EP0625981A1 - Composes azabicyclo servant d'antagonistes des canaux calciques - Google Patents

Composes azabicyclo servant d'antagonistes des canaux calciques

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Publication number
EP0625981A1
EP0625981A1 EP93902470A EP93902470A EP0625981A1 EP 0625981 A1 EP0625981 A1 EP 0625981A1 EP 93902470 A EP93902470 A EP 93902470A EP 93902470 A EP93902470 A EP 93902470A EP 0625981 A1 EP0625981 A1 EP 0625981A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
azabicyclo
compounds
reaction
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Withdrawn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
EP93902470A
Other languages
German (de)
English (en)
Inventor
Barry Sidney Smithkline Beecham Orlek
Thomas Henry Smithkline Beecham Brown
David Gwyn Smithkline Beecham Cooper
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.)
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Ltd
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Filing date
Publication date
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP0625981A1 publication Critical patent/EP0625981A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to novel azabicyclic derivatives, processes for their
  • compositions containing them preparation, pharmaceutical compositions containing them and their use in therapy, in particular as calcium channel antagonists.
  • German OLS 41 16582 describes azabicyclic compounds of the formula
  • A, B and C independently represent -CH2- or a single bond; n is zero, 1 or 2; X is oxygen or sulphur and R is inter alia phenylalkyl. diphenylalkyl, heterocyclicalkyl, phenyl,
  • the present invention provides, a compound of formula (I):
  • R! is hydrogen, C ⁇ _galkyl or phenylC ⁇ alkyl
  • Ar is aryl or heteroaryl, each of which may be optionally substituted
  • p and r are preferably 2 or 3.
  • q is preferably 1 or 2.
  • n, m and A should be chosen such that the length of the chain -(CH2) n A(CH2) is at least two atoms.
  • the length of the chain -(CH2) n A(CH2) m is from 2 to 6 e.g. 2 to 5 atoms.
  • Preferred values for n and m depend on the group A. Thus for example, when A is oxygen the sum of n+m is from 1 to 5, for example n may be zero, 1 or 2 and m may be zero or 1 to 5.
  • A is preferably oxygen or a bond, most preferably oxygen.
  • suitable groups include, for example, unsaturated monocyclic and unsaturated or partially saturated bicyclic or tricyclic ring systems of up to 15 carbon atoms, such as, for example, phenyl, naphthyl, tetrahydronaphthyl, fluorene, fluorenone, dibenzosuberene and dibenzosuberenone .
  • Preferred are optionally substituted phenyl rings.
  • An aryl group may be substituted, for example, by a C ] __2alkylenedioxy group (e.g. phenyl substituted by a 3,4-methylenedioxy group) or by 1 to 3 substituents selected from halogen, C ⁇ alkoxy, nitro, SC ⁇ alkyl, NR 2a R 2b (in which R 2a and R 2b can be independently H or C ⁇ 4alkyl), OCF3, C ⁇ galkyl, trifluoromethyl, CN, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted phenylC ⁇ _4-alkyl and optionally substituted phenylC ⁇ _4alkoxy.
  • a C ] __2alkylenedioxy group e.g. phenyl substituted by a 3,4-methylenedioxy group
  • 1 to 3 substituents selected from halogen, C ⁇ alkoxy, nitro, SC ⁇ alkyl, NR 2a R 2
  • Suitable optionally substituted phenylC ⁇ _4alkyl groups include, for example benzyl.
  • Suitable optionally substituted phenylC ⁇ _4alkoxy groups include, for example benzyloxy groups.
  • Suitable substituents for said optionally substituted phenyl, phenoxy, phenylCj.4alkyl and phenylCj_4alkoxy groups include for example halogen, Cj ⁇ alkyl, C ⁇ alkoxy, nitro and trifluoromethyl groups.
  • the aryl group Ar is a phenyl ring substituted by one or two substituents, in particular, by a phenyl, phenyl (C ⁇ _4)alkyl e.g. benzyl, phenoxy or phenylCj_4alkoxy, e.g. benzyloxy group; or by two chloro atoms especially in the 3- and 4-positions of the phenyl ring.
  • suitable groups include, for example, unsaturated or partially saturated bicyclic and tricyclic ring systems containing at least one heteroatom.
  • a bicyclic ring system preferably contains 8 to 10 ring members, such as quinolinyl, tetrahydroquinolinyl or benzofuranyl.
