EP0710237A1 - Quinolizidines with calcium channel antagonistic activity - Google Patents

Quinolizidines with calcium channel antagonistic activity

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Publication number
EP0710237A1
EP0710237A1 EP94923730A EP94923730A EP0710237A1 EP 0710237 A1 EP0710237 A1 EP 0710237A1 EP 94923730 A EP94923730 A EP 94923730A EP 94923730 A EP94923730 A EP 94923730A EP 0710237 A1 EP0710237 A1 EP 0710237A1
Authority
EP
European Patent Office
Prior art keywords
formula
quinolizidine
compound
mmol
bond
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.)
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Application number
EP94923730A
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German (de)
French (fr)
Inventor
Barry Sidney Smithkline Beecham Pharmaceut ORLEK
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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Publication date
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Publication of EP0710237A1 publication Critical patent/EP0710237A1/en
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/02—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing not further condensed quinolizine ring systems

Definitions

  • the present invention relates to the use of known and novel azabicyclic derivatives in therapy in particular as calcium channel antagonists, novel compounds ⁇ E SS, processes for their preparation, and pharmaceutical compositions containing them.
  • Japanese patent No. 37-4142 describes a process for preparing phenoxyalkyl-3- quinolizidines, which compounds are said to have muscle-contracting properties, particularly on the uterus.
  • US Patent No. 4,689,329 and EPA 241292 describe certain aralkyl-substituted octahydroindolizidines and their use as analgesics.
  • EPA 210883 describes substituted phenylthio- and substituted benzylthio- azabicycloheptanes as intermediates for the preparation of penem derivatives.
  • the present invention therefore provides, in a first aspect, the use of a compound of formula (I):
  • Formula (I) in which p, and q each independently represent an integer from 3 to 5; n is 0 to 6; m is 0 to 6; A is a bond, -CH CH-, -C ⁇ C-, oxygen, sulphur or NR 1 ;
  • R.1 is hydrogen, C j .galkyl orphenylCi ⁇ alkyl
  • Ar is aryl or heteroaryl, each of which may be optionally substituted; or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of disorders wherein a calcium channel antagonist is indicated.
  • H atom is shown on the bridgehead carbon atom to make clear that the (CH2) n A(CH2) m Ar chain cannot be attached at this position.
  • p and q are preferably independently 3 or 4; most preferably p and q are both 4.
  • n should be chosen such that the chain (CH2) n A(CH2) m contains at least 1, preferably 2, atoms. In general the length of the chain (CH2) n A(CH2) m contains at least 1, preferably 2, atoms. In general the length of the chain (CH2) n A(CH2) m contains at least 1, preferably 2, atoms. In general the length of the chain (CH2) n A(CH2) m contains at least 1, preferably 2, atoms. In general the length of the chain (CH2) n A(CH2) m contains at least 1, preferably 2, atoms. In general the length of the chain (CH2) n A(CH2) m contains at least 1, preferably 2, atoms. In general the length of the chain (CH2) n A(CH2) m contains at least 1, preferably 2, atoms. In general the length of the chain (CH2) n A(CH2) m contains at least 1, preferably 2, atoms. In general the length of the chain (CH2) n A(CH2) m contains at
  • n A(CH2) m is from 2 to 6 atoms.
  • Preferred values for n and m depend on the group A.
  • A oxygen the sum of n+m is preferably from 1 to 5, for example n may be 1, 2, 3, 4 or 5 and m may be 0, 1, 2 or 3.
  • A is a bond the sum of n+m should be at least 1.
  • A is preferably oxygen or a bond; most preferably A is oxygen.
  • suitable groups include, for example, unsaturated monocyclic and unsaturated or partially saturated bicyclic and 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 fipom halogen, C ⁇ .4alkoxy, nitro, SC ⁇ _4alkyl, NR a R (in which R a andR 2b can be independently H or Cj ⁇ alkyl), OCF3, Ci .galkyl, trifluoromethyl, CN, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted benzoyl, optionally substituted phenylCj_4alkyl and optionally substituted phenylC ⁇ _4alkoxy.
  • a C ⁇ _2alkylenedioxy group e.g. phenyl substituted by a 3,4-methylenedioxy group
  • Suitable optionally substituted phenylCj_4alkyl groups include, for example benzyl.
  • Suitable optionally substituted phenylCj ⁇ alkoxy groups include, for example benzyloxy groups.
  • Suitable substituents for said optionally substituted phenyl, phenoxy, benzoyl, phenylC ⁇ _4alkyl and phenylC ⁇ _4alkoxy groups include for example halogen, C ⁇ alkyl, C ⁇ _4alkoxy, nitro and trifluoromethyl groups.
  • the aryl group is a phenyl ring substituted by one or two substituents, in particular, by a phenyl, phenyl(C ⁇ _4)alkyl, phenoxy, benzoyl or phenylC ⁇ _4alkoxy 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 :
  • 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, Ci _4alkyl, Ci _4alkoxy, phenyl, phenylCi _4alkyl and phenylCi _4alkoxy.
  • Alkyl groups present in the compounds of formula (I), alone or as part of another group, can be straight or branched.
  • a Ci .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 hydrochlonde, 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 final products and are included within the scope of this invention.
  • the invention also provides a novel compound of formula (IA) :
  • Formula (IA) in which : p and q each independently represent an integer from 3 to 5;
  • R! is hydrogen, Ci.galkyl orphenylCj ⁇ alkvl; na is 0 to 6 and ma is 0 to 6 such that the le Ji of the chain (CH2) n aA(CH2) ma is at least 2 atoms when A is other than S or a bond and is at least 3 atoms when A is S or a bond; and
  • Ar is aryl or heteroaryl, each of which may be optionally substituted, with the provisos that a) when A is a bond the group -(C_H2)naA(CH2) ma * s not ⁇ to me azabicyclic nitrogen atom; b) when A is oxygen, p and q are both 3 or both 4, na is 0 to 6 and ma is zero or 1 then Ar is not unsubstitued phenyl; and c) when A is NH, p and q do not both represent 4.
  • A is oxygen, in which case na is from 1 to 5 and ma is from 0 to 3; or A is a bond in which case the sum of na+ma is from 3 to 6;
  • Ar represents a substituted phenyl group, or an optionally substituted bicyclic or tricyclic heteroaryl group as hereinbefore defined; and the group -(CH2) n aA(CH2)maAr is not ⁇ to *h e azabicyclic nitrogen atom; and salts thereof.
  • Substituted phenyl, and optionally substituted bicyclic heteroaryl or tricyclic heteroaryl groups are as defined for formula (I) above.
  • a phenyl group is substituted by benzyl, benzoyl, benzyloxy, phenyloxy or halogen.
  • a bicyclic aryl group is preferably benzofuranyl, optionally substituted by phenyl.
  • a tricyclic aryl group is preferably dibenzofuranyl.
  • (+) and (-) designations used herein indicate the direction of rotation of plane-polarised light by the compounds.
  • the prefix (+) indicates that the isomer is dextrorotatory (which can also be designated d) and the prefix (-) indicates the levorotatory isomer (which can also be designated 1).
  • the relative orientation of the substituents is defined with respect to the orientation of the bridgehead hydrogen atom. In the case of the quinolizidine ring the bridgehead hydrogen atom is numbered as 9a.
  • the ⁇ -designation refers to an atom or group which projects below the plane of the quinolizidine nucleus and the -designation refers to an atom or group which projects above the plane of the quinolizidine nucleus.
  • 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: (a) for compounds of formula (I) in which A is O, S or NR*, reaction of a compound of formula (II):
  • L(CH2) m Arl can take place under conditions which depend on the nature of the group L and the value of m.
  • L is preferably fluoro and the reaction is preferably effected in the presence of a strong base such as sodium hydride, and in a polar organic solvent such as dimethylsulphoxide or dimethylformamide.
  • the aryl group is preferably substituted by an activating group such as benzoyl, CHO, CF3 or NO2.
  • L may be for example halogen or preferably a sulphonic acid residue such as a tosylate or mesylate and die reaction is carried out under standard conditions in a solvent and optionally in the presence of a base, which solvent and base may if desired be selected from those specified above.
  • the reaction between a compound of formula (III) and a compound of formula (process b) can take place under conditions which depend on the nature of L and A. For example when L* is hydroxy, m is 0 and A is oxygen or sulphur the reaction is carried out in the presence of diediyl azodicarboxylate and triphenyl phosphine.
  • the leaving group L* 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.
  • the reduction of a compound of formula (TV) according to process (c) can be effected by methods known in the art, for example using a reducing agent such as lithium aluminium hydride.
  • a compound of formula (TV) can be prepared (for example as described below) and reduced in a One-pot' reaction, without isolation of compound (IV) itself.
  • the reaction between a compound of formula (V) and a compound of formula ⁇ l Arl 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 of the formula Arl(C.H_2) m +lP(O)(OAlk)2, such as a diethylphosphonate, or a Wittig reagent of the formula (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.
  • Reduction of a compound (VII) according to process (f) may be effected using a reducing agent such as lithium aluminium hydride, in a solvent such as ether or tetrahydrofuran or a mixture thereof.
  • a reducing agent such as lithium aluminium hydride
  • a solvent such as ether or tetrahydrofuran or a mixture thereof.
  • Interconversion reactions according to process (g) may be effected by methods well known in the art.
  • a group Ar* which is convertible to a group Ar may be for example phenyl subtituted by benzoyl or carboxaldehyde, which substituents can be converted respectively to benzyl and methyl by reduction for example with sodium borohydride in trifluoroacetic acid.
  • Conversion of a group Ar* is preferably effected following process (a).
  • Compounds of formula (II) wherein n is 1 to 6 and A* is oxygen may be prepared by reduction of the corresponding ester of formula (VIII) :
  • Formula (VIII) wherein p, q and n are as hereinbefore defined and Alk is a Ci. ⁇ alkyl group e.g. ethyl.
  • the reduction may be effected using a reducing agent such as lithium aluminium hydride in a solvent such as diethyl ether or tetrahydrofuran.
  • Esters of formula (VIII) wherein n is 1 may be prepared by acid or base hydrolysis of the corresponding cyano compound, followed by esterification.
  • base hydrolysis e.g. using potassium hydroxide in aqueous diethylene glycol under reflux, according to the method of Yamada et al., Agr. Biol.
  • cyano intermediate may itself be prepared from the corresponding ketone by reaction with tosylmethyl isocyanide.
  • Ketones corresponding to formula (VIII) can be prepared by methods described in the literature (e.g. J. Chem. Soc., 1931, 437 and J. Am Chem. Soc., 1956, 78, 3457).
  • 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, 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 363,085, 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 a corresponding aldehyde or ketone with triethylphosphonoacetate or triethylphosphonocrotonate followed by catalytic hydrogenation to give the ethoxycarbonylalkyl derivative which is further reduced e.g. using lithium aluminium hydride to the desired hydroxyalkyl compound.
  • triethylphosphonoacetate results in a 2-carbon homologation whilst triethylphosphonocrotonate gives a 4-carbon homologation.
  • Compounds of formula (II) wherein A is S or NR may be prepared from the corresponding hydroxy compound by standard methods, for example via formation of an alkyl halide followed by reaction with an appropriate amine or thiol reagent.
  • Compounds L(CH2) m Arl may be prepared by methods known in the art.
  • Ar* is substituted phenyl e.g. 3,4-dichlorophenyl
  • m is one and L is a tosylate group
  • such compounds can be prepared by d e method of Kochi et al., J. Org. Chem., 1953, 75, 3443.
  • Compounds of formula (IV) wherein R ⁇ is a group -(CH2) n N(Rl)C(O)(CH2) m -iArl can be prepared by reacting a compound of formula (II) wherein A* represents NR* with an acylating agent corresponding to the group - (CH2) m Ar 1 , for example an acid chloride ClOC(CH2) m . i Ar 1 .
  • R ⁇ is a group -(CH2)n-lC(O)N(Rl)(CH2) m Arl
  • R ⁇ represents -(CH2) n -lCO2H or an activated derivative thereof such as an acid halide, ester or anhydride
  • an amine of formula HN(Rl)(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 is oxygen and n is other than zero.
  • Compounds of formula (VI) may be prepared by conventional methods, for example the oxidation of a compound of formula (II) wherein A s oxygen, or conversion of the corresponding ester, e.g. by reaction with thionyl chloride and N,O-dimethyl- hydroxylamine, followed by reduction of the resulting N-methyl-N-methoxy-carboxamide, using diisobutylaluminium hydride.
  • Compounds of formula (VI) wherein n is 1 may be prepared from the corresponding compound wherein n is zero by various methods.
  • the aldehyde wherein n is zero may be treated with (methoxymethyl) triphenyl- phosphonium chloride and potassium t-butoxide, followed by a strong acid, e.g. concentrated sulphuric acid, resulting in the aldehyde wherein n is 1.
  • a strong acid e.g. concentrated sulphuric acid
  • the aldehyde may be converted to die corresponding cyanomethyl derivative as described in EPA 363085 followed by acid hydrolysis, conversion to the N-methyl-N-methoxy- carboxamide and reduction. These procedures may also be used to form higher homologues.
  • a compound of formula (VII) may be prepared by alkylation of a compound of formula (DC) :
  • the compound I_,2(CH2) n A(CH2) m Arl may be prepared by conventional methods.
  • l is a halogen atom
  • A is oxygen
  • m is zero
  • such compounds may be prepared by reacting the appropriate phenol with a dibromoalkane under phase transfer conditions, using e.g. benzyl triethylammonium bromide as catalyst.
  • n A(CH2) m Arl may be prepared by Friedel-Crafts acylation of a compound Ar followed by reduction, optionally without isolation of the intermediate ketone.
  • 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.
  • Compounds of formula (I) have been found to exhibit high calcium influx blocking activity for example in neurons.
