WO1991001316A1 - Nouveau derive de 9-azabicyclo[3.3.1] nonane - Google Patents

Nouveau derive de 9-azabicyclo[3.3.1] nonane Download PDF

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Publication number
WO1991001316A1
WO1991001316A1 PCT/GB1990/001110 GB9001110W WO9101316A1 WO 1991001316 A1 WO1991001316 A1 WO 1991001316A1 GB 9001110 W GB9001110 W GB 9001110W WO 9101316 A1 WO9101316 A1 WO 9101316A1
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WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
formula
methyl
compound according
Prior art date
Application number
PCT/GB1990/001110
Other languages
English (en)
Inventor
Helen Elizabeth Marr
Rodney Eric Haddock
Thomas Weir Ramsay
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 WO1991001316A1 publication Critical patent/WO1991001316A1/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
    • C07D451/14—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

Definitions

  • the invention relates to compounds having pharmacological activity, to a process for their preparation and their use as pharmaceuticals.
  • EP-A-200444 (Beecham Group p.I.e.) describes a group of aryl amides and esters having an azabicyclic side chain and possessing 5-HT3 receptor antagonist activity.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • the compound of formula (I) is preferably in pharmaceutically acceptable form.
  • pharmaceutically acceptable form is meant, inter alia, of a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • a pharmaceutically acceptable level of purity will generally be at least 50% excluding normal pharmaceutical additives, preferably 75%, more preferably 90% and still more preferably 95%.
  • One preferred pharmaceutically acceptable form is the crystalline form, including such form in a pharmaceutical composition.
  • the pharmaceutically acceptable salts of the compound 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, lactic, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, ⁇ -keto glutaric, ⁇ -glycerophosphoric, and glucose-1-phosphoric acids.
  • conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric acids
  • pharmaceutically acceptable organic acids such as acetic, tartaric, lactic, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, ⁇ -keto glutaric, ⁇ -glycerophosphoric, and glucose-1-phosphoric acids.
  • the pharmaceutically acceptable salts of the compound of the formula (I) are usually acid addition salts with acids such as hydrochloric, hydrobromic, phosphoric, sulphuric, citric, tartaric, lactic and acetic acid.
  • the acid addition salt is the hydrochloride salt.
  • Pharmaceutically acceptable salts also include those formed with bases, such as alkali metal salts such as sodium or potassium, formed with the appropriate hydroxide.
  • Examples of pharmaceutically acceptable salts also include quaternary derivatives of the compound of formula (I) such as the compounds quaternised by compounds R a -Twherein R a is C ⁇ _ 6 alkyl, phenyl-C ⁇ _g alkyl or C ⁇ - ⁇ j cycloalkyl, and T is a radical corresponding to an anion of an acid.
  • R a is C ⁇ _ 6 alkyl, phenyl-C ⁇ _g alkyl or C ⁇ - ⁇ j cycloalkyl
  • T is a radical corresponding to an anion of an acid.
  • R a 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 of compound of formula (I) also include internal salts such as pharmaceutically acceptable N-oxides.
  • the compound of the formula (I) and its pharmaceutically acceptable salts, (including quaternary derivatives and N-oxides) may also form pharmaceutically acceptable solvates, such as hydrates, which are included wherever a compound of formula (I) or a salt thereof is herein referred to.
  • 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, displaceable by a nucleophile include halogen such as chloro and bromo; c l -4 alkoxy, such as CH3O and C2H5O-; PhO-; activated hydrocarbyloxy, such as Cl-Cf-O- or CI3CO-; succinimidyloxy; and imidazolyl.
  • halogen such as chloro and bromo
  • c l -4 alkoxy such as CH3O and C2H5O-
  • PhO- activated hydrocarbyloxy, such as Cl-Cf-O- or CI3CO-
  • succinimidyloxy such as Cl-Cf-O- or CI3CO-
  • imidazolyl halogen
  • Q is halogen, most preferably chloro.
  • a group Q is a halide or imidazolyl
  • the reaction is preferably carried out at non-extreme temperatures in an inert non-hydroxylic solvent, such as benzene, dichloromethane, toluene, diethyl ether, tetrahydrofuran (THF) or dimethylformamide (DMF) .
  • an acid acceptor such as an organic base, in particular a tertiary amine, such as triethylamine, trimethylamine, pyridine or picoline, some of which can also function as the solvent.
  • the acid acceptor can be inorganic, such as calcium carbonate, sodium carbonate or potassium carbonate.