  • a tricyclic ring system preferably contains from 11 to 15 ring members, and most preferably has the structure :
  • Y 1 represents Y(CH2)t
  • Y is O, S or NR3 (where R ⁇ is hydrogen or C ⁇ alkyl)
  • s is 0, 1 or 2
  • t is 0 or 1 or is a corresponding dehydro ring system.
  • tricyclic heteroaryl groups include dibenzofuranyl, dibenzothienyl, carbazole, N-methylcarbazole, acridine and dibenzoxepine .
  • the heteroaryl ring can be linked to the remainder of formula (I) via any suitable ring atom.
  • Suitable substituents for said heteroaryl rings include, for example, 1 to 3 substituents selected from halogen, trifluoromethyl, Cj ⁇ alkyl, C ⁇ alkoxy, phenyl, phenylCj ⁇ alkyl, and phenylC ⁇ _4alkoxy .
  • Alkyl groups present in the compounds of formula (I), alone or as part of another group, can be straight or branched.
  • a C ⁇ _4alkyl group may be for example methyl, ethyl, n-propyl, n-butyl or any branched isomer thereof such as isopropyl or t-butyl.
  • a salt of a compound (I) should be pharmaceutically acceptable.
  • pharmaceutically acceptable salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, methanesulphonate or similar pharmaceutically acceptable inorganic or organic acid addition salts.
  • Other non- pharmaceutically acceptable salts may be used for example in the isolation of the final product and are included within the scope of this invention.
  • Particular compounds of the invention include:
  • certain compounds of formula (I) may contain one or more asymmetric centres, for example where p, q and r all have different values.
  • Such compounds will exist as optical isomers (enantiomers). Both the pure enantiomers, racemic mixtures (50% of each enantiomer) and unequal mixtures of the two are included within the scope of the invention. Further, all diastereomeric forms possible (pure enantiomers and mixtures thereof) are within the scope of the invention.
  • a represents -CH CH- the compounds will exist as geometric isomers, and the invention encompasses all such isomers and mixtures thereof.
  • the compounds of the present invention can be prepared by processes analogous to those known in the art.
  • the present invention therefore provides in a further aspect, a process for the preparation of a compound of formula (I) which comprises:
  • reaction between a compound of formula (II) and a compound L(CH2) m Ar can take place under conditions which depend on the nature of the group L and the value of m.
  • L is halogen or a sulphonic acid residue such as a tosylate or mesylate and m is other than zero
  • the reaction is carried out under standard conditions in a solvent, optionally in the presence of a base.
  • a fluoro-substituted aryl compound F-Ar is employed in process (a), (to prepare compounds where m is zero) the reaction is effected in the presence of a strong base such as sodium hydride, and in an inert organic solvent such as dimethylformamide.
  • the aryl group is substituted by an activating group such as CF3 or NO2.
  • an activating group such as CF3 or NO2.
  • the azabicyclic nitrogen atom may be protected during the reaction by methods well known in the art, e.g. by prior formation of a quaternary derivative such as an N-benzyl derivative. Protection may also be effected by formation of a borane (BH3) complex.
  • the N- protecting group should be chosen such that it can be removed without affecting other moieties in the molecule.
  • a benzyl protecting group may not be appropriate when the side chain (CH2) n A(CH2) m Ar also contains a benzyl moiety such as a benzyloxy group.
  • N-protection is preferred when the leaving group L represents halogen, e.g. bromine, but when L is a sulphonic acid residue e.g. a tosylate, N- protection may not be necessary.
  • HA 1 (CH2) m Ar can take place under conditions which depend on the nature of L 1 and A.
  • L is hydroxy
  • m is 0
  • a 1 is oxygen or sulphur
  • the reaction is carried out in the presence of diethyl azodicarboxylate and triphenyl phosphine.
  • the leaving group L 1 may be for example a halogen atom or a sulphonyloxy group eg. methane-sulphonyloxy or p-toluene sulphonyloxy in which case the compound (III) may preferably be protected, e.g. as an acid salt such as a hydrochloride salt.
  • Reaction may be effected in the presence or absence of solvent, at a temperature in the range 0 to 200°C, and may preferably be carried out in the presence of a base.
  • a compound of formula (IV) can be effected by methods known in the art, for example using a reducing agent such as lithium aluminium hydride.
  • a compound of formula (IV) can be prepared (for example as described below) and reduced in a 'one-pot' reaction, without isolation of compound (IV) itself.