  • 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, visceral pain, epilepsy, traumatic head injury, ABDS-related dementia, neuro- degenerative diseases such as Alzheimer's disease and age-related memory disorders; mood disorders and drug addiction withdrawal such as ethanol addiction withdrawal.
  • the present invention provides a method of treatment of anoxia, ischaemia including for example stroke, migraine, visceral pain, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory disorders; mood 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.
  • die compounds of formula (I) are usually administered in a standard pharmaceutical composition.
  • the present invention therefore provides in a further aspect pharmaceutical compositions comprising a novel compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
  • the compounds of formula (I) may be administered by any convenient me ⁇ d for example by oral, parenteral, buccal, rectal or transdermal administration and die pharmaceutical compositions adapted accordingly.
  • the compounds of formula (I) and ⁇ eir pharmaceutically acceptable salts which are active when given orally can be formulated as liquids or solids, 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 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) 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 carriers), for examp e aqueous gums, ce u oses, s cates or o s an e spers on or suspens on t en filled into a soft gelatin capsule.
  • compositions consist of a solution or suspension of die 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.
  • die solution can be lyophilised and d en reconstituted with a suitable solvent just prior to administration.
  • Bodi liquid and solid compositions may contain other excipients known in the pharmaceutical art, 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 die formula (I) or a pharmaceutically acceptable salt thereof calculated as die free base.
  • the daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, eg. 5 to 200 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 60 mg, eg. 1 to 40 mg of die compound of die formula (I) or a pharmaceutically acceptable salt thereof calculated as die free base, the compound being administered 1 to 4 times per day.
  • the compounds of die 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 die 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 tiierapy, 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 batiiing solution was c ange to one a ow ng so at on o a currents.
  • Peak voltage gated Ca 2+ channel currents of up to 10 nA from dorsal root ganglion neurons were recorded using 10 mM Ba 2+ 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 die peak of the current voltage relationship and assessing block at tiiis point reduced any errors due to drifting holding potential. Some cells showed slow rundown of current as is commonly seen when recording Ca 2+ 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.
  • Buffer Suitable buffers include citrate, phosphate, sodium hydroxide/hydrochloric acid.
  • Solvent Typically water but may also include cyclodextrins (1-100 mg) and co-solvents such as propylene glycol, polyethylene glycol and alcohol.
  • Diluent e.g. Microcrystalline cellulose, lactose, starch
  • Binder e.g. Polyvinylpyrrolidone, hydroxypropymethylcellulose
  • Disintegrant e.g. Sodium starch glycollate, crospovidone Lubricant : e.g. Magnesium stearate, sodium stearyl fumarate. ra uspens on
  • Suspending agent e.g. Xandian gum, microcrystalline cellulose
  • Diluent e.g. sorbitol solution, typically water
  • Preservative e.g. sodium benzoate
  • Buffer e.g. citrate
  • Co-solvent e.g. alcohol, propylene glycol, polyethylene glycol, cyclodextrin
  • the title compound was prepared in a similar manner to Example 1 from ( ⁇ ) 3- hydroxymediylquinolizidine (0.51 g, 3.0 mmol), 3,4-dichlorophenol (0.49 g, 3.0 mmol), triphenylphosphine (0.79 g, 3.0 mmol) and diediyl azodicarboxylate (0.47 ml, 3.0 mmol). After a reaction time of 2h at room temperature the mixture was worked up as described in Example 1. The pentane extract was further purified by column chromatography on neutral alumina using 0-1% methanol in chloroform as eluant.
  • the title compound was prepared in a similar manner to Example 1 from ( ⁇ ) 1- hydroxymediylquinolizidine (75:25 mixture of equatorial and axial isomers)(0.21 g, 1.24 mmol), 4-benzyloxyphenol (0.25 g, 1.24 mmol), triphenylphosphine (0.33 g, 1.24 mmol) and diediyl azodicarboxylate (0.2 ml, 1.24 mmol). The reaction was stirred overnight at room temperature, and tiien worked up as described in Example 1 to give the title hydrochloride salt (0.15 g) mp 227-229°C (from methanol/acetone/diediyl etiier).
  • the tide compound was prepared in a similar manner to Example 1 from ( ⁇ ) 1- hydroxymediylquinolizidine (75:25 mixture of equatorial and axial isomers) (0.51 g, 3.0 mmol), 3,4-dichlorophenol (0.54 g, 3.3 mmol), triphenylphosphine (0.87 g, 3.3 mmol) and diediyl azodicarboxylate (0.52 ml, 3.3 mmol). After a reaction time of 2h, tiiin layer chromatography (neutral alumina using 2.5% ethanol in chloroform as eluant) indicated that preferential reaction of the major slower running alcohol precursor had occurred.
  • the tide compound was prepared in a similar manner to Example 1 from ( ⁇ ) (2 ⁇ , 9a ⁇ )-2- (2-hydroxyed ⁇ yl)quinolizidine (0.28 g, 1.5 mmol), 3,4-dichlorophenol (0.32 g, 2.0 mmol), triphenylphosphine (0.52 g, 2.0 mmol) and diediyl azodicarboxylate (0.32 ml, 2.0 mmol).
  • the slower running component (0.3 g, 0.74 mmol) was reduced with lithium aluminium hydride (0.14 g, 3.68 mmol) and worked up as described above to give an oil (0.23 g) which was purified by chromatography on neutral alumina using chloroform as eluant and then converted into die title hydrochloride salt (E7b), mp 124-127°C (from methanol/diethyl edier).
  • the tide compound was prepared in a similar manner to Example 1 from ( ⁇ ) (l ⁇ , 9a ⁇ )-l- hydroxymetiiylquinolizidine (0.2 g, 1.18 mmol), 4-phenoxyphenol (0.4 g, 2.15 mmol), triphenylphosphine (0.43 g, 1.65 mmol) and diethyl azodicarboxylate (0.26 ml, 1.65 mmol). After stirring at room temperature overnight the reaction was worked up as described in Example 1 to give the title hydrochloride salt (Ell), mp 223-225°C (from methanol/acetone/dietiiyl ether).
  • a solution of lithium diisopropylamide in tetrahydrofuran was generated from diisopropylamine (0.565 g, 5.6 mmol), n-butyllithium (3.25 ml of a 1.6M solution in hexanes, 5.2 mmol) and N,N,Nl,Nl-tetramethylethylenediamine (0.78 ml, 5.2 mmol).
  • quinolizidin-4-one (0.61 g, 4.0 mmol) followed by 5-(4- benzyloxyphenoxy)pentyl bromide (1.73 g, 5.2 mmol) according to the procedure described in Example 12.
  • Example 12 After stirring overnight the reaction was quenched widi glacial acetic acid (0.63 ml) and worked up as described in Example 12 to give a light brown syrup which was purified on a silica gel column using a graded eluant of 30% diediyl edier in petroleum ether 40/60 to pure diethyl ether. The faster running component was isolated as a colourless solid (0.64 g), mp 78.5-79°C and the slower running component was obtained as an oil (0.62 g).
  • Stage 2 The faster running component (0.52 g, 1.29 mmol) was treated with lidiium aluminium hydride (0.1 g, 2.59 mmol) in dry tetrahydrofuran as described in Example 12. After lh at room temperature the reaction was worked up as described in Example 12 and then purified on silica gel using 1-5% ethanol in chloroform as eluant. Pooling of pure fractions afforded a solid (0.36 g) which was converted into the title hydrochloride salt (E14a), mp 155- 157°C (from methanol/diethyl ether).
  • the slower running component (0.59 g, 1.46 mmol) was reduced with lithium aluminium hydride (0.11 g, 2.9 mmol) in dry diethyl edier and worked up as described in Example 12.
  • the product was purified on silica gel using diediyl ether as eluant. Pooling of fractions containing the major less mobile product afforded a colourless solid (0.4 g) which was converted into die title hydrochloride salt (E14b), mp 158-161°C (from acetone/dietiiyl ether).
  • lidiium diisopropylamide in tetrahydrofuran was generated from diisopropylamine (0.49 g, 4.9 mmol), n-butyl lithium (2.84 ml of a 1.6M solution in hexanes, 4.55 mmol) and N,N,Nl,N ⁇ -tetramethylethylenediamine (0.685 ml, 4.55 mmol).
  • quinolizidin-4-one 0.535 g, 3.5 mmol
  • 4-(4- benzyloxyphenoxy)butyl bromide (1.45 g, 4.55 mmol) according to die procedure described in Example 12.
  • the faster running component (0.32 g, 0.79 mmol) was treated widi lithium aluminium hydride (0.14 g, 3.9 mmol) in dry tetrahydrofuran as described in Example 12. After 0.75h at room temperature the reaction was worked up as described in Example 12 and then purified on a silica gel column using diediyl ether as eluant Pooling of pure fractions containing the major less mobile product afforded a colourless solid (0.15 g) which was converted into the title hydrochloride salt (E16a) (0.13 g), mp 171-172°C (from acetone/diediyl ether).
  • lidiium diisopropylamide in tetrahydrofuran was generated from diisopropylamine (0.49 g, 4.9 mmol), n-butyllithium (2.84 ml of a 1.6M solution in hexanes, 4.55 mmol) and N,N,N ⁇ ,N ⁇ -tetramethylethylenediamine (0.685 ml, 4.55 mmol).
  • quinolizidin-4-one 0.535 g, 3.5 mmol
  • 3-(4- benzyloxyphenoxy)propyl bromide (1.39 g, 4.55 mmol) according to die procedure described in Example 12.
  • the faster running component (0.28 g, 0.71 mmol) was treated witii lithium aluminium hydride (0.135 g, 3.56 mmol) in dry tetrahydrofuran and worked up as described in Example 12. Purification on a silica gel column using diediyl edier as eluant afforded a colourless solid (90 mg) which was converted into the title hydrochloride salt (E17a) (75 mg), mp 182-183.5°C (from methanol/acetone/diediyl edier).
  • the slower running component (0.27 g, 0.69 mmol) was reduced widi lithium aluminium hydride (0.135 g, 3.55 mmol) in dry diethyl ether.
  • the reaction was worked up as described in Example 12 and die product was converted into die title hydrochloride salt (E17b) (0.17 g), mp 159-160.5°C (from methanol/acetone/diethyl ether).
  • Stage 1 A solution of lithium diisopropylamide in tetrahydrofuran was generated from diisopropylamine (0.43 g, 4.3 mmol), n-butyllithium (2.5 ml of a 1.6M solution in hexanes, 4.0 mmol) and N,N,N ⁇ ,N ⁇ -tetramethylethylenediamine (0.6 ml, 4.0 mmol). To this solution was added quinolizidin-4-one (0.47 g, 3.07 mmol) followed by 2-(4- benzyloxyphenoxy)ethyl bromide (1.22 g, 4.0 mmol) according to the procedure described in Example 12.
  • the faster running component (0.30 g, 0.79 mmol) was treated with lithium aluminium hydride (0.15 g, 3.9 mmol) in dry tetrahydrofuran and worked up as described in Example 12. Purification on a silica gel column using 1 -5% ethanol in chloroform as eluant afforded a pale yellow solid (90 mg) which was converted into die title hydrochloride salt (E18a), mp 192-195°C (from methanol/acetone/diethyl ether).

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Abstract

Known and novel azabicyclic derivatives of formula (I) such as quinolizidines with calcium channel antagonist activity, in which: p, and q each independently represent an integer from 3 to 5; n is 0 to 6; m is 0 to 6; A is a bond, -CH=CH-, -C C-, oxygen, sulphur or NR1; R1 is hydrogen, C¿1-8?alkyl or phenylC1-4alkyl; and Ar is aryl or heteroaryl, each of which may be optionally substituted; or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of disorders wherein a calcium channel antagonist is indicated and novel compound of formula (IA), in which: p and q each independently represent aninteger form 3 to 5; A is a bond, -CH=CH-, -C C-, oxygen, sulphur or NR?1; R1¿ is hydrogen, C¿1-8?alkyl or phenylC1-4alkyl; na is 0 to 6 and ma is 0 to 6 such that the length of the chain (CH2)naA(CH2)ma is at least 2 atoms when A is other than S or a bond and is at least 3 atoms when A is S or a bond; and Ar is aryl or heteroaryl, each of which may be optionally substituted, with a provisos that: a) when A is a bond the group -(CH2)naA(CH2)ma is not α to the azabicyclic nitrogen atom; b) when A is oxygen, p and q are both 3 or both 4, na is 0 to 6 and ma is zero or 1 then Ar is not unsubstituted phenyl; and c) when A is NH, p and q do not both represent 4.

Description

QUINOLIZIDINES WITH CALCIUM CHANNEL ANTAGONISTIC ACTIVITY
The present invention relates to the use of known and novel azabicyclic derivatives in therapy in particular as calcium channel antagonists, novel compounds ≤E SS, processes for their preparation, and pharmaceutical compositions containing them.
Japanese patent No. 37-4142 describes a process for preparing phenoxyalkyl-3- quinolizidines, which compounds are said to have muscle-contracting properties, particularly on the uterus. US Patent No. 4,689,329 and EPA 241292 describe certain aralkyl-substituted octahydroindolizidines and their use as analgesics.
EPA 210883 describes substituted phenylthio- and substituted benzylthio- azabicycloheptanes as intermediates for the preparation of penem derivatives.
Various aryl- and heteroaryl-aminoalkyl substituted quinolizidines are described for example in Farmaco. Ed. Sci. 1968, 23(4) 344-59; Chem. Pharm. Bull. (Tokyo) 7,
1083-9 (1959); and Indian J. Chem. Sect. B 1985, 24B(6) 636-8.
We have now found that certain substituted quinolizidines exhibit activity as calcium channel antagonists. They are thus of potential use in the treatment of disorders where calcium channel blockade is indicated, in particular disorders related to an accumulation of calcium in the brain cells of a mammal.
