EP0494140A1 - Dibenzofurancarboxamides - Google Patents

Dibenzofurancarboxamides

Info

Publication number
EP0494140A1
EP0494140A1 EP90905138A EP90905138A EP0494140A1 EP 0494140 A1 EP0494140 A1 EP 0494140A1 EP 90905138 A EP90905138 A EP 90905138A EP 90905138 A EP90905138 A EP 90905138A EP 0494140 A1 EP0494140 A1 EP 0494140A1
Authority
EP
European Patent Office
Prior art keywords
hexahydrodibenzofuran
chloro
compound according
carboxamide
azabicyclo
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Withdrawn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
EP90905138A
Other languages
German (de)
English (en)
Other versions
EP0494140A4 (en
Inventor
Raymond D. Youssefyeh
Henry F. Campbell
Donald E. Kuhla
John Edward Airey
Scott Ira Klein
Matthew Ray Powers
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.)
Rorer International Holdings Inc
Original Assignee
Rorer International Holdings Inc
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 Rorer International Holdings Inc filed Critical Rorer International Holdings Inc
Publication of EP0494140A1 publication Critical patent/EP0494140A1/fr
Publication of EP0494140A4 publication Critical patent/EP0494140A4/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/91—Dibenzofurans; Hydrogenated dibenzofurans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • 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
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention is directed to certain specific novel chemical compounds and their valuable use as pharmaceutical agents as 5HT 3 antagpnists having unique CNS, anti-emetic and gastric prokinetic activity void of any significant D 2 receptor binding properties .
  • This invention also describes novel processes necessary for their preparation, separation and purification.
  • This invention relates to the compounds described by general Formula I and to therapeutic compositions comprising as active ingredient a compound of Formula I :
  • R 1 is hydrogen, amino or alkylamino, halo
  • R 2 is hydrogen, halo, sulfamyl, alkylsulfamyl or alkylsulfonyl;
  • R' is hydrogen or alkyl or together with a
  • R' group may form a double bond; and R is .
  • Preferred compounds of this invention include those compounds of Formulae II, III and IV.
  • R 1 and R 2 are as described above and R is
  • Preferred compounds include those of Formulae II, III and IV where
  • R 1 is amino or loweralkylamino and R 2 is hydrogen
  • R 1 is hydrogen and R 2 is halo, or
  • R 1 is amino and R 2 is halo.
  • the more preferred compounds include those of Formula II and especially where halo is chloro or bromo and loweralkyl is methyl.
  • the most preferred compounds include those compounds of
  • the present compounds may be prepared by the following general procedure.
  • this reaction may be carried out at decreased temperatures, such as 0°C by adding ethyl chloroformate to a reaction mixture of the acid in chloroform in the presence of triethylamine. This is then reacted with the amine of the formula H 2 N-R to obtain the desired product. Condensation may also be carried out in the presence of a dehydrating catalyst such as a carbodiimide in a solvent at normal temperatures.
  • a dehydrating catalyst such as a carbodiimide in a solvent at normal temperatures.
  • the most preferred compounds may be prepared by reacting the R 1 and R 2 substituted 5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acids, acid halides or esters with
  • the starting materials such as the acid or amine which have a specific configuration to obtain the desired stereospecific amide.
  • the amide may be formed as above and then separated by known techniques into the desired stereoisomers. Preparation and separation will be described in more detail later in this application.
  • the starting materials that is the substituted dibenzofuran-4-carboxylic acids, 6,7,8,9-tetrahydrodibenzofuran-4- carboxylic acids and the 5a,6,7,8,9,9a-hexahydrodibenzofuran- 4-carboxylic acids are also novel. They may be prepared by the following reaction schemes:
  • Salicylic acid is first esterified and then the
  • Deesterification of the esters 7 and 8 may be carried out with aqueous base, as above.
  • R 2 substitution is halo
  • the above reaction sequence may be carried out starting with 5-halo salicyclic acid.
  • R 2 is sulfamyl it is best that this group be protected initially with an acetyl group on the like and then deacetylated.
  • R 1 is an amine function this also should be protected with an acetyl group or the like and then
  • Halogenation may also be carried out en the 1-acetylamino compounds of the esters 16, 19 and 22. Halogenation occurs in the 2-position.
  • hydrolysis gives the desired 1-amino-2-halo-4- carboxylic acids 27, 30 and 33 of this invention.
  • Certain compounds of this invention have at least one asymmetric carbon atom such as the 5a,6,7,8,9,9a-hexahydrodibenzofuran compounds or those compounds wherein at least one R' is other than hydrogen or still those compounds where the R group contains an asymmetric carbon atom. Further, certain compounds of this invention may exist in their cis or trans configuration with respect to the dihydrofuran ring.
  • those compounds of Formula I may be obtained either as racemic mixtures, diastereoisomeric mixtures or as individual enantiomers.