  • reaction between a compound of formula (V) and a compound of formula X Ar in process (d) can take place under standard conditions known to those skilled in the art for the formation of carbon-carbon bonds.
  • Process (e) may be effected using a Wadsworth-Emmons reagent for example of the formula Ar(CH2) m + ⁇ P(O)(OAlk)2, such as a diethylphosphonate, or a Wittig reagent of the formula Ar(CH2) m --- ⁇ -iPPh3X (where X is an anion) which compounds are available commercially or can be prepared by known methods.
  • the reaction may be carried out in a solvent such as tetrahydrofuran, optionally containing a crown ether such as 15-crown-5, or 18-crown-6, and in the presence of a strong base such as sodium hydride, or potassium t-butoxide.
  • Interconversion reactions according to process (f) may be effected by methods well known in the art.
  • Esters wherein n is greater than 1 may be prepared by conversion of an ester wherein n is 1 to the corresponding N-methyl-N-methoxycarboxamide (e.g. by hydrolysis of the ester followed by reaction with thionyl chloride and N,O-dimethylhydroxylamine hydrochloride), which is then reduced to the aldehyde using diisobutylaluminium hydride.
  • the aldehyde is further converted to the cyanomethyl derivative for example as described in EPA 363085, followed by acid hydrolysis, and esterification to form an ester wherein n is 2.
  • the sequence may be repeated to form higher homologues.
  • compounds of formula (II) may be prepared by reaction of an aldehyde of formula (VI) with triethylphosphonoacetate or triethylphosphonocrotonate, followed by catalytic hydrogenation to give an ethoxycarbonylalkyl derivative which is further reduce e.g. using lithium aluminium hydride, to the desired hydroxyalkyl compound.
  • triethylphosphonoacetate results in a 2-carbon homologation whils triethylphosphonocrotonate gives a 4-carbon homologation.
  • l-benzyl-4-piperidone may be converted to the 4-hydroxy-4- hydroxymethyl compound by the method described in EPA 188255, via corresponding cyano and ester derivatives.
  • a compound of formula (II) wherein n is zero, and p, q and r are each 2 may be prepared by the method of CA. Grob and P. Brenneisen (Helv. Chim.
  • the compounds of formula L(CH2) m Ar and HA 1 (CH2) m Ar may be prepared by standard methods well known in the art.
  • compounds L(CH2) m Ar wherein Ar is a substituted phenyl group and L is halo, e.g. bromo may be prepared by Friedel-Crafts acylation of the corresponding substituted benzene derivative, using an appropriate acid _ chloride and catalysed by aluminium trichloride, followed by reduction in situ with triethylsilane.
  • Ar represents a phenyl group substitued by benzyloxy compounds L(CH2) m Ar may be prepared according to the following scheme :
  • -(CH2) n N(R 1 )C(O)(CH2) rn -iAr can be prepared by reacting a compound of formula (II) wherein A 1 represents NR 1 with an acylating agent corresponding to the group - (CH2) m Ar, for example an acid chloride ClOC(CH2) m -i Ar.
  • -(CH2) n -lC(O)N(R )(CH2) m Ar may be prepared for example by reaction of a corresponding compound wherein R 4 represents -(CH2) n -iCO2-H or an activated derivative thereof such as an acid halide, ester or anhydride, with an amine of formula HN(R 1 )(CH2) m Ar. It will be appreciated that when the acid itself is employed, reaction with the amine should be effected in the presence of a coupling agent.
  • the carboxylic acid may itself be prepared for example by oxidation of the corresponding alcohol, ie. a compound of formula (II) wherein A 1 is oxygen.
  • Compounds of formula (VI) may be prepared by conventional methods, for example the oxidation of a compound of formula (II) wherein A 1 is oxygen, or conversion of the corresponding ester, e.g. via the corresponding N-methyl-N-methoxycarboxamide and reduction with diisobutylaluminium hydride, as described hereinabove.
  • Compounds of _ formula (VI) wherein n is 1 may be prepared from the corresponding compound wherein n is zero by various methods. For example the aldehyde wherein n is zero may be treated with (methoxymethyl) triphenylphosphonium chloride and potassium t-butoxide, followed by a strong acid, e.g.
  • aldehyde wherein n is 1.
  • the aldehyde may be converted to the corresponding cyanomethyl derivative as described in EPA 363085 followed by acid hydrolysis, conversion to the N-methyl- N-methoxycarboxamide and reduction. These procedures may also be used to form higher homologues.
