PHENOXYALKYL SUBSTITUTED PIPERIDINES, PYRROLIDINES, MORPHOLINES AND THIOMORPHOLINES AS CALCIUM CHANNEL ANTAGONISTS

Abstract: Compounds of formula (I), in which W is -(CH2)4, (CH2)5, -(CH2)2O(CH2)2 or -(CH2)2S(CH2)2 n is 0 to 6; m is 0 to 3; A is a bond, -CH=CH-, -CC-, oxygen, sulphur or NR<1>; R<1> is hydrogen, C1-8alkyl or phenyl C1-4alkyl; and Ar is a group (a) where X is a bond, O, CH2, CO or OCH2 and Hal is fluoro or chloro; and salts thereof are calcium channel antagonists with activity in neurons and are useful in the treatment of conditions such as ischaemic stroke.

Description: PHENOXYALKYL SUBSTITUTED PIPERIDINES , PYRROLIDINES , MORPHOLINES AND THIOMORPHOLINES AS CALCIUM CHANNEL ANTAGONISTS The present invention relates to cyclic secondary amine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy. . International Applications No's WO92 02501 , WO92/02502, WO92/22527 and WO93/15052 describe various tertiary nitrogen-containing heterocyclic compounds, which compounds are said to have activity as calcium blocking agents. Corresponding secondary amines are described as potential intermediates. In our co-pending International Application No. WO94/13291 (PCT EP93/03473) we describe various cyclic secondary amine derivatives as calcium channel antagonists. We have now found that certain of these compounds are particularly advantageous as calcium channel antagonists. The present invention therefore provides, in a first aspect, a compound of formula (I): Formula (I) in which W is -(CH 2 ) 4 , (CH 2 ) 5 , -(CH 2 ) 2 0(CH 2 )2 or -(CH 2 ) 2 S(CH 2 ) 2 n is 0 to 6; m is 0 to 3; A is a bond, -CH=CH-, -C≡C-, oxygen, sulphur or NR 1 ; Rl is hydrogen, Cj.galkyl orphenylCj^alkyl; and Ar is a group where X is a bond, O, CH 2 , CO or OCH and Hal is fluoro or chloro; or a pharmaceutically acceptable salt thereof as a therapeutic agent. Compounds analogous to those of formula (I) wherein Ar represents various substituted phenyl groups are known from the aforementioned patent applications; however none possess the particular Ar groups defined hereinabove. The present compounds of formula (I) therefore represent a novel selection from the prior art. Compounds of formula (I) and their pharmaceutically acceptable salts may for example be used in the treatment of disorders wherein a calcium channel antagonist is indicated. In the compounds of formula (I) W preferably represents (CH >4 or (CH 2 )5. The group -(CH2) n A(CH2) m Ar may be substituted on any carbon atom in the ring. When W is (CH 2 )4 or (CH 2 )5 the substituent is preferably α to the ring nitrogen atom. The values of n, m and A should be chosen such that the chain (CH 2 ) n A(CH ) m contains at least one atom. In general, the length of the chain -(CH 2 ) n A(CH 2 ) 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 from 1 to 5; for example n may be 1 or 2 and m may be zero. A is preferably oxygen or a bond. Particularly preferred compounds of formula (I) are those wherein W is (CH 2 )5 and the substituent -(CH 2 ) n A(CH 2 ) m Ar is oc to the ring nitrogen atom. Preferably A is oxygen, n is 1 or 2 and m is zero. Preferably X is O or CO. Preferably the group is in the 3- or 4-position relative to the - (CH 2 ) n A(CH 2 ) m - group, particularly preferably the 4-position. Preferred compounds according to the invention may therefore be represented by formula (IA): Formula (IA) wherein n is 1 or 2, X is O or CO and Hal is as hereinbefore defined. Preferably in compounds of formulae (I) and (IA) Hal is in the 3- or 4-position relative to the X group, particularly preferably the 4-position. Most preferably Hal is fluoro. Alkyl groups present in the compounds of formula (I), alone or as part of another group, can be straight or branched. Thus a Ci.βalkyl group may be for example methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl or any branched isomer thereof such as iso- propyl, tert-butyl or sec-pentyl. 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 hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, methanesulphonate or similar pharmaceutically acceptable inorganic or organic acid addition salts. Other non- pharmaceutically acceptable salts, such as oxalates, may be used for example in the isolation of final products and are included within the scope of this invention. 