The present invention therefore provides, in a first aspect, the use of a compound of formula (I):
Formula (I) in which p, and q each independently represent an integer from 3 to 5; n is 0 to 6; m is 0 to 6; A is a bond, -CH=CH-, -C≡C-, oxygen, sulphur or NR 1 ;
R.1 is hydrogen, Cj.galkyl orphenylCi^alkyl; and
Ar is aryl or heteroaryl, each of which may be optionally substituted; or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of disorders wherein a calcium channel antagonist is indicated. In formula (I) above, the H atom is shown on the bridgehead carbon atom to make clear that the (CH2)nA(CH2)mAr chain cannot be attached at this position. p and q are preferably independently 3 or 4; most preferably p and q are both 4.
The values of m and n should be chosen such that the chain (CH2)nA(CH2)m contains at least 1, preferably 2, atoms. In general the length of the chain
-(CH2)nA(CH2)m is from 2 to 6 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 preferably from 1 to 5, for example n may be 1, 2, 3, 4 or 5 and m may be 0, 1, 2 or 3. When A is a bond the sum of n+m should be at least 1. A is preferably oxygen or a bond; most preferably A is oxygen.
When Ar represents aryl, suitable groups include, for example, unsaturated monocyclic and unsaturated or partially saturated bicyclic and 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 Cι_2alkylenedioxy group (e.g. phenyl substituted by a 3,4-methylenedioxy group) or by 1 to 3 substituents selected fipom halogen, Cι.4alkoxy, nitro, SCι_4alkyl, NR aR (in which R a andR2b can be independently H or Cj^alkyl), OCF3, Ci .galkyl, trifluoromethyl, CN, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted benzoyl, optionally substituted phenylCj_4alkyl and optionally substituted phenylCι_4alkoxy.
Suitable optionally substituted phenylCj_4alkyl groups include, for example benzyl. Suitable optionally substituted phenylCj^alkoxy groups include, for example benzyloxy groups. Suitable substituents for said optionally substituted phenyl, phenoxy, benzoyl, phenylCι_4alkyl and phenylCι_4alkoxy groups include for example halogen, C^alkyl, Cι_4alkoxy, nitro and trifluoromethyl groups.
Preferably the aryl group is a phenyl ring substituted by one or two substituents, in particular, by a phenyl, phenyl(Cι_4)alkyl, phenoxy, benzoyl or phenylCι_4alkoxy group; or by two chloro atoms especially in the 3- and 4-positions of the phenyl ring.
When Ar represents heteroaryl 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 :
wherein γl represents Y(CH2)S, Y is O, S or NR^ (where R^ is hydrogen or Cι_4alkyl), Z is (CH2)r or CH=CH, r is 0, 1 or 2 and s is 0 or 1, or a corresponding dehydro ring system. Examples of 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, Ci _4alkyl, Ci _4alkoxy, phenyl, phenylCi _4alkyl and phenylCi _4alkoxy. Alkyl groups present in the compounds of formula (I), alone or as part of another group, can be straight or branched. Thus, a Ci .4alkyl group may be for example methyl, ethyl, n-propyl, n-butyl or any branched isomer thereof such as isopropyl or t-butyl.
It will be appreciated that for use in medicine a salt of a compound (I) should be pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include inorganic and organic acid addition salts such as hydrochlonde, 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 final products and are included within the scope of this invention. The invention also provides a novel compound of formula (IA) :
Formula (IA) in which : p and q each independently represent an integer from 3 to 5;
A is a bond, -CH=CH-, -C≡C-, oxygen, sulphur or NR*;
R! is hydrogen, Ci.galkyl orphenylCj^alkvl; na is 0 to 6 and ma is 0 to 6 such that the le Ji of the chain (CH2)naA(CH2)ma is at least 2 atoms when A is other than S or a bond and is at least 3 atoms when A is S or a bond; and
Ar is aryl or heteroaryl, each of which may be optionally substituted, with the provisos that a) when A is a bond the group -(C_H2)naA(CH2)ma *s not α to me azabicyclic nitrogen atom; b) when A is oxygen, p and q are both 3 or both 4, na is 0 to 6 and ma is zero or 1 then Ar is not unsubstitued phenyl; and c) when A is NH, p and q do not both represent 4.
In the compounds of formula (IA) preferred values of A, Ar, p, and q are as described above for formula (I) and preferred values for na and ma are as described for n and m in formula (I).
Most preferably in the compounds of formula (IA) p and q each represent 4;
A is oxygen, in which case na is from 1 to 5 and ma is from 0 to 3; or A is a bond in which case the sum of na+ma is from 3 to 6;
Ar represents a substituted phenyl group, or an optionally substituted bicyclic or tricyclic heteroaryl group as hereinbefore defined; and the group -(CH2)naA(CH2)maAr is not α to *he azabicyclic nitrogen atom; and salts thereof. Substituted phenyl, and optionally substituted bicyclic heteroaryl or tricyclic heteroaryl groups are as defined for formula (I) above. Preferably a phenyl group is substituted by benzyl, benzoyl, benzyloxy, phenyloxy or halogen. A bicyclic aryl group is preferably benzofuranyl, optionally substituted by phenyl. A tricyclic aryl group is preferably dibenzofuranyl. Particular compounds of the invention, which are believed to be novel; include:
(±) (3α, 9aα)-3-(4-benzyloxyphenoxymethyl)quinolizidine,
(±) (3α, 9aα)-3-(3,4-dichlorophenoxymethyl)quinolizidine,
(±) (lα, 9aα)-l-(4-benzyloxyphenoxymethyl)quinolizidine,
(±) (lα, 9aα)-l-(3,4-dichlorophenoxymethyl)quinolizidine, (±) (2β, 9aα)-2-[2-(4-benzyloxyphenoxy)ethyl]quinolizidine,
(±) (2β, 9aα)-2-[2-(3,4-dichlorophenoxy)ethyl]quinolizidine.
(±) (3α, 9aα)-3-[5-(2-dibenzofuranyloxy)pentyl]quinolizidine,
(±) (3β, 9aα)-3-[5-(2-dibenzofuranyloxy)pεntyl]quinolizidine
(±) (2β, 9aα)-2-[2-(3,4-dichlorobenzyloxy)ethyl]quinolizidine, (±) (3α, 9aα) and (3β, 9aα)-3-(3,4-dichlorobenzyloxymethyl)quinolizidine,
(±) (3α, 9aα)-3-[3-(4-benzyloxyphenyl)propyloxymethyl]quinolizidine,
(±) (lα, 9aα)-l-[4-(phenoxy)phenoxymethyl]quinolizidine,
(±) (3α, 9aα)-3-[6-(4-phenoxyphenyl)hexyl]quinolizidine,
(±) (3β, 9aα)-3-[6-(4-phenoxyphenyl)hexyl]quinolizidine, (±) (lα, 9aα)-l-(4-benzylphenoxymethyl)quinolizidine,
(±) (3α, 9aα)-3-[5-(4-benzyloxyphenoxy)pentyl]quinolizidine,
(±) (3β, 9aα)-3-[5-(4-benzyloxyphenoxy)pentyl]quinolizidine,
(±) (lα, 9aα)-l-[5-(2-phenylbenzo[b]furanyloxy)methyl]quinolizidine, (+) (3α, 9aα)-3-[4-(4-benzyloxyphenoxy)butyl]quinolizidine,
(±) (3β, 9aα)-3-[4-(4-benzyloxyphenoxy)butyl]quinolizidine,
(±) (3α, 9aα)-3-[3-(4-benzyloxyphenoxy)propyl]quinolizidine,
(±) (3β, 9aα)-3-[3-(4-benzyloxyphenoxy)propyl] quinolizidine,
(±) (3α, 9aα)-3-[2-(4-benzyloxyphenoxy)ethyl]quinolizidine, (±) (3β, 9aα)-3-[2-(benzyloxyphenoxy)ethyl]quinolizidine,
(±) (3α, 9aα)-3-(4-benzylphenoxymethyl)quinolizidine,
(+) (3β, 9aα)-3-(4-benzoylphenoxymethyl)quinolizidine,
(±) (3β, 9aα)-3-(4-benzylphenoxymethyl)quinolizidine, and salts thereof. It will be appreciated that the compounds of formula (I) may contain one or more asymmetric centres. 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. In addition, when A represents -CH=CH- the compounds will exist as geometric isomers, and the invention encompasses all such isomers and mixtures thereof.
In accordance with convention the (+) and (-) designations used herein indicate the direction of rotation of plane-polarised light by the compounds. The prefix (+) indicates that the isomer is dextrorotatory (which can also be designated d) and the prefix (-) indicates the levorotatory isomer (which can also be designated 1). The relative orientation of the substituents is defined with respect to the orientation of the bridgehead hydrogen atom. In the case of the quinolizidine ring the bridgehead hydrogen atom is numbered as 9a. The α-designation refers to an atom or group which projects below the plane of the quinolizidine nucleus and the -designation refers to an atom or group which projects above the plane of the quinolizidine nucleus.
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: (a) for compounds of formula (I) in which A is O, S or NR*, reaction of a compound of formula (II):
Formula (II) in which p, q, and n are as described for formula (I) and A is O, S or NR , with a compound of formula L CH2)mArl (wherein m is as described for formula (I), Arl represents Ar or a group convertible thereto, and L is a leaving group) and if necessary subsequently converting a group Arl to a group Ar,
(b) for compounds of formula (I) in which A is O, S or NR* , reaction of a compound of formula (III):
Formula (III) in which p, q and n are as described for formula (I) and L is a group displaceable by a nucleophile, with a compound of formula where m, A* and Ar* are as hereinbefore defined;
(c) for compounds of formula (I) in which A is NR!, reduction of a compound of formula (IN) :
Formula (IV) in which R^ represents the group
-(CH2)nΝ(R1)C(O)(CH2)m.ιArl or -(CH2)n-lC(O)N(Rl)(CH2)mAr1, and p, q, n, m, and Ar^ are as hereinbefore defined; (d) for compounds of formula (I) in which A is a bond, reaction of a compound of formula (V) :
Formula (V)
(wherein l . p, q, m and n are as hereinbefore defined). with a compound of formula X*Ar^ in which Ar* is as hereinbefore defined, and X* is an alkali metal;
(e) for compounds wherein A is -CH=CH- reaction of a compound of formula (VI) :
Formula (VI)
(wherein n, p and q are as hereinbefore defined) with a reagent serving to introduce the group =C(CH2)mAr1;
(f) to prepare a compound of formula (I) wherein the substituent -(CH2)nA(CH2)mArl is β to the nitrogen atom, reduction of a compound of formula (VII):
Formula (VII) (wherein p, q, m, n, A and Ar are as hereinbefore defined). (g) Interconversion of one compound of formula (I) to a different compound of formula (I) e.g. the reduction of a compound wherein A is -CH=CH- to a compound wherein A is -CH2CH2-; or conversion of a group Arl to Ar; and optionally after any of the above processes forming a salt of formula (I). In process (a) the reaction between a compound of formula (II) and a compound
L(CH2)mArl can take place under conditions which depend on the nature of the group L and the value of m. For example, when m is zero, L is preferably fluoro and the reaction is preferably effected in the presence of a strong base such as sodium hydride, and in a polar organic solvent such as dimethylsulphoxide or dimethylformamide. In this case, the aryl group is preferably substituted by an activating group such as benzoyl, CHO, CF3 or NO2. When m is other than zero L may be for example halogen or preferably a sulphonic acid residue such as a tosylate or mesylate and die reaction is carried out under standard conditions in a solvent and optionally in the presence of a base, which solvent and base may if desired be selected from those specified above. The reaction between a compound of formula (III) and a compound of formula (process b) can take place under conditions which depend on the nature of L and A. For example when L* is hydroxy, m is 0 and A is oxygen or sulphur the reaction is carried out in the presence of diediyl azodicarboxylate and triphenyl phosphine. Such a reaction is known as the Mitsunobu reaction (as described in Synthesis 1981, 1). Alternatively the leaving group L* 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. The reduction of a compound of formula (TV) according to process (c) can be effected by methods known in the art, for example using a reducing agent such as lithium aluminium hydride. Conveniently a compound of formula (TV) can be prepared (for example as described below) and reduced in a One-pot' reaction, without isolation of compound (IV) itself. The reaction between a compound of formula (V) and a compound of formula χl Arl 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 of the formula Arl(C.H_2)m+lP(O)(OAlk)2, such as a diethylphosphonate, or a Wittig reagent of the formula (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. Reduction of a compound (VII) according to process (f) may be effected using a reducing agent such as lithium aluminium hydride, in a solvent such as ether or tetrahydrofuran or a mixture thereof. Compounds of formula (VII), which are prepared as described hereinafter, themselves exist as mixtures of axial and equatorial diastereoisomers. These may be separated by chromatography prior to reduction, which affords a convenient method of obtaining the individual diastereomers of formula (I).
Interconversion reactions according to process (g) may be effected by methods well known in the art. Thus for example conversion of a compound (I) wherein A represents -CH=CH- into a compound (I) wherein A represents-CH2-CH2- may be effected by catalytic reduction. A group Ar* which is convertible to a group Ar may be for example phenyl subtituted by benzoyl or carboxaldehyde, which substituents can be converted respectively to benzyl and methyl by reduction for example with sodium borohydride in trifluoroacetic acid. Conversion of a group Ar* is preferably effected following process (a). Compounds of formula (II) wherein n is 1 to 6 and A* is oxygen may be prepared by reduction of the corresponding ester of formula (VIII) :
COsAlk
Formula (VIII) wherein p, q and n are as hereinbefore defined and Alk is a Ci.βalkyl group e.g. ethyl. The reduction may be effected using a reducing agent such as lithium aluminium hydride in a solvent such as diethyl ether or tetrahydrofuran. Esters of formula (VIII) wherein n is 1 may be prepared by acid or base hydrolysis of the corresponding cyano compound, followed by esterification. When the nucleus is a quinolizidine, base hydrolysis (e.g. using potassium hydroxide in aqueous diethylene glycol under reflux, according to the method of Yamada et al., Agr. Biol. Chem., 1971, 35, 285) gives predominantly the equatorial form of the product, whilst acid hydrolysis generally results in a mixture of isomers, the ratio of which depends on the precise reaction conditions employed. The cyano intermediate may itself be prepared from the corresponding ketone by reaction with tosylmethyl isocyanide. Ketones corresponding to formula (VIII) can be prepared by methods described in the literature (e.g. J. Chem. Soc., 1931, 437 and J. Am Chem. Soc., 1956, 78, 3457). 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, 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 363,085, followed by acid hydrolysis, and esterification to form an ester wherein n is 2. The sequence may be repeated to form higher homologues.