  • a compound of formula (I) When a compound of formula (I) is obtained as a mixture of enantiomers, these may be separated by conventional methods such as crystallisation in the presence of a resolving agent, or chromatography, for example using a chiral HPLC column.
  • the compounds of the invention have been found to exhibit high calcium influx blocking activity for example in neuronal cells.
  • the compounds are expected to be of use in therapy in treating conditions and diseases related to an accumulation of calcium in the brain cells of mammals, in particular humans.
  • the compounds are expected to be of use in the treatment of anoxia, ischaemia including for example stroke, migraine, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory disorders, and drug addiction withdrawal such as ethanol addiction withdrawal.
  • a method of treatment of conditions or diseases related to (e.g. caused or exacerbated by) the accumulation of calcium in the brain cells of mammals (e.g. humans) which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treatment of anoxia, ischaemia including for example stroke, migraine, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory disorders, and drug addiction withdrawal such as ethanol addiction withdrawal, which comprises administering to a subject in need thereof, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition or a disease related to (e.g. caused or exacerbated by) the accumulation of calcium in the brain cells of a mammal (e.g. a human).
  • a mammal e.g. a human
  • the compounds of the present invention are usually administered in a standard pharmaceutical composition.
  • the present invention therefore provides in a further aspect pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
  • the compounds of the invention may be administered by any convenient method, for example by oral, parenteral, buccal, rectal or transde ⁇ nal administration, and the pharmaceutical compositions adapted accordingly.
  • the compounds of formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical carrier(s) include magnesium stearate, starch, lactose, sucrose and cellulose.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures.
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • Compounds of the invention may also be administered parenterally, by bolus injection or continuous infusion.
  • Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • Both liquid and solid compositions may contain other excipients known in the pharmaceutical an, such as cyclodextrins.
  • composition is in unit dose form such as a tablet, capsule or ampoule.
  • Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 0.1 to 60 mg) of a compound of the formu a ' J) or a pharmaceutically acceptable salt thereof calculated as the free base.
  • the compounds of the invention may be administered by continuous intravenous infusion, preferably at a dose of up to 400 mg per day.
  • the total daily dosage by oral administration will be in the range 1 to 2000 mg and the total daily dosage by parenteral administration will be in the range 0.1 to 400 mg.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more.
  • the pipette (internal solution) contained in mM: CsCl, 130; HEPES, 10; EGTA, 10; MgCL 2 , 4; ATP, 2; buffered to pH 7.2 with CsOH.
  • Cells were bathed in a normal Tyrodes solution before establishment of whole cell recording when the bathing solution was changed to one allowing isolation of Ca 2+ currents.
  • the external solution for recording Ca 2+ channel currents contained in mM: BaCL 2 , 10; TEA-C1, 130; glucose, 10; HEPES, 10; MgCL 2 , 1; buffered to pH 7.3 with TEA-OH. Barium was used as the charge carrier as this assists in current isolation and calcium dependent inactivation of current is avoided.
  • Peak voltage gated Ca 2+ channel currents of up to 10 nA from dorsal root ganglion neurons were recorded using 10 mM Ba + as charge carrier. Currents were evoked from a holding potential of -80 mV to a test potential of 0 or +10 mV every 15 seconds. This test potential was at the peak of the current voltage relationship and assessing block at this point reduced any errors due to drifting holding potential. Some cells showed slow rundown of current as is commonly seen when recording Ca + currents. The rundown rate was measured in control conditions and extrapolated through the time of drug application to derive a control value to relate the drug affected current to. Block by 20 ⁇ M drug was assessed 3 minutes after drug application.
  • a tonicity adjusting agent eg. sodium chloride, dextrose or mannitol may also be added.
  • the title compound was prepared in a similar manner to Preparation 2 from methyl 1- azabicyclo[2.2.1]hept-4-yl carboxylate (B.S. Orlek et al., J. Med. Chem., 1991, 34, 2726) (3.13g, 20.2 mmol) and lithium aluminium hydride (1.92g, 50.6 mmol). This afforded the title compound as a colourless solid (1.76g, 69%) b.p. 250°C, 0.3 mmHg (Kugelrohr).
  • the title compound was prepared in a similar manner to Preparation 11 from 5- bromovaleryl chloride (13.39 ml, 0.1 mol), aluminum chloride (13.33g, 0.1 mol), diphenyl ether (25.5g, 0.15mol) and triethylsilane (48 ml, 0.3 mol). This afforded the title compound as a clear oil (17.56g, 55%) b.p. 165-180°C at 0.2 mm Hg.