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 the use of all such isomers and mixtures thereof. Particular compounds according to the invention include: (±)2-[2- { 4-(4-fluorobenzoyl)phenoxy } ethyljpiperidine (±)2- [2- { 4-(4-fluorobenzyl)phenoxy } ethyl]piperidine (+) 2- [2- { 4-(4-fluorobenzyl)phenoxy } ethyl]piperidine (-) 2-[2- { 4-(4-fluorobenzyl)phenoxy } ethyl]piperidine (±)2-[2- { 4-(4-fluorophenoxy)phenoxy } ethyl]piperidine (±)2-[2- { 4-(4-chlorobenzoyl)phenoxy } ethyljpiperidine (±)2-[2- { 4-(4-chlorobenzyl)phenoxy } ethyljpiperidine (±)2-[2-{4-(4-chlorophenoxy)phenoxy}ethyl]piperidine and salts thereof. It is believed that compounds of the present invention will have a relatively simple pharmacokinetic profile and extended durations of action in vivo. The present compounds are also characterised by having improved solubility. The compounds according to the present invention can be prepared by processes analogous to those known in the art, for example the general methods described in WO92/02501 , WO92/02502, WO92/22527 and WO93/15052. Thus, in a further aspect the present invention provides a process for the preparation of a compound of formula (I) which process 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 W and n are as described for formula (I), A 1 is O, S or NR 1 , and R 4 is an N-protecting group with a compound of formula L(CH 2 ) m Ar in which m and Ar are as described for formula (I), and L is a leaving group; (b) for compounds of formula (I) in which A is O, S or NR-*, reaction of a compound of formula (HI): Formula (III) in which W, n and R 4 are as described above and L*- is a group displaceable by a nucleophile, with a compound of formula HA 1 (CH 2 ) m Ar where m and Ar are as described for formula (I) and A 1 is as described for formula (II); or (c) for compounds of formula (I) in which A is NR*, reduction of a compound of formula (IV) : Formula (IV) in which R-5 represents the group -(CH 2 ) n N(Rl)C(O)(CH 2 ) m .! Ar or -(CH 2 ) n . 1 C(O)N(Rl)(CH 2 ) m Ar, R 4a is hydrogen or an N-protecting group, and W, n, m, and Ar are as described above. (d) for compounds of formula (I) in which A is a bond, reaction of a compound of formula (V) : Formula (V) (wherein W, R , L**, m and n are as hereinbefore defined); with a compound of formula X-^Ar in which Ar is as described for formula (I), and X s an alkali metal; (e) For compounds where W is (CH 2 )5 and A is O, S, NR 1 or a bond, reduction of a compound of formula (VI): Formula (VI) wherein A, Ar m and n are as hereinbefore defined, R 4a is hydrogen or an N-protecting group and X " is a counter ion; (f) For compounds wherein A is -CH=CH-, reaction of a compound of formula (Nil) : Formula (VII) (wherein W, R 4 and n are as hereinbefore defined) with a reagent serving to introduce the group (CH ) m Ar (g) Interconversion of one compound of formula (I) to a different compound of formula (I), e.g. the reduction of a compound wherein A represents -CH=CH- to a compound wherein -(CH 2 ) n A(CH 2 ) m - contains the moiety -CH 2 -CH -, or reduction of a benzoyl substituent on the group Ar to a benzyl group; followed where necessary by removal of the Ν-protecting group R 4 , and optionally thereafter forming a salt. In process (a) the reaction between a compound of formula (II) and a compound L(CH 2 ) m Ar 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, such that the compound of formula (II) is reacted with a compound F-Ar. The reaction is preferably effected in the presence of a strong base such as sodium hydride, and in an inert organic solvent such as DMSO or dimethylformamide. When L is halogen or a sulphonic acid residue such as a tosylate or mesylate and m is other than zero, the reaction is carried out under standard conditions in a solvent, optionally in the presence of a base. The reaction between a compound of formula (HI) and a compound of formula HAl(CH 2 ) m Ar (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 diethyl 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 this case the reaction may be effected in the presence or absence of solvent and at temperature in the range 0 to 200°C. The reduction of a compound of formula (IV) 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 (IV) 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 Ar in process (d) can take place under standard conditions known to those skilled in the art for the formation of carbon-carbon bonds. Reduction of a compound of formula (VI) according to process (e) may be effected for example by hydrogenation, using a noble metal catalyst such as platinum, palladium or platinum oxide, suitably in a solvent such as an alcohol eg. ethanol. Process (f) may be effected using a Wadsworth-Emmons reagent of the formula Ar(CH 2 ) m+ ιP(O)(OAlk) 2 , such as a diethylphosphonate, or a Wittig reagent of the formula Ar(CH ) m+ ιPPh3X" (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 tert-butoxide. 