Alternatively, compounds of formula (II) may be prepared by reaction of a corresponding aldehyde or ketone with triethylphosphonoacetate or triethylphosphonocrotonate followed by catalytic hydrogenation to give the ethoxycarbonylalkyl derivative which is further reduced e.g. using lithium aluminium hydride to the desired hydroxyalkyl compound. It will be appreciated that use of triethylphosphonoacetate results in a 2-carbon homologation whilst triethylphosphonocrotonate gives a 4-carbon homologation.
Compounds of formula (II) wherein A is S or NR may be prepared from the corresponding hydroxy compound by standard methods, for example via formation of an alkyl halide followed by reaction with an appropriate amine or thiol reagent.
Compounds L(CH2)mArl may be prepared by methods known in the art. Thus for example when Ar* is substituted phenyl e.g. 3,4-dichlorophenyl, m is one and L is a tosylate group, such compounds can be prepared by d e method of Kochi et al., J. Org. Chem., 1953, 75, 3443.
Compounds of formula (HI) wherein L* is OH can be prepared as described for compounds of formula (II), and compounds of formula (HI) wherein L * is a halogen atom, or a mesyloxy or tosyloxy group can be prepared from the corresponding alcohol in conventional manner.
Compounds of formula (IV) wherein R^ is a group -(CH2)nN(Rl)C(O)(CH2)m-iArl can be prepared by reacting a compound of formula (II) wherein A* represents NR* with an acylating agent corresponding to the group - (CH2)mAr1 , for example an acid chloride ClOC(CH2)m. i Ar1.
Compounds of formula (TV) wherein R^ is a group -(CH2)n-lC(O)N(Rl)(CH2)mArl may be prepared for example by reaction of a corresponding compound wherein R^ represents -(CH2)n-lCO2H or an activated derivative thereof such as an acid halide, ester or anhydride, with an amine of formula HN(Rl)(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 is oxygen and n is other than zero.
Compounds of formula (V) may be prepared in analogous manner to compounds of formula (III); where necessary the chain length may be increased using methods well known in the art.
Compounds of formula (VI) may be prepared by conventional methods, for example the oxidation of a compound of formula (II) wherein A s oxygen, or conversion of the corresponding ester, e.g. by reaction with thionyl chloride and N,O-dimethyl- hydroxylamine, followed by reduction of the resulting N-methyl-N-methoxy-carboxamide, using diisobutylaluminium hydride. 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) triphenyl- phosphonium chloride and potassium t-butoxide, followed by a strong acid, e.g. concentrated sulphuric acid, resulting in the aldehyde wherein n is 1. Alternatively the aldehyde may be converted to die corresponding cyanomethyl derivative as described in EPA 363085 followed by acid hydrolysis, conversion to the N-methyl-N-methoxy- carboxamide and reduction. These procedures may also be used to form higher homologues.
A compound of formula (VII) may be prepared by alkylation of a compound of formula (DC) :
Formula (IX) with a compound L2(CH2)nA(CH2)mArl, wherein L2 is a leaving group, such as halo e.g. bromo or a sulphonic acid residue such as tosylate or mesylate. The reaction is preferably carried out under strongly basic conditions using for example lithium di- isopropylamide, in a solvent such as tetrahydrofuran. Compounds of formula (DC) wherein p and q are both 4 can be prepared by memods known in the literature, for example as described in J. Am. Chem. Soc., 1949, 21,
879.
The compound I_,2(CH2)nA(CH2)mArl may be prepared by conventional methods. Thus for example when l is a halogen atom, A is oxygen and m is zero, such compounds may be prepared by reacting the appropriate phenol with a dibromoalkane under phase transfer conditions, using e.g. benzyl triethylammonium bromide as catalyst.
When A represents a bond compounds Of the formula L2(CH2)nA(CH2)mArl may be prepared by Friedel-Crafts acylation of a compound Ar followed by reduction, optionally without isolation of the intermediate ketone. 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.
Compounds of formula (I) have been found to exhibit high calcium influx blocking activity for example in neurons. As such 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. For example, the compounds are expected to be of use in the treatment of anoxia, ischaemia including for example stroke, migraine, visceral pain, epilepsy, traumatic head injury, ABDS-related dementia, neuro- degenerative diseases such as Alzheimer's disease and age-related memory disorders; mood disorders and drug addiction withdrawal such as ethanol addiction withdrawal.
In a further aspect of the invention" there is therefore provided a method of treatment of conditions or diseases related to (e.g. caused or exacerbated by) the accumulation of calcium in die brain cells of mammals which comprises administering to a subject in need diereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Thus, for example, the present invention provides a method of treatment of anoxia, ischaemia including for example stroke, migraine, visceral pain, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory disorders; mood 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.
For use in medicine, die compounds of formula (I) are usually administered in a standard pharmaceutical composition. The present invention therefore provides in a further aspect pharmaceutical compositions comprising a novel compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
The compounds of formula (I) may be administered by any convenient me όd for example by oral, parenteral, buccal, rectal or transdermal administration and die pharmaceutical compositions adapted accordingly.
The compounds of formula (I) and Λeir pharmaceutically acceptable salts which are active when given orally can be formulated as liquids or solids, 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. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose. A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, 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 carriers), for examp e aqueous gums, ce u oses, s cates or o s an e spers on or suspens on t en filled into a soft gelatin capsule.
Compounds of die invention may also be administered parenterally, by bolus injection or continuous infusion. Typical parenteral compositions consist of a solution or suspension of die 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. Alternatively, die solution can be lyophilised and d en reconstituted with a suitable solvent just prior to administration.
Bodi liquid and solid compositions may contain other excipients known in the pharmaceutical art, such as cyclodextrins.
Preferably the 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 die formula (I) or a pharmaceutically acceptable salt thereof calculated as die free base.
The daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, eg. 5 to 200 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 60 mg, eg. 1 to 40 mg of die compound of die formula (I) or a pharmaceutically acceptable salt thereof calculated as die free base, the compound being administered 1 to 4 times per day. Alternatively the compounds of die invention may be administered by continuous intravenous infusion, preferably at a dose of up to 400 mg per day. Thus, the total daily dosage by oral administration will be in the range 1 to 2000 mg and die total daily dosage by parenteral administration will be in the range 0.1 to 400 mg. Suitably the compounds will be administered for a period of continuous tiierapy, for example for a week or more.
BIOLOGICAL DATA
Ca2+ Current Measurement Cell preparations
Sensory neurons from dorsal root ganglia were dissociated from 1 day old rat pups (Forda et al, Developmental Brain Research, 22 (1985), 55-65). Cells were plated out onto glass coverslips and used within 3 days to permit effective voltage clamp of Ca2+ currents.
Solutions
The pipette (internal solution) contained in mM: CsCl, 130; HEPES, 10; EGTA, 10; MgCL2, 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 batiiing solution was c ange to one a ow ng so at on o a currents. e externa so u on or recording Ca2+channel currents contained in mM: BaCL2, 10; TEA-Cl, 130; glucose, 10; HEPES, 10; MgCL2, 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. Compounds were dissolved in DMSO to make a 20 mM stock solution. At die drug concentration used d e vehicle (0.1 %) had no significant effect on Ca + currents. All experiments were performed at 21 to 24°C. Whole cell currents were recorded using List EPC-7 amplifiers and stored, digitised for later analysis using PC based software similar to that described previously (Benham & Tsien, Journal of Physiology (1988), 404, 767-784).
RESULTS
Ca + currents
Peak voltage gated Ca2+ channel currents of up to 10 nA from dorsal root ganglion neurons were recorded using 10 mM Ba2+ 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 die peak of the current voltage relationship and assessing block at tiiis point reduced any errors due to drifting holding potential. Some cells showed slow rundown of current as is commonly seen when recording Ca2+ 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 μM drug was assessed 3 minutes after drug application.
Compounds of die invention gave percentage inhibition of plateau Ca2+ current in the range 71 - 99%.
The following represent typical pharmaceutical formulations according to die present invention, which may be prepared using standard methods.
IV Infusion
Buffer : Suitable buffers include citrate, phosphate, sodium hydroxide/hydrochloric acid.
Solvent : Typically water but may also include cyclodextrins (1-100 mg) and co-solvents such as propylene glycol, polyethylene glycol and alcohol.
Tablet
Compound 1 - 40 mg
Diluent/Filler * 50 - 250 mg
Binder 5 - 25 mg Disentegrant * 5 - 50 mg
Lubricant 1 - 5 mg
Cyclodextrin 1 - 100 mg
* may also include cyclodextrins
Diluent : e.g. Microcrystalline cellulose, lactose, starch
Binder : e.g. Polyvinylpyrrolidone, hydroxypropymethylcellulose
Disintegrant : e.g. Sodium starch glycollate, crospovidone Lubricant : e.g. Magnesium stearate, sodium stearyl fumarate. ra uspens on
Compound 1 - 40 mg
Suspending Agent 0.1 - 10 mg
Diluent 20 - 60 mg Preservative 0.01 - 1.0 mg
Buffer to pH ca 5 - 8
Co-solvent 0 - 40 mg
Flavour 0.01 - 1.0 mg
Colourant 0.001 - 0.1 mg
Suspending agent :e.g. Xandian gum, microcrystalline cellulose
Diluent : e.g. sorbitol solution, typically water
Preservative : e.g. sodium benzoate
Buffer : e.g. citrate Co-solvent : e.g. alcohol, propylene glycol, polyethylene glycol, cyclodextrin
The following non-limiting examples illustrate the preparation of compounds of formula (I) :
Preparation 1
(±) 1-Cyanoquinolizidine
A solution containing freshly distilled quinolizidin-1-one (G R Clemo and G R Ramage, J. Chem. Soc., 1931, 437) (4.59g, 0.03 mol), p-toluenesulphonylmethyl isocyanide (7.61 g, 0.039 mol) and absolute ed anol (3.0 ml, 0.05 mol) in dry dimethoxyediane (150 ml) was cooled below 0°C. Potassium t-butoxide (8.4 g, 0.075 mol) was added in portions while maintaining the temperature below 0°C. The reaction was tiien heated at 35-40°C for 0.75h. The mixture was filtered and the precipitate was washed with etiier. The combined filtrate and washings were filtered again and then concentrated in vacua to give an oil which was extracted into pentane. After discarding insoluble impurities, distillation in a Kugelrδhr apparatus (bp approx. 150°C at 0.4 mm Hg) afforded the title compound as a pale yellow oil (3.94 g) consisting of a mixture of diastereomers.
Preparation 2 (±) (lα, 9aα) and (lβ, 9aα)Methyl quinolizidine-l-carboxylate Method A A solution o 1-cyanoqu noliz dine . -g, . 2 mol, mixture of diastereomers n hydrochloric acid (60 ml) was heated under reflux for 12h. At this point tiiin layer chromatography (neutral alumina using chloroform as eluant) indicated tiiat the faster running nitrile component had been consumed while die slower running nitrile precursor appeared to be largely intact. The reaction was concentrated in vacua and tiien co-distilled witii successive portions of toluene. After trituration with dietiiyl etiier die residue was vacuum dried to give a hygroscopic foam which was dissolved in methanol and treated witii sodium hydrogen carbonate (6.0 g, 0.069 mol). The mixture was stirred at room temperature for 5h then concentrated in vacuo. The residue was washed widi ether to remove unreacted nitrile and die ether insoluble material was dissolved in methanol
(150 ml), treated witii ediereal hydrogen chloride (40 ml of a 1M solution) and refluxed for 5h. The reaction was concentrated in vacuo, treated with saturated aqueous potassium carbonate, and extracted into chloroform. The combined organic extracts were dried over sodium sulphate and then concentrated in vacuo to give an oil. Distillation using a Kugelrohr apparatus (bp approx. 140°C at 0.2 mm Hg) afforded die title compound as a colourless liquid (1.6 g) consisting of a 5: 1 "mixture of equatorial and axial esters.
Method B
Hydrolysis of (±) 1-cyanoquinolizidine (mixture of diastereomers) with potassium hydroxide in aqueous dieώylene glycol followed by esterification ( Y. Yamada, K. Hatano and M. Matsui, Agr. Biol. Chem., 1971, 35, 285) afforded (±) (lα, 9aα) mediyl quinolizidin- 1 -carboxylate.
Preparation 3 (±) (lα, 9aα) and (lβ, 9aα)-l-Hydroxymethylquinolizidine
To a suspension of lithium aluminium hydride (0.61 g, 16.2 mmol) in dry ether (25 ml) stirred at ice temperature under nitrogen was added dropwise to a solution of (±) (lα, 9aα) and (lβ, 9aα)methyl quinolizidine- 1 -carboxylate (1.6 g, 8.1 mmol) in the same dry solvent (40 ml). After stirring at room temperature for 4h the reaction was quenched by die addition of wet ether followed by water! The precipitate was removed by filtration, and washed dioroughly with ether containing 2% methanol. The combined filtrate and washings were concentrated in vacua to give a colourless solid (1.33 g) consisting of a 75:25 mixture of the title alcohols respectively.