  • the title compound was prepared in a similar manner to Example 1 from 4-(2- hydroxyethyl)-l-azabicyclo[2.2.1] heptane (0.5g, 3.55mmol), 4 ⁇ benzyloxyphenol (1.06g, 5.32mmol), triphenylphosphine (1.21g, 4.61mmol) and diethyl azodicarboxylate (0.80g, 4.61mmol). This afforded the title compound as a white solid (0.24g), m.p. 209-212°C (from methanol-diethyl ether.
  • the title compound was prepared in a similar manner to Example 1 from ( ⁇ )5- hydroxymethyl-l-azabicyclo[3.2.1]octane (0.5g, 3.55mmol), 4-hydroxydiphenylmethane (0.98g, 5.32mmol), triphenylphosphine (1.21g, 4.61mmol) and diethyl azodicarboxylate (0.80g, 4.61mmol). This afforded the title compound as a white solid (0.15g), m.p. 168°C (dec) (from methanol -ether).
  • the title compound was prepared in a similar manner to Example 1 from ( ⁇ )5- hydroxymethyl-l-azabicyclo[3.2.1]octane (0.53g, 3.76mmol), 2-hydroxydibenzofuran (1.04g, 5.64mmol) triphenylphosphine (1.28g, 4.89mmol) and diethyl azodicarboxylate (0.85g, 4.89mmol).
  • the crude product was chromatographed on neutral alumina in a gradient of 0.5-2% methanol in toluene. Pooling of fractions containing the faster running component and conversion of the resulting gum into the hydrochloride salt afforded the title compound as a white solid (0.98g), m.p. 224-225 C (from methanol-acetone-diethyl ether).
  • the title compound was prepared in a similar manner to Example 1 from ( ⁇ ) 5-(2- hydroxyethyl)-l-azabicyclo[3.2.1]octane (0.53g, 3.42 mmol), 2-hydroxydibenzofuran (0.95g, 5.13 mmol), triphenylphosphine (1.17g, 4.45 mmol) and diethyl azodicarboxylate (0.54ml, 3.42 mmol) employing a reaction time of 2h.
  • the crude product was purified by chromatography on neutral alumina using 0.5-2% methanol in toluene as eluant, and converted into the hydrochloride salt to give the title compound as a coulourless solid (0.7g), m.p. 137-138°C (from methanol-acetone-diethyl ether).
  • the title compound was prepared in a similar manner to Example 1 from 4-(2- hydroxyethyl)-l-azabicyclo[2.2.1]heptane (0.62g, 4.4 mmol), 4-phenoxyphenol (1.23g, 6.61 mmol), triphenylphosphine (1.5g, 5.72 mmol) and diethyl azodicarboxylate (0.9 ml, 5.72 mmol).
  • the reaction mixture was concentrated in vacuo, and the residue was converted into the hydrochloride salt with ethereal hydrogen chloride. After trituration with ether, the salt was treated with saturated aqueous potassium carbonate (20 ml) and extracted into chloroform (3x25 ml).
  • the reaction was quenched with glacial acetic acid (0.5ml) and then concentrated in vacuo. After co-evaporation with successive portions of toluene, the residue was disolved in ethanol (10 ml) and hydrogenated at atmospheric pressure over 10% Pd-C (O.lg) for 2h. The reaction mixture was filtered through a pad of kieselguhr and the filtrate was concentrated in vacuo. The residue was treated with saturated aqueous potassium carbonate (20 ml) and extracted into chloroform (3x20ml). The combined extracts were dried over sodium sulphate and concentrated in vacuo.
  • the crude product was purified by flash chromatography on neutral alumina using 0-15% methanol in chloroform as eluant After pooling pure fractions the product was treated with ethereal hydrogen chloride to give the title compound as a colourless solid (0.14g), m.p. 129-131°C (from acetone- diethyl ether).
  • the title compound was prepared in a similar manner to Example 1 from 4- hydroxymed ⁇ yl-l-azabicyclo[2.2.1]heptane (0.5g, 3.94 mmol), 4-benzyloxyphenol (1.18g, 5.91 mmol), triphenylphosphine (1.55g, 5.91 mmol) anddietiiyl azodicarboxylate (0.93ml, 5.91 mmol). After a reaction period of 5h the mixture was worked up as previously described for Example 1. Purification on neutral alumina using 5% ethanol in chloroform as eluant afforded a pale yellow oil which was treated with ethereal hydrogen chloride to give the title compound as a colourless solid (0.09g), m.p. 206-208°C (from methanol- acetone-diediyl ether).