  • the product may exist as mixtures of two or four diastereomers.
  • certain other compounds within the scope of this invention could have a number of stereocenters.
  • a compound with x stereocenters can have a maximum of 2 X stereoisomers.
  • a compound having three such centers gives rise to a maximum of eight stereoisomers, while one having four produces sixteen, etc.
  • the product may be synthesized as a mixture of the isomers and then the desired isomer separated by conventional techniques such as chromatography or
  • R contains an asymmetric carbon atom it is convenient to carry out condensation of 5a,6,7,8,9,9a- hexahydrodibenzofuran-4-carboxylic acid with 3-amino-1-azabicyclo[2.2.2.]octane or the like using the optically pure materials.
  • the hexahydrodibenzofuran-4-carboxylic acid is resolved prior to condensation with resolved 3-aminoquinuclidine.
  • 3-aminoquinuclidine results in S(-)3-aminoquinuclidine and R(+)3-aminoquinuclidine.
  • one of the most preferred compounds of this invention i.e., 2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-[N-(1-azabicyclo[2.2.2.]octan-3-yl)]carboxamide, has three asymmetric centers. These are at the 5a and 9a
  • stereoisomeric mixture of 4-[N-(1-azabicyclo[2.2.2.]octan- 3-yl)]-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofurancarboxamides.
  • Such a mixture can exist as a single entity having its own chemical, physical and pharmacological properties and lies within the scope of the present invention.
  • This mixture consists of eight individual stereoisomers having unique absolute configurations. Each of these stereoisomers also has its own chemical, physical and pharmacological properties and lies within the scope of this invention.
  • the stereoisomeric mixture can be divided into cis and trans configurations having their own specific properties and are also within the scope of this invention.
  • enantiomerically pure moiety results in forms that are separable by fractional crystallization, distillation or chromotography.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid
  • organic acids such as methane sulfonic acid
  • benzenesulfonic acid acetic acid, propionic acid, maleic acid, oxalic acid, succi ⁇ ic acid, glycolic acid, lactic acid, salicylic acid, benzoic acid, nicotinic acid, phthalic acid, stearic acid, oleic acid, abietic acid, etc.
  • the compounds of this invention have gastric prokinetic and anti-emetic properties and lack D 2 receptor binding activity. As such they possess therapeutic value in the treatment of upper bowel motility and
  • the compounds of this invention may be useful in the treatment of disorders related to impaired gastrointestinal motility such as
  • the compounds of this invention exhibit 5-HT3 antagonism and are considered to be useful in the treatment of psychotic disorders such as schizophrenia and anxiety and in the prophylaxis treatment of migraine and cluster headaches. We have further found that these compunds are selective in that they have little or no dopaminergic antagonist activity.
  • the test is designed to assess the effects of a test agent on gastric emptying of amberlite beads in the rat.
  • the procedure is a modification of those used in L.E. Borella an W. Lippman (1980) Digestion 20: 26-49.
  • Amberlite® beads are placed in a phenol red solution and allowed to soak for several hours.
  • Phenol red serves as an indicator, changing the beads from yellow to purple as their environment becomes more basic. After soaking, the beads are rinsed with 0.1 NaOH to make them purple and then washed with deionized water to wash away the NaOH.
  • the beads are filtered several times through 1.18 and 1.4 mm sieves to obtain beads with diameters in between these sizes. This is done using large quantities of deionized water. The beads are stored in saline until ready to use.
  • Rats Male Sprague-Dawley rats are fasted 24 hours prior to the study with water ad libitum. Rats are randomly divided in treatment groups with an N of 6 or 7.
  • Test agents are prepared in 0.5% methylcellulose and administered to the rats orally in a 10 ml/kg dose volume. Control rats receive 0.5%
  • rats are given 60 Amberlite® beads intragastrically.
  • the beads are delivered via a 3 inch piece of PE 205 tubing attached to a 16 gauge tubing adapter and syringe.
  • a small piece of PE 50 tubing is placed inside the tubing adapter to prevent the beads from being pulled back into the syringe.
  • the beads are flushed into each rat's stomach with 1 ml saline.
  • Rats are sacrificed 30 minutes after receiving the beads and their stomachs are removed. The number of beads remaining in each stomach is counted after rinsing the beads with NaOH.
  • the number of beads remaining in each stomach is subtracted from 60 to obtain the number of beads emptied.
  • the mean number of beads ⁇ S.E.M. is determined for each treatment group. The percent change from control is calculated as follows:
  • Statistical significance may be determined using a t-test for independent samples with a probability of 0.05 or less considered to be significant.
  • ferrets are dosed with the compound in 0.9% saline (i. v.) at a dose volume of 2.0 ml/kg.