In a similar manner (±) (lα, 9aα)methylquinolizidin-l -carboxylate was converted into (±) (lα, 9aα)-l-hydroxymethylquinolizidine. ep
(±) E,Z 2-(Carbethoxymethylene)quinolizidine
A solution of triethylphosphonoacetate (23.1 g, 0.01 mol) in dry dimetiioxyethane (80 ml) was treated with potassium t-butoxide (10.51 g, 0.094 mol). After stirring at room temperature for 20 min the mixture was cooled in an ice bath and treated dropwise witii a solution of quinolizidin-2-one (N J Leonard, R W Fulmer and A S Hay, J. Am. Chem. Soc., 1956, 78, 3457) (8.0 g, 0.052 mol) in dimethoxyetiiane (80 ml) over a period of 15 min. The mixture was stirred overnight and d en concentrated in vacuo. The solid residue was partitioned between ethyl acetate (100 ml) and 5M hydrochloric acid (200 ml). The aqueous layer was washed with tiiree further portions of etiiyl acetate, and die pH was adjusted to approx. 10 witii potassium carbonate. The resulting mixture was extracted witii diediyl etiier ( 3 x 150 ml) and die combined organic layers were dried over sodium sulphate and concentrated in vacuo to give the title compound as a yellow oil (9.4 g) which was used in die next stage without further purification.
Preparation 5
(±) (2β, 9aα)-2-(EthoxycarbonyImethyl)quinolizidine
A solution of (±)E,Z 2-(carbethoxymetiιylene) quinolizidine (7.0 g, 0.031 mol) and acetic acid (10 ml) in ethanol (100 ml) was hydrogenated over 10% Pd/C (1.0 g) at room temperature and a pressure of 200 psi for 14h. The catalyst was removed by filtration through Kieselguhr. The filtrate was concentrated in vacuo and the residue was treated witii aqueous potassium carbonate and extracted witii ethyl acetate (2 x 100 ml). The combined organic extracts were dried over sodium sulphate and concentrated in vacuo to give the title compound as a yellow oil (6.70 g).
Preparation 6
(±) (2β, 9aα)-2-(2-Hydroxyethyl)quinolizidine
A solution of (±) (2β, 9aα)-2-(ethoxycarbonylmethyl)quinolizidine (3.0 g, 0.013 mol) in dry tetrahydrofuran (10 ml) was added at room temperature to a stirred suspension of litiiium aluminium hydride (0.5 g, 0.013 mol) in dry tetrahydrofuran (40 ml) under nitrogen. After stirring for lh the reaction was cooled in ice and treated witii water (0.5 ml), 10% sodium hydroxide (0.5 ml) and finally water (1.5 ml). After filtration dirough Kieselguhr the filtrate was concentrated in vacuo. The residual yellow oil was distilled in a Kugelrδhr apparatus (bp approx 120°C at 0.15 mm Hg) to give the title compound as a colourless oil (2.2 g). Preparation 7
4-(4-Benzyloxyphenoxy)butyl bromide
A mixture of 4-benzyloxyphenol (10.0 g, 0.05 mol), 1,4-dibromobutane (53.9 g, 0.25 mmol) and benzyl triethylammonium bromide (0.57 g, 0.0025 mol) in dichloromethane (30 ml) was treated with an aqueous solution of sodium hydroxide (3.0 g dissolved in 75 ml of water) and die mixture was heated under reflux overnight. The reaction was diluted with dichloromethane and die aqueous layer was separated. The organic phase was washed witii water (3x100 ml) followed by brine (100 ml) then dried over sodium sulphate. The solution was concentrated in vacuo using azeotropic distillation witii toluene to remove volatiles. The residue was treated witii pentane and die solid which precipitated was collected to afford the title compound (13.5 g), mp 73°C (from diethyl ether/pentane).
The following compounds were prepared in a similar manner: 5-(4-Benzyloxyphenoxy)pentyl bromide 3-(4-Benzyloxyphenoxy)propyl bromide 2-(4-BenzyIoxyphenoxy)ethyl bromide 2-(5-Bromopentyloxy)dibenzofuran
Preparation 8
6-[4-(Phenoxy)phenyI]hexyl bromide
To a suspension of aluminium chloride (12.5 g, 0.094 mol) in dry dichloromethane (200 ml) was added 6-bromohexanoyl chloride (20.0 g, 0.094 mol) over 20 rnin. The resulting solution was added over 30 min. to a stirred solution of diphenyl ether (30.0 g, 0.17 mol) in dry dichloromethane (150 ml) under nitrogen. The mixture was left stirring overnight at room temperature and then treated with triethylsilane (32.0 ml, 0.2 mol) over 30 min. The reaction was stirred for 3 h and a further portion of triethylsilane (10.0 ml, 0.063 mol) was added during this period. The reaction was poured into a mixture of ice/water/diethyl ether. The organic layer was washed with water and brine tiien dried over magnesium sulphate and concentrated in vacuo to afford an oil (50 g). Unreacted diphenyl ether was removed by distillation on a kugelrohr apparatus collecting die fraction which distilled at approx. 175°C at 0.01 mm Hg. Further purification by chromatography on silica using hexane as eluant followed by distillation on a kugelrohr apparatus afforded the title compound as a clear oil (15.7 g). Preparation 9 3-(4-Benzyloxyphenyl)-l-propanol
A solution of 3-(4-hydroxyphenyl)-l-propanol (2.5 g, 16.4 mmol) in acetone (40 ml) containing potassium carbonate (5.9 g, 42.75 mmol) was treated witii benzyl bromide (2.54 ml, 21.35 mmol) and refluxed for 3h. The mixture was concentrated in vacuo and partitioned between water (50 ml) and chloroform (50 ml). The aqueous phase was further extracted with chloroform (2x50 ml) and die combined organic extracts were dried over sodium sulphate and concentrated in vacuo. Purification by chromatography on silica using 0-8% methanol in chloroform as eluant afforded the title compound as a colourless solid (3.92 g, 99%).
*H Nmr (CDC13) δ: 1.36 (1H, s), 1.85 (2H, m), 2.63 (2H, t, J=7Hz), 3.65 (2H, t, J=7Hz), 5.04 (2H, s), 6.91 (2H, d, J=8Hz), 7.11 (2H, d, J=8Hz), 7.27-7.50 (5H, m).
Preparation 10 3-(4-Benzyloxyphenyl)propyl p-toluenesulphonate
A solution of 3-(4-benzyloxyphenyl)-l-propanol (4.15 g, 17.1 mmol) in absolute chloroform (30 ml) was cooled in ice and treated witii pyridine (3.92 ml, 48.5 mmol) followed by p-toluenesulphonyl chloride (6.16 g, 32.3 mmol). The mixture was allowed to warm slowly to room temperature and left overnight. After dilution widi diethyl etiier (90 ml) the solution was washed widi 1M orthophosphoric acid (50 ml) followed by saturated aqueous potassium hydrogen carbonate (50 ml) and water (50 ml). The organic phase was dried over sodium sulphate and tiien purified by chromatography on silica using 0-8% methanol in chloroform as eluant to give the title compound as a colourless solid (5.1 g, 75%). *H Nmr (CDCI3) δ: 1.92 (2H, q, J=7Hz), 2.45 (3H, s), 2.57 (2H, t, J=7Hz), 4.01 (2H, t, J=7Hz), 5.02 (2H, s), 6.83 (2H, d, J=8Hz), 6.97 (2H, d, J=8Hz), 7.30-7.47 (7H, m), 7.78 (2H, d, J=8Hz).
Preparation 11 2-Phenyl-5-hydroxybenzo[b]furan
A solution of 2-phenyl-5-methoxybenzo[b]furan (K K Thomas and M M Bokadia, J Indian Chem. Soc. 1966, 43, 713) (0.5 g, 2.23 mmol) in absolute chloroform (4 ml) was treated widi trimethylsilyl iodide (0.44 ml, 3.09 mmol) and warmed at 50°C for 48h. A further quantity (0.22 ml) of trimethylsilyl iodide was added during this period. The reaction mixture was diluted with methanol (20 ml), treated widi brine (40 ml) and extracted into diediyl ether (2x40 ml). The combined extracts were washed widi aqueous sodium metabisulphite, followed by brine (40 ml) and dried over sodium sulphate. After concentrat on n vacuo t e res ue was s e to g ve t e e compoun as a co our ess solid (0.41 g, 88%) b.p. 250°C, 0.1 mm Hg (Kugelrohr).
Example 1 (±) (3a, 9aa)-3-(4-Benzyloxyphenoxymethyl)quinolizidine hydrochlonde
A solution containing (±) 3-hydroxymethylquinolizidine (mixture of diastereomers) (H R Lewis and C W Shoppee, J. Chem. Soc. 1956, 313) (0.51 g, 3.0 mmol) in dry tetrahydrofuran (15 ml) was treated under nitrogen with triphenylphosphine (0.87 g, 3.3 mmol) and 4-benzyloxyphenol (0.66 g, 3.3 mmol). A solution of diediyl azodicarboxylate (0.52 ml, 3.3 mmol) in dry tetrahydrofuran was added dropwise over a period of 30 min and die reaction was left stirring overnight. At this point, thin layer chromatography (neutral alumina using chloroform/ethanol 19/1 as eluant) indicated preferential reaction of the slower running alcohol precursor. The mixture was concentrated in vacuo, and the residue was partitioned between chloroform (100 ml) and water (100 ml). The organic layer was washed witii water (2 x 100 ml), then dried over sodium sulphate and concentrated in vacuo. The residue was extracted into a mixture of diediyl ether and pentane, and insoluble material was discarded. After evaporation of solvent the residue was extracted into pentane and treated widi ethereal hydrogen chloride to give die title hydrochlonde salt (0.22 g) mp 240-241°C (from methanol/diethyl ether). H Nmr (CDCI3) δ: 1.48 (IH, m), 1.63 (IH, m), 1.80 (IH, m), 1.80-2.00 (5H, m), 2.05- 2.28 (2H, m), 2.42 (IH, m), 2.52-2.75 (3H, m), 2.96 (IH, m), 3.40-3.50 (2H, m), 3.77 (IH, dd, J=9.6, 3.8Hz), 3.90 (IH, dd, J=9.6, 4.6Hz), 5.01 (2H, s), 6.78 (2H, m), 6.90 (2H, m), 7.29-7.46 (5H, m).
Example 2
(±) (3a, 9aa)-3-(3,4-Dichlorophenoxymethyl)quinoiizidine hydrochlonde
The title compound was prepared in a similar manner to Example 1 from (±) 3- hydroxymediylquinolizidine (0.51 g, 3.0 mmol), 3,4-dichlorophenol (0.49 g, 3.0 mmol), triphenylphosphine (0.79 g, 3.0 mmol) and diediyl azodicarboxylate (0.47 ml, 3.0 mmol). After a reaction time of 2h at room temperature the mixture was worked up as described in Example 1. The pentane extract was further purified by column chromatography on neutral alumina using 0-1% methanol in chloroform as eluant. Pooling of fractions containing the major slower running component afforded a ciystallising oil which was converted into the title hydrochlonde salt°(0.17 g) mp 235-237°C (dec) (from methanol/acetone/diethylether).
XH Nmr (CDCI3) δ: 1.35-1.70 (2H, ), 1.75-2.50 (8H, m), 2.55-2.80 (3H, m), 2.92-3.10 (IH, m), 3.45 (2H, m), 3.78 (IH, dd, J=9, 6Hz), 3.92 (IH, dd, J=9, 4Hz), 6.70 (IH, dd, J=8, 2Hz), 6.95 (IH, d, J=2Hz), 7.30 (IH, d, J=8Hz). Example 3
(±) (lα, 9aα)-l-(4-Benzyloxyphenoxymethyl)quinoIizidine hydrochloride
The title compound was prepared in a similar manner to Example 1 from (±) 1- hydroxymediylquinolizidine (75:25 mixture of equatorial and axial isomers)(0.21 g, 1.24 mmol), 4-benzyloxyphenol (0.25 g, 1.24 mmol), triphenylphosphine (0.33 g, 1.24 mmol) and diediyl azodicarboxylate (0.2 ml, 1.24 mmol). The reaction was stirred overnight at room temperature, and tiien worked up as described in Example 1 to give the title hydrochloride salt (0.15 g) mp 227-229°C (from methanol/acetone/diediyl etiier). *H Nmr (CDCI3) δ: 1.45 (IH, m), 1.72-2.15 (7H, m), 2.30-2.75 (5H, m), 2.98 (IH, m), 3.42 (2H, m), 3.78 (IH, dd, J=8, 1Hz), 4.06 (IH, dd, J=8, 3Hz), 5.00 (2H, s), 6.80 (2H, d, J=8Hz), 6.89 (2H, d, J=8Hz), 7.35 (5H, m).
Example 4 (±) (lα, 9aα)-l-(3,4-Dichlorophenoxymethyl)quinolizidine hydrochloride
The tide compound was prepared in a similar manner to Example 1 from (±) 1- hydroxymediylquinolizidine (75:25 mixture of equatorial and axial isomers) (0.51 g, 3.0 mmol), 3,4-dichlorophenol (0.54 g, 3.3 mmol), triphenylphosphine (0.87 g, 3.3 mmol) and diediyl azodicarboxylate (0.52 ml, 3.3 mmol). After a reaction time of 2h, tiiin layer chromatography (neutral alumina using 2.5% ethanol in chloroform as eluant) indicated that preferential reaction of the major slower running alcohol precursor had occurred. The reaction was worked up as described in Example 1 to give the title hydrochloride salt (0.57 g) mp 179-181°C (from metiianol/acetone/dietiiyl ether). !H Nmr (CDCI3) δ: 1.50 (IH, m), 1.70-2.18 (7H, m), 2.32-2.88 (5H, m), 3.00 (IH, m), 3.50 (2H, m), 3.88 (IH, dd, J=9, 2Hz), 4.14 (IH, dd, J=9, 3Hz), 6.80 (IH, dd, J=9, 3Hz), 7.02 (IH, d, J=3Hz), 7.40 (IH, d, J=9Hz).