  • no acid acceptor is used, as it is not necessary. Temperatures of 0-100°C, in particular 10-80°C are suitable. If a group Q is C ⁇ _4 alkoxy, phenoxy, activated hydrocarbyloxy or succinimidyloxy then the reaction is preferably carried out in an inert solvent, such as toluene or dimethylformamide. In this instance, it is preferred that the group Q is CI3CO- or succinimidyloxy and that the reaction is carried out in toluene at reflux temperature.
  • X is preferably protected hydroxy, wherein the protecting group is preferably benzyl, which is removed conventionally by hydrogen, using a suitable catalyst, such as palladium on carbon.
  • the intermediates of the formula (II) are novel and form an aspect of the invention. They may be prepared from 7-bromo-7-methoxy-lH-indazole according to the method described in the Example hereinafter, or an obvious equivalent thereto.
  • the compound of formula (I) is preferably isolated in substantially pure form.
  • compositions of the compound of this invention may be formed conventionally.
  • the acid addition salts may be formed, for example, by reaction of the base compound of formula (I) with a pharmaceutically acceptable organic or inorganic acid.
  • the compounds of the present invention are 5-HT3 receptor antagonists and it is thus believed may generally be used in the treatment or prophylaxis of emesis, migraine, cluster headaches, trigeminal neuralgia and visceral pain.
  • Compounds which are 5-HT 3 antagonists are also of potential use in the treatment of CNS disorders such as anxiety and psychosis; drug withdrawal syndrome; cardiac arrhythmia, obesity and gastrointestinal diseases, such as irritable bowel syndrome.
  • Antiemetic activity includes, in particular, that of preventing nausea and vomiting induced by cytotoxic agents used in cancer chemotherapy.
  • cytotoxic agents include cisplatin, doxorubicin and cyclophosphamide.
  • Antiemetic activity also includes that of preventing radiation induced nausea and vomiting and motion sickness.
  • 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 suitably adapted for enteral 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; 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, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or
  • Oral liquid preparations are usually in the form of aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs or 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 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.
  • 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 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 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 migraine, cluster headache, trigeminal neuralgia, visceral pain, emesis and/or anxiety 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.
  • a unit dose for a 70kg adult will normally contain 0.0005 to lOOmg for example 0.001 to 50mg, 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 10 ⁇ 7 to 5mg/kg/day, more usually 10 ⁇ 5 to 3mg/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 migraine, cluster headache, trigeminal neuralgia, visceral pain, emesis and/or anxiety.
  • Example 1 illustrates the preparation of the compound of formula (I).
  • Methyl 7-methoxy-lH-indazole-3-carboxylate (7.6g) was dissolved in methanol (100ml), 10% aqueous sodium hydroxide (40ml) added and the resulting solution warmed until hydrolysis of the ester was complete. The methanol was removed by evaporation and water was added to the aqueous residue. This solution was acidified with 5N hydrochloric acid to give a precipitate which was collected by filtration washed with water and dried under suction to give the product as a white solid.
  • the compounds were evaluated for antagonism of the von Bezold-Jarisch reflex evoked by 5-HT in the anaesthetised rat according to the following method:
  • the compound of the Example gave an ED5 0 value of 0.52 ⁇ 0.13 ⁇ g/kg (n-8) .

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composé de formule (I) et ses sels acceptables en pharmacologie, ayant une activité antagoniste du récepteur 5-HT3, procédé de préparation dudit composé et son utilisation en tant que produit pharmaceutique.
PCT/GB1990/001110 1989-07-21 1990-07-19 Nouveau derive de 9-azabicyclo[3.3.1] nonane WO1991001316A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8916682.1 1989-07-21
GB898916682A GB8916682D0 (en) 1989-07-21 1989-07-21 Pharmaceutical compounds

Publications (1)

Publication Number Publication Date
WO1991001316A1 true WO1991001316A1 (fr) 1991-02-07

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PCT/GB1990/001110 WO1991001316A1 (fr) 1989-07-21 1990-07-19 Nouveau derive de 9-azabicyclo[3.3.1] nonane