  • ferrets are again dosed with the 0.9% saline (i.v.) mixture at a dose volume of 2.0 ml/kg.
  • Cisplatin is administered (i.v.) 30 minutes after the first dosing with the 0.9% saline.
  • Cisplatin 10 mg/kg is administered in a dose volume of 2.0 ml/kg.
  • the time of cisplatin administration is taken as time zero. Ferrets are observed for the duration of the experiment (4 hours). The elapsed time to the first emetic episode is noted and recorded, as are the total number of periods of emesis.
  • An emetic (vomiting) episode is characterized by agitated behavior, such as pacing around the cage and rapid to and fro movements. Concurrent with this behavior are several retching movements in a row, followed by a single, large, retch which may or may not expulse gastric contents. Immediately following the single large retch, the ferret relaxes. Single coughs or retches are not counted as vomiting
  • the D-2 dopamine receptor binding assay has been developed with slight modifications using the method of Ian Cresse, Robert Schneider and Solomon H.
  • Spiroperidol is a butyrophenone neuroleptic whose affinity for dopamine receptors in brain tissue is greater than that of any other known drug. It is a highly specific D-1 dopamine (non-cyclase linked) receptor agent with K, values of 0.1-0.5 for D-2 inhibition and 300 nM for D-1 inhibition.
  • Sodium ions are important regulators of dopamine receptors.
  • the affinity of the D-2 receptor is markedly enhanced by the presence of millimolar concentrations of sodium chloride.
  • the Kd in the absence and presence of 120 mM sodium chloride is 1.2 and 0.086 nM respectively.
  • Sodium chloride (120 mM) is included in all assays as a standard condition.
  • the caudate nucleus (corpus striatum) is used as the receptor source because it contains the highest density of dopamine receptors in the brain and periphery.
  • Tissue can be stored indefinitely at -70°C.
  • caudate is homogenized in 30 ml of tris buffer (pH 7.7 at 25°C) using the polytron homogenizer. The homogenate is centrifuged at 40,000 g (18,000-19,000 RPM in SS-34 rotor) for 15 minutes. Pellet is resuspended in fresh buffer and centrifuged again. The final pellet is resuspended in 150 volumes of assay buffer.
  • Specific 3 H-spiroperidol binding is assayed in a total 2 ml reaction volume consisting of 500 ⁇ l of caudate homogenate, 50 mM tris buffer (pH 7.4 at
  • TRIS TRIS (pH 7.7 at 25°C) and filtration through GF/B glass fiber filters on a Brandel Receptor Binding Filtration apparatus. Filters are washed twice with an additional 5 ml of tris buffer each. Assay groups are performed in triplicate and 1 ⁇ M d(+) butaclamol is used to determine nonspecific binding. Filters are placed in vials containing 10 ml of Ecoscint phosphor, shaken for 30 minutes and dpm determined by liquid scintillation spectrophotometry using a quench curve. Proteins are determined by the method of Bradford, M. Anal. Biochem 72, 248(1976) using Bio- Rad's coomassie blue G-250 dye reagent. Bovine gamma globulin supplied by BIO-RAD is used as the protein standard.
  • the jugular vein is cannulated for intravenous (i.v.) injection of drugs.
  • the results of these above tests indicate that the compounds for this invention exhibit a valuable balance between the peripheral and central action of the nervous system and may be useful in the treatment of disorders related to impaired gastro-intestinal motilitv such as gastric emptying, dyspepsia, flatulence, esophogeal reflux and peptic ulcer and in the treatment of disorders of the central nervous system such as psychosis.
  • the compounds of the present invention can be administered to a mammalian host in a variety of forms adapted to the chosen route of administration, i.e., orally, or parenterally.
  • Parenteral administration in this respect includes administration by the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transepthelially including transdermal, opthalmic, sublingual and buccal; topically including opthalmic, dermal, ocular, rectal and nasal inhalation via insufflation and aerosol and rectal systemic.
  • the active compound may..be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet.
  • the active compound may be incorporated with excipient and used in the form of ingestibel tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preprations should contain at least 0.1% of active compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 6% of the weight of the unit.
  • the amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.
  • preparations according to the present invention are prepared so that an oral dosage unit form contains between about 50 and 300 mg cf active compound.
  • the tablets, troches, pills, capsules and the like may also contain the following: A binder such as gum tragacanth, acacia, corn starch or gelating; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, lginic acid and the like; a lubricant such as
  • magnesium stearate magnesium stearate
  • a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of
  • the dosage unit form When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both.
  • a syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and formulations.
  • the active compound may also be administered parenterally or intraperiotoneally.