Example 5
(±) (2β, 9aα)-2-[2-(4-Benzyloxyphenoxy)ethyl]quinoIizidine hydrochloride The title compound was prepared in a similar manner to Example 1 from (±) (2β, 9aα)-2- (2-hydroxyethyl)quinolizidine (0.32 g, 1.75 mmol), 4-benzyloxyphenol (0.46 g, 2.3 mmol), triphenylphosphine (0.60 g, 2.3 mmol), and diethyl azodicarboxylate (0.36 ml, 2.3 mmol). After stirring overnight at room temperature the reaction was worked up as described in Example 1 to give the title hydrochloride salt (0.33 g) mp 199-202°C (from methanol/diethyl edier).
*H Nmr (CDCI3 δ: 1.48 (IH, m), 1.70-2.85 (15H, m), 3.45 (2H, m), 3.95 (2H, m), 5.03 (2H, s), 6.78 (2H, d, J=8Hz), 6.90 (2H, d, J=8Hz), 7.35 (5H, m). Example 6
(±) (2β, 9aα)-2-[2-(3,4-DichIorophenoxy)ethylJquinolizidine hydrochloride
The tide compound was prepared in a similar manner to Example 1 from (±) (2β, 9aα)-2- (2-hydroxyedιyl)quinolizidine (0.28 g, 1.5 mmol), 3,4-dichlorophenol (0.32 g, 2.0 mmol), triphenylphosphine (0.52 g, 2.0 mmol) and diediyl azodicarboxylate (0.32 ml, 2.0 mmol).
After stirring at room temperature for 6h, the reaction was worked up as described in
Example 1 to give the title hydrochloride salt (0.3 g) mp 189-191°C (from methanol/diethyl ether). 1H Nmr (CDCI3) δ: 1.48 (IH, m), 1.70-2.88 (15H, m), 3.45 (2H, ), 3.95 (2H, m), 6.72
(IH, dd, J=9, 3Hz), 6.95 (IH, d, J=3Hz), 7.31 (IH, d, J=9Hz). '
Example 7
(±) (3α, 9aα)-3-[5-(2-Dibenzofuranyloxy)pentyI]quinoIizidine hydrochloride (E7a) (Equator'al isomer) and (±) (3β, 9aα)-3-[5-(2-Dibenzofuranyloxy)pentyI]- quinolizidine hydrochloride (E7b) (Axial isomer).
Stage 1
A stirred solution of diisopropylamine (0.57 g, 5.66mmol) in dry tetrahydrofuran was cooled under nitrogen to -65°C and treated with n-butyllitiiium (3.3 ml of a 1.6M solution in hexanes, 5.28 mmol). The mixture was allowed to warm to -20°C and tiien cooled to - 65°C. A solution of quinolizidin-4-one (V. Boekelheide and S. Rothchild, J. Am. Chem. Soc., 1949, 71, 879) (0.51 g, 3.3 mmol) in dry tetrahydrofuran (3 ml) was added dropwise, whilst maintaining the temperature below -60°C. The reaction was stirred for a further lOmin. and then treated witii a solution of 2-(5-bromopentyloxy)dibenzofuran (1.66 g, 5.0 mmol) in dry tetrahydrofuran (5 ml). The reaction mixture was allowed to warm slowly to room temperature and then left stiπing overnight. The reaction was quenched witii glacial acetic acid (0.8 ml) and then concentrated in vacuo. The residue was partitioned between saturated aqueous potassium carbonate (20 ml) and chloroform (25 ml). The aqueous phase was further extracted with chloroform (2x25 ml) and die combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel using a graded eluant of 20% diethyl ether in petroleum ether to pure diethyl ether, followed by 1-2% methanol in diethyl ether. The faster running component was isolated as a solid (0.69 g) and the slower running component was obtained as an oil (0.55 g). A solution of the faster running component (0.6 g, 1.48 mmol) in dry diediyl edier (10 ml) was added dropwise under nitrogen to a suspension of lithium aluminium hydride (0.32 g, 8.42 mmol) in dry diediyl etiier (20 ml). After stirring at room temperature for 1 h the reaction was quenched with wet diethyl edier followed by a minimum amount of water. The mixture was filtered and die precipitate was washed widi 5% methanol in diethyl ether. The combined filtrate and washings were concentrated in vacuo. The residue was treated widi saturated aqueous potassium carbonate and extracted into chloroform (3x20 ml). The combined organic layers were dried over sodium sulphate and concentrated in vacuo. Purification by flash chromatography on neutral alumina using a graded eluant of 2-5% edianol in chloroform afforded an oil (0.35 g) which solidified on cooling and was converted into die title hydrochloride salt (E7a), mp 205-207°C (from methanol/diethyl ether). !H Nmr (DMSO-d^ δ: 1.05-1.63 (10H, m), 1.65-1.85 (8H, m), 1.90 (IH, m), 2.55 (IH, m), 2.81 (IH, m), 2.88 (IH, m), 3.25 (2H, m), 4.07 (2H, t, J=7Hz), 7.08 (IH, dd, J= 6, 1.5Hz), 7.37 (IH, t, J=7Hz), 7.50 (IH, t, J=7Hz), 7.58 (IH, d, J=7Hz), 7.72 (IH, d, J=1.5Hz), 8.13 (IH, d, J=7Hz).
The slower running component (0.3 g, 0.74 mmol) was reduced with lithium aluminium hydride (0.14 g, 3.68 mmol) and worked up as described above to give an oil (0.23 g) which was purified by chromatography on neutral alumina using chloroform as eluant and then converted into die title hydrochloride salt (E7b), mp 124-127°C (from methanol/diethyl edier). H Nmr of free base (CDC13) δ: 1.18-1.76 (18H, m), 1.78-1.96 (3H, m), 2.10 (IH, dd, J=10, 2Hz), 2.61 (IH, d, J=l IHz), 2.67 (IH, d, J=l IHz), 4.05 (2H, t, J=7Hz), 7.03 (IH, dd, J=7, IHz), 7.25-7.58 (5H, m, overlapping signals), 7.90 (IH, d, J=6Hz).
Example 8
(±) (2β, 9aα)-2-[2-(3,4-Dichlorobenzyloxy)ethyI]quinoIizidine hydrochloride (E8) A solution of (±) (2β, 9aα)-2-(2-hydroxyethyl)quinolizidine (0.18 g, 1.0 mmol) in dry N,N-dimedιylformamide (5 ml) was treated witii sodium hydride (33 mg of an 80% dispersion in oil; 1.1 mmol) and stirred under nitrogen at 50°C for 2h. To this solution was added dropwise a solution of 3,4-dichlorobenzyl p-toluenesulphonate (0.33 g, 1.0 mmol) in N,N-dimeriιylformamide (1 ml). After stirring overnight the the reaction was concentrated in vacuo using azeotropic distillation with toluene. The residue was extracted into a mixture of diediyl edier and ediyl acetate and washed with water followed by brine. The organic layer was dried over sodium sulphate and concentrated in vacuo. Chromatography on silica gel using 0-20% ethanol in chloroform as eluant afforded an oil (E8) mp 170-172°C (from acetone/diethyl ether).
*H Nmr (CDCI3) δ: 1.45 (IH, m), 1.51-2.18 (11H, m), 2.30-2.75 (4H, m), 3.42 (2H, br d, J=12Hz), 3.50 (2H, t, J=6.5Hz), 4.42 (2H, s), 7.13 (IH, dd, J=7, IHz), 7.42 (2H, m).
Example 9
(±) (3α, 9aα) and (3β, 9aα)-3-(3,4-Dichlorobenzyloxymethyl)quinolizidine hydrochloride (E9)
A solution of (±) 3-hydroxymethylquinolizidine (mixture of diastereomers) (1.0 g, 5.9 mmol) in dry N,N-dimedιylformamide (30 ml) was treated widi sodium hydride
(0.16 g of an 80% dispersion in oil; 6.5 mmol) and stirred under nitrogen at 40-50°C for 2h. The temperature was raised to 50-60°C and a solution of 3,4-dichlorobenzyl p- toluenesulphonate (1.29 g, 3.9 mmol) in N,N-dimethylformamide (6 ml) was added dropwise over a period of 3.5h. At this stage thin layer chromatography (silica gel, 20% ethanol in chloroform) indicated tiiat most of the slower running equatorial isomer had been consumed. The reaction was concentrated in vacuo using azeotropic distillation with toluene. The residue was partitioned between water and diethyl edier and the aqueous layer was further extracted widi diethyl ether. The combined organic extracts were dried over sodium sulphate and concentrated to give a brown syrup (1.5 g). Chromatography on neutral alumina using 0-20% ethanol in chloroform as eluant afforded an oil which was converted into the title hydrochloride salt°(E9), mp 128-135°C (from acetone/diediyl ether) and shown by NMR to consist of a 4: 1 mixture of equatorial and axial isomers. H Nmr (DMSO-c δ: 1.30-3.20 (14H, m), 3.23-3.70 (4H, m), 4.40 (IH, d, J=14Hz) and 4.48 (IH, d, J=14Hz)(major isomer), 4.55 (IH, d, J=12Hz) and 4.86 (IH, d, J=12Hz)(minor isomer), 7.13 ( IH, d, J=7Hz)(major isomer), 7.26 ( IH, d, J=7Hz)(minor isomer), 7.42 (2H, m).
Example 10
(+) (3α, 9aα) 3-[3-(4-Benzyloxyphenyl)propyloxymethyl]quinolizidine hydrochloride (JEW)
A solution of (±) 3-hydroxymedιylquinolizidine (mixture of diastereomers) (1.0 g, 5.9 mmol) in dry N,N-dimetiιylformamide (30 ml) was treated widi sodium hydride (0.16 g of an 80% dispersion in oil; 6.5 mmol) and stirred under nitrogen at 40°C for 2h. The temperature was raised to 50-60°C and a solution of 3-(4-benzyloxyphenyl)propyl p- toluenesulphonate (1.42 g, 3.9 mmol) in N,N-dimedιylformamide (6 ml) was added dropwise over a period of 6h. Stirring was continued at this temperature for a further 2h. The reaction was worked up as described in Example 9. Chromatography on neutral alumina using 0-1% ethanol in chloroform as eluant afforded an oil (1.17 g) consisting of two c ose runn ng components y t n ayer c romatograp y neutra a um na, et ano in chloroform). The mixture was converted into die hydrochloride salt and purified by fractional crystallisation from diethyl ether/acetone. The first crop mother liquors were crystallised to afford the title hydrochloride salt (E10), mp 105-108°C (from acetone/diethyl ether).
*H Nmr (CDCI3) δ: 1.30-2.85 (21H, m), 3.20-3.55 (3H, m), 5.05 (2H, s), 6.90 (2H, d, J=8Hz), 7.09 (2H, d, J=8Hz), 7.23-7.55 (5H, ).
Example 11 (±) (lα, 9aα) l-[4-(Phenoxy)phenoxymethyl]quinolizidine hydrochloride (Ell)
The tide compound was prepared in a similar manner to Example 1 from (±) (lα, 9aα)-l- hydroxymetiiylquinolizidine (0.2 g, 1.18 mmol), 4-phenoxyphenol (0.4 g, 2.15 mmol), triphenylphosphine (0.43 g, 1.65 mmol) and diethyl azodicarboxylate (0.26 ml, 1.65 mmol). After stirring at room temperature overnight the reaction was worked up as described in Example 1 to give the title hydrochloride salt (Ell), mp 223-225°C (from methanol/acetone/dietiiyl ether).
*H Nmr (CDCI3) δ: 1.48 (IH, m), 1.75-2.20 (7H, m), 2.25-2.80 (5H, m), 3.00 (IH, m), 3.45 (2H, br t, J=l IHz), 3.82 (IH, dd, J=8, 1.5Hz), 4.12 (IH, dd, J=8, 2Hz), 6.80-7.15 (7H, m), 7.32 (2H, d, J=8Hz).
Example 12
(±) (3α, 9aα)-3-[6-(4-Phenoxyphenyl)hexyl]quinolizidine hydrochloride (12a) (Equatorial isomer) and (±) (3β, 9aα)-3-[6-(4-Phenoxyphenyl)hexyl]quinoIizidine hydrochloride (12b) (Axial isomer). Stage 1
A stirred solution of diisopropylamine (0.78 g, 7.7 mmol) in dry tetrahydrofuran (30 ml) was cooled under nitrogen to -65°C and treated dropwise widi n-butyllithium (4.5 ml of a 1.6M solution in hexanes, 5.28 mmol) keeping the temperature below -60°C. After 15min the reaction was treated with a solution of N,N,Nl,Nl-tetramethylethylenediamine (0.84 g, 7.2 mmol) in dry tetrahydrofuran (2 ml). The mixture was allowed to warm to -20°C and tiien cooled to back to -65°C. A solution of quinolizidin-4-one (V. Boekelheide and S. Rothchild, J. Am. Chem. Soc., 1949, 71, 879.) (0.85 g, 5.5 mmol) in dry tetrahydrofuran (4 ml) was added dropwise, whilst maintaining the temperature below -60°C. The reaction was stirred for a further 15min and then treated dropwise with a solution of 6-[4- (phenoxy)phenyljhexyl bromide (2.4 g, 7.2 mmol) in dry tetrahydrofuran (4 ml). The reaction mixture was allowed to warm slowly to room temperature and tiien left stirring overnight. The reaction was quenched with glacial acetic acid (0.86 ml) and then concentrate n vacuo. e res ue was par one etween water m an e iy edier (25 ml). The aqueous phase was further extracted with diediyl edier (2x25 ml) and the combined organic layers were washed widi brine, dried over sodium sulphate and concentrated in vacuo. The residual brown oil (2.7 g) was purified on silica gel using a graded eluant of 20-90% diediyl ether in petroleum ether. The faster running component was isolated as an oil (0.80 g) and die slower running component was also obtained as an oil (0.38 g).