  • the title compound was prepared in a similar manner to Example 10 from 1 -benzyl- 1- azoniabicyclo[2.2.1]heptan-4-ol p-toluenesuphonate (0.5g, 1.33 mmol), sodium hydride (80 mg of an 80% dispersion in mineral oil, 2.66 mmol) and 4-(4-phenoxyphenyl)butyl bromide (0.89g, 2.91 mmol).
  • the crude product was purified by chromatography on silic using 5-10% ethanol in chloroform as eluant, and treated with ethereal hydrogen chloride to give the title compound as a colourless solid m.p. 115-117.5°C (from acetone-diethyl ether).

Abstract

Composés répondant à la formule (I), dans laquelle p, q et r, indépendamment les uns des autres, représentent un nombre entier compris entre 1 et 4; n est compris entre 0 et 6; m est compris entre 0 et 6; A représente une liaison, -CH=CH-, -C=C-, oxygène, soufre ou NR1; R1 représente hydrogène, alkyle C1-8 ou phénylalkyleC1-4; et Ar représente aryle ou hétéroaryle, dont chacun est éventuellement substitué; et leurs sels. Ils sont utilisables en médecine, notamment comme antagonistes des canaux calciques. On a également prévu un procédé de préparation des composés de la formule (I), et des compositions pharmaceutiques les contenant.
EP93902470A 1992-01-28 1993-01-27 Composes azabicyclo servant d'antagonistes des canaux calciques Withdrawn EP0625981A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9201751 1992-01-28
GB929201751A GB9201751D0 (en) 1992-01-28 1992-01-28 Compounds
PCT/GB1993/000174 WO1993015080A1 (fr) 1992-01-28 1993-01-27 Composes azabicyclo servant d'antagonistes des canaux calciques

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EP0625981A1 true EP0625981A1 (fr) 1994-11-30

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JP (1) JPH07503462A (fr)
KR (1) KR950700305A (fr)
AU (1) AU3364593A (fr)
CA (1) CA2128536A1 (fr)
GB (1) GB9201751D0 (fr)
MX (1) MX9300406A (fr)
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ZA (1) ZA93549B (fr)

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GB9314973D0 (en) * 1993-07-20 1993-09-01 Smithkline Beecham Plc Medicaments
UY25225A1 (es) 1997-10-29 2000-12-29 Smithkline Beecham Plc Derivados de pleuromutilina utiles como agentes antimicrobianos
AU1600599A (en) 1998-02-27 1999-09-15 Warner-Lambert Company Heterocyclic substituted aniline calcium channel blockers
US6166052A (en) * 1998-03-11 2000-12-26 Warner-Lambert Company Heteroaryl alkyl alpha substituted peptidylamine calcium channel blockers
PL362989A1 (en) 2000-12-22 2004-11-15 Almirall Prodesfarma Ag Quinuclidine carbamate derivatives and their use as m3 antagonists
ES2203327B1 (es) 2002-06-21 2005-06-16 Almirall Prodesfarma, S.A. Nuevos carbamatos de quinuclidina y composiciones farmaceuticas que los contienen.
ES2204295B1 (es) 2002-07-02 2005-08-01 Almirall Prodesfarma, S.A. Nuevos derivados de quinuclidina-amida.
ES2362326T3 (es) 2007-10-01 2011-07-01 Comentis, Inc. Derivados de 1h-indol-3-carboxilato de quinuclidin-4-ilmetilo como ligandos del receptor nicotínico alfa 7 de la acetilcolina para el tratamiento de enfermedad de alzheimer.
WO2016007630A1 (fr) 2014-07-11 2016-01-14 Alpharmagen, Llc Composés de quinuclidine pour moduler l'activité du récepteur nicotinique alpha7 de l'acétylcholine

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GB9201751D0 (en) 1992-03-11
JPH07503462A (ja) 1995-04-13
WO1993015080A1 (fr) 1993-08-05
CA2128536A1 (fr) 1993-08-05
ZA93549B (en) 1994-09-22
KR950700305A (ko) 1995-01-16
AU3364593A (en) 1993-09-01
MX9300406A (es) 1994-07-29

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