  • Solutions of the active compound as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactanc such as hydroxypropyl- cellulose. Dispersion can also be prepared in
  • glycerol liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It may be stable under the conditions of manufacture and storage and must be preserved against the
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimersal, and the like. In many cases. it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions of agent delaying absorption, for example, aluminum
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vaccum drying and the freeze drying technique which yield a powder of the active ingredient plus any additional desired ingredient from previously sterile-filtered solution thereof.
  • the therapeutic compounds of this invention may be administered to a mammal alone or in combination with pharmaceutically acceptable carriers, as noted above, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice.
  • the physician will determine the dosage of the present therapeutic agents which will be most suitable for prophylaxis or treatment and will vary with the form of administration and the particular compound chosen, and also, it will vary with the particular patient under treatment. He will
  • the therapeutic dosage will generally be from 0.1 to 20 mg or from about 0.01 mg to about 50 mg/kg of body weight per day and higher although it may be administered in several different dosage units from once to several times a day. Higher dosages are required for oral administration.
  • the compounds of the present invention may be prepared by the following representative examples .
  • Methyl 2-(cyclohexen-3-yloxy)-5-chlorobenzonate (4.5 g) is heated to 210°C for 3 hours. The residue is dissolved in hexane and purified by flash
  • reaction mixture is diluted with 100 ml chloroform and the organic layer separated, washed twice with water, dried over magnesium sulfate and evaporated to dryness to give 1.2 g of oily product.
  • the latter is purified by flash chromatography using 10%
  • Example 1 with salicylic acid, 5-bromosalicylic acid or 5-methylsulfonylsalicylic acid then the products prepared following the procedures of Examples 1-6 are 5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(N-1-azabicylo[2.2.2.]oct-3-yl)carboxamide; 2-bromo-5a,6,7,8, 9,9a-hexahydrodibenzofuran-4-(N-1-azabicyclo[2.2.2.]- oct-3-yl)carboxamide; and 2-methylsulfonyl-5a,6,7,8, 9,9a-hexahydrodibenzofuran-4-(N-1-azabicyclo[2.2.2.]- oct-3-yl)carboxamide.
  • the methanol is removed in vacuum, diluted with water, filtered, acidified with acetic acid, filtered, extracted with ethyl acetate, washed with water, dried over magnesium sulfate and evaporated to dryness to obtain 1-amino-2-chloro- 5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acid. This is purified by crystallization from ethyl acetate/ether.
  • Example 8 When 2-methoxy-4-amino-5-chlorobenzoic acid is replaced in Example 8 with 2-methoxy-4-aminobenzoic acid; 2-methoxy-4-methylamino-5-chlorobenzoic acid; 2-methoxy-5-sulfamylbenzoic acid; or 2-methoxy-5- methylsulfamyl benzoic acid then the products prepared following the procedures of Examples 8-16 are 1-amino-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(N- 1-azabicylo[2.2.2.]oct-3-yl)carboxamide; 1-methylamino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4- (N-1-azabicyclo[2.2.2.]oct-3-yl)carboxamide;
  • Example 29 The oil from Example 29 in 1600 ml of methanol is cooled in an ice bath and 120 g of KBH4 is added in small portions with stirring while keeping the temperature between 10-20°C. After addition is complete the temperature is allowed to rise. Most of the solvent is removed and the mixture is filtered, slurried in acetone twice and filtered. The original filtrate and acetone washes are combined and evaporated to one-half the original volume, filtered through a bed of celite and evaporated to dryness. The dark amber oil is filtered through a bed of celite to obtain a clear amber oil. This is dissolved in 200 ml of 2-propanol and a solution of 500 ml isopropanol and 559 g of concentrated HCl added in small portions. The temperature is held between
  • the resolved acid salt (88.1 g) is treated with 250 ml of 1 N HCl.
  • the resultant suspension is extracted with methylene chloride (250 ml) which is washed with 1 N HCl
  • chloroform is heated to 35°C. To this is added 47 g of thionyl chloride keeping the temperature between 38 and 42°C. This is allowed to stir for two hours at 42°C. The solvent is removed under vacuum.
  • the acid chloride prepared above dissolved in 100 ml toluene is added drop wise to the S-3-aminoquinuclidine in toluene keeping everything under nitrogen.
  • reaction mixture is held at about 20-25°C during the addition. After addition the mixture is heated to 40°c and 200 ml toluene added. The reaction is allowed to stand at room temperature overnight after which time 1 N methanolic NaOH is added until basic. This is then washed with 3 x 500 ml water to a pH 7, dried over magnesium sulfate and evaporated to dryness at 5 mm vacuum and 70°C to obtain 2-chloro-cis-5aS,6,7,8,9,9aS-hexahydrodibenzofuran-4-[N-(1- azabicyclo[2.2.2.]octan-3(S)-yl)carboxamide. (M.P. 256°C)