Stage 2 A solution of the faster running component (0.74 g, 1.8 mmol) in dry tetrahydrofuran
(20 ml) was added dropwise under nitrogen to a suspension of lithium aluminium hydride (0.35 g, 9.1 mmol) in dry diethyl edier (50 ml). After stirring at room temperature for 0.5 h the reaction was quenched witii wet diediyl edier followed by a minimum amount of water. The mixture was filtered and die precipitate was washed witii 5% methanol in diediyl edier. The combined filtrate and washings were concentrated in vacuo to give a colourless oil which was extracted into pentane and converted into d e title hydrochloride salt (E12a) (0.51 g), mp 131-133°C (from acetone/diethyl ether). *H Nmr (CDC13) δ: 0.98-2.75 (26H, m), 3.28 (IH, br d, J=10Hz), 3.40 (IH, br d, J=10Hz), 6.78-7.45 (9H, m).
The slower running component (0.4 g, 1.0 mmol) was reduced widi lithium aluminium hydride (0.19 g, 5.0 mmol) and worked up as described above to give an oil which was extracted into pentane and then converted into die title hydrochloride salt (E12b) (0.36 g), mp 149-149.5°C (from acetone/diethyl ether). H Nmr of free base (CDCI3) δ: 1.10-1.65 (22H, m), 1.90 (IH, m), 2.08 (IH, br d, J=l IHz), 2.45-2.75 (2H, t, J=7Hz ± 2H, m), 6.80-7.40 (9H, m).
Example 13
(±) (lα, 9aα)-l-(4-Benzylphenoxymethyl)quinolizidine hydrochloride (E13) The title compound was prepared in a similar manner to Example 1 from (±) (lα, 9aα)-l- hydroxymethylquinolizidine (0.17 g, 1.0 mmol), 4-benzylphenol (0.24 g, 1.3 mmol), triphenylphosphine (0.34 g, 1.3 mmol) and diethyl azodicarboxylate (0.21 ml, 1.3 mmol). After stirring at room temperature for 6h the reaction was concentrated in vacuo. The residue was partitioned between chloroform and water, and the pH of the aqueous layer was adjusted to 9 with sodium hydrogen carbonate. The aqueous phase was further extracted widi chloroform, and the combined organic layers were washed with brine, dried over sodium sulphate and concentrated in vacuo. The residue was extracted into pentane and converted into the title hydrochloride salt (E13) (0.14 g), mp 158-161°C (from acetone/diediyl ether). lH Nmr (CDCI3) δ: 1.42 (IH, m), 1.65-2.1°5 (7H, m), 2.25-2.80 (5H, m), 2.96 (IH, m), 3.45 (2H, m), 3.80 (IH, dd, J=8, IHz), 3.93 (2H, s), 4.10 (IH, dd, J=8, 3Hz), 6.80 (IH, d, J=8Hz), 7.02-7.40 (7H, m).
Example 14
(±) (3α, 9aα)-3-[5-(4-Benzyloxyphenoxy)pentyl]quinoIizidine hydrochloride (E14a) (Equatorial isomer) and (±) (3β, 9aα)-3-[5-(4-Benzyloxyphenoxy)pentyl]quinolizidine hydrochloride (14b) (Axial isomer).
Stage 1
A solution of lithium diisopropylamide in tetrahydrofuran was generated from diisopropylamine (0.565 g, 5.6 mmol), n-butyllithium (3.25 ml of a 1.6M solution in hexanes, 5.2 mmol) and N,N,Nl,Nl-tetramethylethylenediamine (0.78 ml, 5.2 mmol). To this solution was added quinolizidin-4-one (0.61 g, 4.0 mmol) followed by 5-(4- benzyloxyphenoxy)pentyl bromide (1.73 g, 5.2 mmol) according to the procedure described in Example 12. After stirring overnight the reaction was quenched widi glacial acetic acid (0.63 ml) and worked up as described in Example 12 to give a light brown syrup which was purified on a silica gel column using a graded eluant of 30% diediyl edier in petroleum ether 40/60 to pure diethyl ether. The faster running component was isolated as a colourless solid (0.64 g), mp 78.5-79°C and the slower running component was obtained as an oil (0.62 g).
Stage 2 The faster running component (0.52 g, 1.29 mmol) was treated with lidiium aluminium hydride (0.1 g, 2.59 mmol) in dry tetrahydrofuran as described in Example 12. After lh at room temperature the reaction was worked up as described in Example 12 and then purified on silica gel using 1-5% ethanol in chloroform as eluant. Pooling of pure fractions afforded a solid (0.36 g) which was converted into the title hydrochloride salt (E14a), mp 155- 157°C (from methanol/diethyl ether).
*H Nmr (CDCI3) δ: 0.98-2.70 (22H, m), 3.60 (IH, d, J=l IHz), 3.40 (IH, d, J=l 1Hz), 3.90 (2H, t, J=7Hz), 5.00 (2H, s), 6.80 (2H,d, J=9Hz), 6.90 (2H, d, J=9Hz), 7.28-7.50 (5H, m).
The slower running component (0.59 g, 1.46 mmol) was reduced with lithium aluminium hydride (0.11 g, 2.9 mmol) in dry diethyl edier and worked up as described in Example 12. The product was purified on silica gel using diediyl ether as eluant. Pooling of fractions containing the major less mobile product afforded a colourless solid (0.4 g) which was converted into die title hydrochloride salt (E14b), mp 158-161°C (from acetone/dietiiyl ether).
ΪH Nmr of free base (CDCI3) δ: 1.20-1.83 (20H, m), 1.89 (IH, dt, J=12, 3Hz), 2.09 (IH, dd, J=12, 3Hz), 2.59 (IH, d, J=12Hz), 2.66 (IH, d, J=12Hz), 3.90 (2H, t, J=6.5Hz), 5.01 (2H, s), 6.82 (2H, d, J=8Hz), 6.88 (IH, d, J=8Hz), 7.28-7.45 (5H, m).
Example 15
(±) (lα, 9aα)-l-[5-(2-Phenylbenzo[b]furanyIoxy)methyl]quinoIizidine hydrochloride
(E15) The title compound was prepared in a similar manner to Example 1 from (±) (lα, 9aα)-l- hydroxymediylquinolizidine (0.1 g, 0.59 mmol), 5-hydroxy-2-phenylbenzo[b]furan (0.15 g, 0.77 mmol), triphenylphosphine (0.2 g, 0.77 mmol) and diethyl azodicarboxylate (0.12 ml, 0.77 mmol). After stirring at room temperature overnight the reaction was worked up as described in Example 13. The crude product was extracted into diediyl edier/pentane. Purification on a silica gel column using 0-15% ethanol in chloroform as eluant afforded a colourless solid (0.1 g) which was converted into the title hydrochloride salt (E15) (50 mg), mp 244-246°C (from acetone/diethyl ether). 1H Nmr (CDCI3) δ: 1.46 (IH, m), 1.75-2.20 (7H, m), 2.30-2.80 (5H, m), 3.02 (IH, m), 3.46 (2H, m), 3.88 (IH, d, J= 8Hz), 4.17 (IH. dd, J=8, 1.5Hz), 6.83 (IH, dd, J=8, IHz), 6.98 (2H, d, J=8Hz), 7.30-7.53 (4H, m), 7.86 X , d, J=7Hz).
Example 16
(±) (3α, 9aα)-3-[4-(4-Benzyloxyphenoxy)butyl]quinolizidine hydrochloride (16a) (Equatorial isomer) and (±) (3β, 9aα>3-[4-(4-benzyloxyphenoxy)butyl]quinoIizidine hydrochloride (16b) (Axial isomer).
Stage 1
A solution of lidiium diisopropylamide in tetrahydrofuran was generated from diisopropylamine (0.49 g, 4.9 mmol), n-butyl lithium (2.84 ml of a 1.6M solution in hexanes, 4.55 mmol) and N,N,Nl,N^-tetramethylethylenediamine (0.685 ml, 4.55 mmol). To this solution was added quinolizidin-4-one (0.535 g, 3.5 mmol) followed by 4-(4- benzyloxyphenoxy)butyl bromide (1.45 g, 4.55 mmol) according to die procedure described in Example 12. After stirring overnight the reaction was quenched with glacial acetic acid (0.57 ml) and worked up as described in Example 12 to give a yellow solid which was purified on a silica gel column using 30-90% diethyl ether in petroleum ether 40/60 as eluant. The faster running component was isolated as a colourless solid (0.34 g). The slower running component was obtained as an oil (0.32 g) which solidified on standing. Stage 2
The faster running component (0.32 g, 0.79 mmol) was treated widi lithium aluminium hydride (0.14 g, 3.9 mmol) in dry tetrahydrofuran as described in Example 12. After 0.75h at room temperature the reaction was worked up as described in Example 12 and then purified on a silica gel column using diediyl ether as eluant Pooling of pure fractions containing the major less mobile product afforded a colourless solid (0.15 g) which was converted into the title hydrochloride salt (E16a) (0.13 g), mp 171-172°C (from acetone/diediyl ether). iH Nmr (CDC13) δ: 1.10 (IH, m), 1.15 -1.60 (5H, m), 1.62-1.85 (5H, m), 1.87-2.28 (5H, m), 2.83-2.65 (4H, m), 3.30 (IH, br d, J=12Hz), 3.40 (IH, br d, J=12Hz), 3.89 (2H, t, J=6.5Hz), 5.01 (2H, s), 6.82 (2H, d, J=8Hz), 6.88 (2H, d, J=8Hz), 7.28-7.47 (5H,m).
The slower running component (0.31 g, 0.76 mmol) was reduced with lithium aluminium hydride (0.14 g, 3.8 mmol) in dry diediyl edier. The reaction was worked up as described in Example 12 and die product was converted into die title hydrochloride salt (E16b)
(0.23 g), mp 148.5-149.5°C (from acetone/diethyl ether).
*H Nmr (CDCI3) δ: 1.05-3.35 (21H, ), 3."45 (IH, m), 3.92 (2H, m, overlapping signals),
5.00 and 5.01 (conformers) (2H, s), 6.82 and 6.84 (confoimers) (2H, d, J=9Hz), 6.90 and 6.92 (conformers) (2H, d, J=9Hz), 7.29-7.50 (5H, m).
Example 17
(±) (3α, 9aα)-3-[3-(4-Benzyloxyphenoxy)propyIJquinoIizidine hydrochloride (E17a) (Equatorial isomer) and (±) (3β, 9aα)-3-[3-(4-Benzyloxyphenoxy)propyl]- quinolizidine hydrochloride (E17b) (Axial isomer).
Stage 1
A solution of lidiium diisopropylamide in tetrahydrofuran was generated from diisopropylamine (0.49 g, 4.9 mmol), n-butyllithium (2.84 ml of a 1.6M solution in hexanes, 4.55 mmol) and N,N,N^,N^-tetramethylethylenediamine (0.685 ml, 4.55 mmol). To this solution was added quinolizidin-4-one (0.535 g, 3.5 mmol) followed by 3-(4- benzyloxyphenoxy)propyl bromide (1.39 g, 4.55 mmol) according to die procedure described in Example 12. After stirring overnight the reaction was quenched with glacial acetic acid (0.57 ml) and worked up as described in Example 12. Purification on a silica gel column using 40-90% diethyl ether in petroleum ether 40/60 as eluant afforded the faster running component as a colourless solid (0.29 g) and the slower running component as an oil (0.27 g). Stage 2
The faster running component (0.28 g, 0.71 mmol) was treated witii lithium aluminium hydride (0.135 g, 3.56 mmol) in dry tetrahydrofuran and worked up as described in Example 12. Purification on a silica gel column using diediyl edier as eluant afforded a colourless solid (90 mg) which was converted into the title hydrochloride salt (E17a) (75 mg), mp 182-183.5°C (from methanol/acetone/diediyl edier). *H Nmr (CDCI3) δ: 1.12 (IH, ), 1.28-1.53 (3H, m), 1.68-1.89 (5H, m), 1.90-2.17 (4H, m), 2.23 (IH, q, J=10Hz), 2.35-2.70 (4H, m), 3.32 (IH, br d, J=12Hz), 3.41 (IH, br d, J=12Hz), 3.90 (2H, t, J=6.5Hz), 5.01 (2H, s), 6.80 (2H, d, J=8Hz), 6.88 (2H, d, J=8Hz), 7.28-7.50 (5H, m).
The slower running component (0.27 g, 0.69 mmol) was reduced widi lithium aluminium hydride (0.135 g, 3.55 mmol) in dry diethyl ether. The reaction was worked up as described in Example 12 and die product was converted into die title hydrochloride salt (E17b) (0.17 g), mp 159-160.5°C (from methanol/acetone/diethyl ether). lH Nmr (CDCI3) δ: 1.10-3.38 (19H, m), 3.48 (IH, m), 3.82-4.10 (2H, m, overlapping signals), 5.00 and 5.02 conformers) (2H, s), 6.82 and 6.84 (conformers) (2H, d, J=9Hz), 6.89 and 6.91 (conformers) (2H, d, J=9Hz), 7.28-7.50 (5H,m).
Example 18
(±) (3α, 9aα)-3-[2-(4-Benzyloxyphenoxy)ethyI]quinoIizidine hydrochloride (E18a) (Equatorial isomer) and (±) (3β, 9aα)-3-[2-(4-Benzyloxyphenoxy)ethyl]quinolizidine hydrochloride (E18b) (Axial isomer).
