or disease associated with the GABA A receptors. This includes especially convulsions, anxiety, sleep disorders and memory disorders.
  • Suitable dosage range are 0.01 -100 milligrams daily, 0 1 -50 milligrams daily, and especially 0 1-30 milligrams daily, dependent as usual upon the exact mode of administration, form in which administered, the indication towards which the administration is directed, the subject involved and the body weight of the subject involved, and further the preference and experience of the physician or veterinarian in charge.
  • N-hydroxyphtalimide 5.0 g, 30.7 mmol
  • DMF 50 ml
  • triethylamine 4.27 ml, 30.7 mmol
  • 1 ,2-dibromoethane 10.6 ml, 0.12 mmol
  • the reaction mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was trituated with water to leave the crystalline product (6.56 g, 89%).
  • N-(2-Bromoethoxy)phtalimide (6.56 g, 27.3 mmol) was suspended in THF (30 ml). Gaseous dimethylamine was gently bubbled through this suspension until a clear orange-red solution had formed. This resulting solution was stirred at ambient temperature overnight. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column-chromatography on silica gel using a mixture of ethyl acetate and methanoi (9:1 v/v) as the eluent. Yield: 4.53 g (71%).
  • O-(2-Hvdroxyethyl)hvdroxylamine A solution of N,N-dimethyl-2-(5,6-dihydro-1 ,4,2-dioxazin-3-yl)benzamide (4.53 g, 19.4 mmol) in hydrochloric acid (50 ml, 6M) was heated to reflux overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. Toluene was added to the residue and the resulting mixture was evaporated to dryness to yield the desired product (3.3 g, contaminated with dimethylammonium chloride) which was used without further purification.

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  • Plural Heterocyclic Compounds (AREA)
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EP98947406A 1997-10-10 1998-10-08 Benzimidazole derivate, pharmazeutische zusammensetzungen die sie enthalten und ihre verwendung Withdrawn EP1023286A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DK116097 1997-10-10
DK116097 1997-10-10
PCT/DK1998/000432 WO1999019323A1 (en) 1997-10-10 1998-10-08 Benzimidazole compounds, pharmaceutical compositions containing the compounds and their use

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EP1023286A1 true EP1023286A1 (de) 2000-08-02

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EP (1) EP1023286A1 (de)
JP (1) JP2001519429A (de)
CN (1) CN1275127A (de)
AU (1) AU742172B2 (de)
CA (1) CA2304379A1 (de)
NZ (1) NZ503435A (de)
TW (1) TW424088B (de)
WO (1) WO1999019323A1 (de)
ZA (1) ZA989238B (de)

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ZA989238B (en) 1999-05-17
TW424088B (en) 2001-03-01
AU9433298A (en) 1999-05-03
JP2001519429A (ja) 2001-10-23
CA2304379A1 (en) 1999-04-22
CN1275127A (zh) 2000-11-29
NZ503435A (en) 2001-12-21
AU742172B2 (en) 2001-12-20
WO1999019323A1 (en) 1999-04-22

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