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WO (1) WO1991001316A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0491664A1 (fr) * 1990-12-18 1992-06-24 Sandoz Ltd. Antagonistes de sérotonine
WO1994001095A2 (fr) * 1992-07-03 1994-01-20 Smithkline Beecham Plc Medicaments pour le traitement de douleurs viscerales et de migraines
ES2109186A1 (es) * 1995-02-10 1998-01-01 Smithkline Beecham Plc Nuevo procedimiento para preparar granisetron.
ES2109187A1 (es) * 1995-02-10 1998-01-01 Smithkline Beecham Plc Nuevo procedimiento para preparar granisetron.
ES2124162A1 (es) * 1995-03-01 1999-01-16 Smithkline Beecham Plc Un nuevo procedimiento para preparar compuestos farmaceuticamente activos.
ES2124163A1 (es) * 1995-03-01 1999-01-16 Smithkline Beecham Plc Un nuevo procedimiento para preparar compuestos farmaceuticamente activos.
ES2125162A1 (es) * 1995-03-25 1999-02-16 Smithkline Beecham Plc Procedimiento para preparar un compuesto farmaceuticamente activo.
FR2792318A1 (fr) * 1999-04-16 2000-10-20 Synthelabo Derives d'indazole, leur preparation et leur application en therapeutique

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0189002A2 (fr) * 1984-12-20 1986-07-30 Sandoz Ag Traitement de maladies gastro-intestinales utilisant des 5-HT3 antagonistes
EP0200444A2 (fr) * 1985-04-27 1986-11-05 Beecham Group Plc Azabicyclononyl-indazole carboxamide ayant une activité antagoniste de la 5-HT

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0189002A2 (fr) * 1984-12-20 1986-07-30 Sandoz Ag Traitement de maladies gastro-intestinales utilisant des 5-HT3 antagonistes
EP0200444A2 (fr) * 1985-04-27 1986-11-05 Beecham Group Plc Azabicyclononyl-indazole carboxamide ayant une activité antagoniste de la 5-HT

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0491664A1 (fr) * 1990-12-18 1992-06-24 Sandoz Ltd. Antagonistes de sérotonine
US5272154A (en) * 1990-12-18 1993-12-21 Sandoz Ltd. 3,7 substituted indole and indazole compounds and pharmaceutical compositions containing them
US5543426A (en) * 1990-12-18 1996-08-06 Sandoz Ltd. Use of certain 3,7-disubstituted indole compounds for treating depression or cognitive disorders
WO1994001095A2 (fr) * 1992-07-03 1994-01-20 Smithkline Beecham Plc Medicaments pour le traitement de douleurs viscerales et de migraines
WO1994001095A3 (fr) * 1992-07-03 1994-04-14 Smithkline Beecham Plc Medicaments pour le traitement de douleurs viscerales et de migraines
ES2109187A1 (es) * 1995-02-10 1998-01-01 Smithkline Beecham Plc Nuevo procedimiento para preparar granisetron.
ES2109186A1 (es) * 1995-02-10 1998-01-01 Smithkline Beecham Plc Nuevo procedimiento para preparar granisetron.
ES2124162A1 (es) * 1995-03-01 1999-01-16 Smithkline Beecham Plc Un nuevo procedimiento para preparar compuestos farmaceuticamente activos.
ES2124163A1 (es) * 1995-03-01 1999-01-16 Smithkline Beecham Plc Un nuevo procedimiento para preparar compuestos farmaceuticamente activos.
ES2125162A1 (es) * 1995-03-25 1999-02-16 Smithkline Beecham Plc Procedimiento para preparar un compuesto farmaceuticamente activo.
FR2792318A1 (fr) * 1999-04-16 2000-10-20 Synthelabo Derives d'indazole, leur preparation et leur application en therapeutique
WO2000063215A2 (fr) * 1999-04-16 2000-10-26 Sanofi-Synthelabo Derives d'indazole, leur preparation et leur application en therapeutique
WO2000063215A3 (fr) * 1999-04-16 2001-02-01 Sanofi Synthelabo Derives d'indazole, leur preparation et leur application en therapeutique

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Publication number Publication date
GB8916682D0 (en) 1989-09-06

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