Stage 1 A solution of lithium diisopropylamide in tetrahydrofuran was generated from diisopropylamine (0.43 g, 4.3 mmol), n-butyllithium (2.5 ml of a 1.6M solution in hexanes, 4.0 mmol) and N,N,N^,N^-tetramethylethylenediamine (0.6 ml, 4.0 mmol). To this solution was added quinolizidin-4-one (0.47 g, 3.07 mmol) followed by 2-(4- benzyloxyphenoxy)ethyl bromide (1.22 g, 4.0 mmol) according to the procedure described in Example 12. After stiπing overnight the reaction was quenched with glacial acetic acid (0.46 ml) and worked up as described in Example 12. Purification on silica gel using 50- 100% diethyl edier in petroleum ether 40/60 as eluant afforded the faster running • component as a colourless solid (0.43 g) and die slower running component as a colourless solid (0.45 g). Stage 2
The faster running component (0.30 g, 0.79 mmol) was treated with lithium aluminium hydride (0.15 g, 3.9 mmol) in dry tetrahydrofuran and worked up as described in Example 12. Purification on a silica gel column using 1 -5% ethanol in chloroform as eluant afforded a pale yellow solid (90 mg) which was converted into die title hydrochloride salt (E18a), mp 192-195°C (from methanol/acetone/diethyl ether). *H Nmr (CDCI3) δ: 1.25 (IH, m), 1.45 (IH, m), 1.62-1.85 (5H, m), 1.88-2.20 (4H, m), 2.40 (2H, m), 2.50-2.75 (3H, m), 3.41 (2H, br d, J=12Hz), 3.98 (2H, t, J=7Hz), 5.00 (2H, s), 6.80 (2H, d, J=9Hz), 6.90 (2H, d, J=9Hz), 7.30-7.45 (5H, m).
The slower running component (0.44 g, 1.16 mmol) was reduced widi lidiium aluminium hydride (0.135 g, 3.55 mmol) in a mixture of dry tetrahydrofuran and dry diethyl edier. The reaction was worked up as described in Example 12 to give a colourless solid (0.41 g) which was converted into the title hydrochloride salt (E18b), mp 147-149°C (from acetone)
*H Nmr (CDCI3) δ: 1.20-3.38 (17H, m), 3.45 (IH, m), 3.95-4.18 (2H, m), 5.00 and 5.02 (conformers) (2H, s), 6.78 and 6.80 (conformers) (2H, d, J=9Hz), 6.88 and 6.90 (conformers) (2H, d, J=9Hz), 7.30-7.48 (5H, m).
Example 19
(±) (3α, 9aα 3-(4-Benzylphenoxymethyl)quinolizidine hydrochloride (E19) (Equatorial isomer).
The title compound was prepared in a similar manner to Example 1 from (±) 3- hydroxymediylquinolizidine (75:25 mixture of equatorial and axial isomers)(0.32 g, 1.90 mmol), 4-benzylphenol (0.35 g,1.90 mmol), triphenylphosphine (0.5 g, 1.90 mmol) and diediyl azodicarboxylate (0.30 ml, 1.90 mmol). After stirring at room temperature for 6h, thin layer chromatography (alumina; 5% methanol in chloroform) indicated diat most of the slower running equatorial alcohol had been consumed leaving die axial isomer largely intact The reaction was worked up as described in Example 13. The crude product was extracted into pentane and converted into die title hydrochloride salt (E19) (0.18 g), mp 179-181°C (from acetone/diethyl ether). lH Nmr (CDCI3) δ: 1.47 (IH, m), 1.63 (IH, m), 1.70-2.28 (7H, m), 2.40 (IH, m), 2.55- 2.75 (3H, m), 2.95 (IH, m), 3.42 (2H, m), 3.79 (IH, dd, J=9.6, 4.8Hz), 3.90 (3H, m, overlapping signals), 6.77 (2H, d, J=2Hz), 7.09 (2H, d, J=8.8Hz), 7.16 (3H, m), 7.27 (2H, t, J=7.2Hz), Example 20
(±) (3β, 9aα)-3-(4-Benzoylphenoxymethyl)quinolizidine hydrochloride (E20) (Axial isomer).
A solution of (±) (3β, 9aα)-3-hydroxymetiιylquinolizidine (0.57 g, 3.37 mmol) in dry dimediyl sulphoxide (10 ml) was treated under argon widi sodium hydride (0.12 g of an 80% dispersion in oil, 4.04 mmol) and die mixture was stirred at room temperature for 2h. A solution of 4-fluorobenzophenone (0.81 g, 4.04 mmol) in dry dimethyl sulphoxide (10 ml) was added slowly, and die stirred mixture was then warmed to 75°C over 30 min and maintained at this temperature for a further 45 min. After being cooled in ice die reaction was quenched widi glacial acetic acid (0.5 ml). The mixture was concentrated in vacuo using azeotropic distillation widi xylene. The residue was partitioned between water and chloroform. The aqueous phase was saturated witii potassium carbonate and further extracted with chloroform. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. Chromatography on neutral alumina using 0-1% ethanol in chloroform as eluant afforded a pale yellow oil (1.2 g). A portion of this material was converted into the title hydrochloride salt (E20), mp 191-193°C (from acetone/diediyl ether).
1H Nmr (CDC13) δ: 1.40-2.30 (9H, m), 2.42-3.00 (4H, m), 3.10-3.60 (3H, m), 3.93 (IH, dd, J=9.5, 6Hz) and 4.04 (IH, dd, J=9.5, 4Hz)(minor conformer), 4.62 (IH, dd, J=10, 6.5Hz) and 4.68 (IH, dd, J= 10, 10Hz)(major conformer), 6.93 (2H, d, J=9Hz)(minor conformer), 7.10 (2H, d, J=9Hz)(major conformer), 7.42-7.88 (7H, m).
Example 21
(±) (3β, 9aα)-3-(4-Benzylphenoxymethyl)quinolizidine hydrochloride (E21) (Axial isomer).
To an ice-cooled solution of (±) (3β, 9aα)-3-(4-benzoylphenoxymethyl)quinolizidine (0.84 g, 2.4 mmol) in dry dichloromethane (10 ml) containing trifluoroacetic acid (15 ml) was added one pellet of sodium borohydride (0.4 g). The reaction was stirred at ice temperature for 6h and then at room temperature overnight. A second pellet of sodium borohydride (0.4 g) was added widi ice cooling and the mixture was stirred overnight at room temperature. The reaction was cooled in ice, treated widi water (20 ml) and basified with sodium hydroxide pellets. After extraction into diethyl edier (4x30 ml) the combined organic layers were dried over sodium sulphate and concentrated in vacuo. Chromatography on silica gel using diediyl edier as eluant afforded a pale yellow oil (0.69 g) which solidified on standing, and was converted into the title hydrochloride salt (E21) (0.5 g), mp 212-214°C (dec.)(from methanol/acetone/dietiiyl ether). *H Nmr (CDCI3) δ: 1.40-2.30 (9H, m), 2.35-3.55 (7H, m), 3.81 (IH, dd, J=10, 5.5Hz) and 3.92 (IH, dd, J=10, 4Hz)(minor conformer), 3.90 and 3.92 (2H, s)(conformers), 4.45 (IH, dd, J=10, 6Hz) and 4.55 (IH, dd, J=10, 10Hz)(major conformer), 6.79 (2H, d, J=llHz)(minor conformer), 6.95 (2H, d, J=llHz)(major conformer), 7.05-7.30 (7H, m).

Claims

Use of a compound of formula (I):
Formula (I) in which p, and q each independently represent an integer from 3 to 5; n is 0 to 6; m is 0 to 6;
A is a bond, -CH=CH-, -C≡C-, oxygen, sulphur or NR1;
R1 is hydrogen, Cj.galkyl orphenylCj.4alkyl; and
Ar is aryl or heteroaryl, each of which may be optionally substituted; or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of disorders wherein a calcium channel antagonist is indicated.
2. A compound of formula (IA) :
Formula (IA) in which : p and q each independently represent an integer from 3 to 5; A is a bond, -CH=CH-, -C≡C-, oxygen, sulphur or NR*; R1 is hydrogen, Cj.galkyl 0rphenylC1.4a._kyl; na is 0 to 6 and ma is 0 to 6 such tiiat the length of the chain (CH2)naA(CH2)ma is at least
2 atoms when A is other than S or a bond and is at least 3 atoms when A is S or a bond; and Ar is aryl or heteroaryl, each of which may be optionally substituted, with the provisos that a) when A is a bond die group -(CH2)naA(CH2)ma is not α to the azabicyclic nitrogen atom; b) when A is oxygen, p and q are both 3 or both 4, na is 0 to 6 and a is zero or 1 tiien Ar is not unsubstitued phenyl; and c) when A is NH, p and q do not both represent 4; or a salt thereof.
3. A compound according to claim 2 wherein p and q are independently 3 or 4.
4. A compound according to either claim 2 or claim 3 wherein A is oxygen or a bond.
5. A compound according to any of claims 2 to 4 wherein the length of the chain -(CH2)nA(CH2)m is from 2 to 6 atoms.
6. A compound of formula (I) selected from : (±) (3α, 9aα)-3-(4-benzyloxyphenoxymethyl)quinolizidine, (±) (3α, 9aα)-3-(3,4-dichlorophenoxymethyl)quinolizidine, (+) ( 1 α, 9aα)- 1 -(4-benzyloxyphenoxymethyl)quinolizidine,
(±) (lα, 9aα)-l-(3,4-dichlorophenoxymethyl)quinolizidine,
(±) (2β, 9aα)-2-[2-(4-benzyloxyphenoxy)ethyl]quinolizidine,
(±) (2β, 9aα)-2-[2-(3,4-dichlorophenoxy)ethyl]quinolizidine.
(±) (3α, 9aα)-3-[5-(2-dibenzofuranyloxy)pentyl]quinolizidine, (±) (3β, 9aα)-3-[5-(2-dibenzofuranyloxy)pentyl]quinolizidine
(±) (2β, 9aα)-2-[2-(3,4-dichlorobenzyloxy)ethyl]quinolizidine,
(±) (3α, 9aα) and (3β, 9aα)-3-(3,4-dichlorobenzyloxymethyl)quinolizidine,
(±) (3α, 9aα)-3-[3-(4-benzyloxyphenyl)propyloxymethyl]quinolizidine,
(±) (lα, 9aα)-l-[4-(phenoxy)phenoxymethyl]quinolizidine, (±) (3α, 9aα)-3-[6-(4-phenoxyphenyl)]hexyl quinolizidine,
(±) (3β, 9aα)-3-[6-(4-phenoxyphenyl)hexyl]quinolizidine,
(±) (lα, 9aα)-l-(4-benzylphenoxymethyl)quinolizidine,
(±) (3α, 9aα)-3-[5-(4-benzyloxyphenoxy)pentyl]quinolizidine, ± , aα - - - -benzy oxyp enoxy penty qu no z ne,
(+) ( 1 α, 9aα)- 1 -[5-(2-phenylbenzo[b]f uranyloxy)methyl]quinolizidine,
(±) (3α, 9aα)-3-[4-(4-benzyloxyphenoxy)butyl]quinolizidine,
(±) (3β, 9aα)-3-[4-(4-benzyloxyphenoxy)butyl]quinolizidine, (±) (3α, 9aα)-3-[3-(4-benzyloxyphenoxy)propyl]quinolizidine,
(±) (3β, 9aα)-3-[3-(4-benzyloxyphenoxy)propyl] quinolizidine,
(±) (3α, 9aα)-3-[2-(4-benzyloxyphenoxy)ethyl]quinolizidine,
(±) (3β, 9aα)-3-[2-(benzyloxyphenoxy)ethyl]quinolizidine,
(±) (3α, 9aα)-3-(4-benzylphenoxymethyl)quinolizidine, (±) (3β, 9aα)-3-(4-benzoylphenoxymethyl)quinolizidine,
(+) (3β, 9aα)-3-(4-benzylphenoxymethyl)quinolizidine, and salts thereof.
7. A process for the preparation of a compound of formula (I) which comprises:
(a) for compounds of formula (I) in which A is O, S or NR 1 , reaction of a compound of formula (II):
Formula (II) in which p, q, and n are as described for formula (I) and A1 is O, S or NR1, with a compound of formula L(CH2)mAr in which m is as described for formula (I), Ar1 is Ar as hereinbefore defined or a group convertible thereto and L is a leaving group, and if necessary converting a group Ar1 to a group Ar;
(b) for compounds of formula (I) in which A is O, S or NR , reaction of a compound of formula (III):
Formula (HI) in which p, q and n are as described for formula (I) and L is a group displaceable by a nucleophile, widi a compound of formula HA (CH2)m r where m, A1 and Ar1 are as hereinbefore defined;
(c) for compounds of formula (I) in which A is NR , reduction of a compound of formula (IV) :
Formula (IV) in which R^ represents the group
-(CH2)nN(R1)C(O)(CH2)m.ι Ar1 or -(CH2)n-lC(O)N(R1)(CH2)mAr1, and p, q, n, m, and Ar1 are as hereinbefore defined;
(d) for compounds of formula (I) in which A is a bond, reaction of a compound of formula (V) :
Formula (V)
(wherein L1, p, q, m and n are as hereinbefore defined), witii a compound of formula X^r1 in which Ar1 is as hereinbefore defined, and X1 is an alkali metal; e or compoun s w ere n s - = - reac on o a compoun o ormu a
Formula (VI)
(wherein n, p and q are as hereinbefore defined) with a reagent serving to introduce die group =C(CH2)mAr1;
(f) to prepare a compound of formula (I) wherein the substituent (-(CH2)nA(CH2)mAr1 is β to the nitrogen 'atom, reduction of a compound of formula (VII):
Formula (VII)
(wherein p, q, m, n, A and Ar1 are as hereinbefore defined).
(g) Interconversion of one compound of formula (I) to a different compound of formula (I) and optionally thereafter forming a salt.
8. A compound of formula (I) as hereinbefore defined or a pharmaceutically acceptable salt thereof for use in therapy.
9. A method of treatment of a condition or disease caused or exacerbated by the accumulation of calcium in the brain cells of a mammal which comprises administering to a subject in need tiiereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
EP94923730A 1993-07-20 1994-07-11 Quinolizidines with calcium channel antagonistic activity Withdrawn EP0710237A1 (en)

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