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Abstract

Cette invention se rapporte à certains dibenzofurancarboxamides et concerne leur utilisation comme antagonistes 5HT3 possédant un CNS unique, une activité procinétique gastrique et anti-émetique ne possédant aucune propriété significative de liaison de récepteur D2. Cette invention décrit également de nouveaux procédés nécessaires pour réaliser leur préparation.
EP19900905138 1989-09-27 1989-09-27 Dibenzofurancarboxamides Withdrawn EP0494140A4 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1989/004221 WO1991004738A1 (fr) 1989-09-27 1989-09-27 Dibenzofurancarboxamides

Publications (2)

Publication Number Publication Date
EP0494140A1 true EP0494140A1 (fr) 1992-07-15
EP0494140A4 EP0494140A4 (en) 1992-09-02

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Country Status (5)

Country Link
EP (1) EP0494140A4 (fr)
DK (1) DK40292A (fr)
FI (1) FI921332A (fr)
NO (1) NO921191L (fr)
WO (1) WO1991004738A1 (fr)

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Publication number Priority date Publication date Assignee Title
US5710274A (en) * 1996-02-28 1998-01-20 Neurogen Corporation N-aminoalkyldibenzofurancarboxamides; new dopamine receptor subtype specific ligands
CN116535379B (zh) * 2023-06-29 2023-09-19 希格生科（深圳）有限公司 化合物及其医药用途

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EP0220339A1 (fr) * 1978-12-30 1987-05-06 Beecham Group Plc Dérivés d'azabicycloalkyl
EP0339950A2 (fr) * 1988-04-27 1989-11-02 Rhone-Poulenc Rorer International (Holdings) Inc. Dibenzofurancarboxamides, leur utilisation comme agents pharmaceutiques, composition les contenant et procédé de préparation

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US4612319A (en) * 1982-04-14 1986-09-16 Beecham Group P.L.C. Bridged quinolizidinylbenzamides, compositions containing them and methods for their use

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Publication number Priority date Publication date Assignee Title
EP0220339A1 (fr) * 1978-12-30 1987-05-06 Beecham Group Plc Dérivés d'azabicycloalkyl
EP0339950A2 (fr) * 1988-04-27 1989-11-02 Rhone-Poulenc Rorer International (Holdings) Inc. Dibenzofurancarboxamides, leur utilisation comme agents pharmaceutiques, composition les contenant et procédé de préparation
WO1989010364A1 (fr) * 1988-04-27 1989-11-02 Rorer International (Overseas) Inc. Dibenzofurancarboxamides

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Title
See also references of WO9104738A1 *

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FI921332A0 (fi) 1992-03-26
WO1991004738A1 (fr) 1991-04-18
EP0494140A4 (en) 1992-09-02
DK40292D0 (da) 1992-03-26
FI921332A (fi) 1992-03-26
DK40292A (da) 1992-05-26
NO921191D0 (no) 1992-03-26
NO921191L (no) 1992-03-26

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