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 (CH 2 ) n A(CH ) m contains the moiety -CH 2 -CH 2 - may be effected by catalytic reduction and reduction of a benzoyl substituent to benzyl may be carried out using a reducing agent such as sodium borohydride in trifluoroacetic acid. Protecting groups R 4 include lower alkyl groups such as methyl; aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl; and acyl groups such as acetyl, trifluoroacetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl. In process (e) a protecting group R 4a is preferably alkyl e.g. methyl or aralkyl e.g. benzyl. Such groups may be removed by methods which are well known in the art. An alkyl group such as methyl may be removed by treatment with a haloalkyl haloformate such a 1-chloromethylchloroformate, aralkyl group such as benzyl may be cleaved by hydrogenolysis, and an acyl group such as benzoyl may be cleaved by hydrolysis. It will be appreciated that a protecting group R 4 or R 4a present in any of the above compounds (II) to (VII) as well as compounds (Vffl) below should be chosen such that it will not be cleaved by or participate in any of the reactions that the particular compound is intended to undergo, and furthermore such that its removal will not disturb any other groups or moieties present in the molecule. Such factors can be readily ascertained by those skilled in the art, to whom appropriate protecting groups will thus be readily apparent. Compounds of formula (II) can be prepared from the corresponding compounds in which R 4 is hydrogen, by methods well known in the art. For example an acyl group may be introduced by reaction with an appropriate acid derivative such as an acid chloride or anhydride, or an activated ester, e.g. an alkyldicarbonate such as di-tert-butyldicarbonate or a haloformate such as ethylchloroformate. The corresponding compounds of formula (II) in which R 4 is hydrogen are available commercially, known in the literature or can be prepared by standard techniques; for example by reduction of the corresponding hydroxyalkylpyridine. Alternatively, the compounds of formula (II) in which A 1 is oxygen can be prepared by reduction of a compound of formula (VIII): Formula (VIII) in which R 4 and n are as hereinbefore described. In this instance R 4 should be a group such as alkyl, which is not cleaved by reductive conditions. 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-5 is a group -(CH 2 ) n N(R 1 )C(O)(CH 2 ) m -iAr can be prepared by reacting a compound of formula (II) wherein A 1 represents NR 1 with an acylating agent corresponding to the group - (CH ) m Ar, for example an acid chloride ClOC(CH 2 ) m _ι Ar. Compounds of formula (IV) wherein R-5 is a group -(CH 2 ) n . * C(O)N(R 1 )(CH 2 ) m Ar may be prepared for example by reaction of a corresponding compound wherein R-5 represents -(CH 2 ) n .ι CO 2 H or an activated derivative thereof such as an acid halide, ester or anhydride, with an amine of formula HN(Rl)(CH 2 ) m Ar. It will be appreciated that when the acid itself is employed, reaction with the amine should be effected in the presence of a coupling agent. The carboxylic acid may itself be prepared for example by oxidation of the corresponding alcohol, ie. a compound of formula (II) wherein A 1 is oxygen. Compounds of formula (V) may be prepared in analogous manner to compounds of formula (HI); where necessary the chain length may be increased using methods well known in the art. A compound of formula (VI) may be prepared using the general methods described in processes (a) to (d) above. Compounds of formula (VII) may be prepared by conventional methods, for example the oxidation of a compound of formula (II) wherein A 1 is oxygen, or conversion of the corresponding ester, e.g. by reaction with thionyl chloride and N,O-dimethylhydroxylamine hydrochloride, to give the N-methyl-N-methoxy- carboxamide, which can be reduced to the aldehyde using diisobutylaluminium hydride. Compounds of formula (VII) wherein n is i may be prepared from the corresponding compound wherein n is zero by various methods. For example the aldehyde wherein n is zero may be treated with (methoxymethyl) triphenylphosphonium chloride and potassium t-butoxide, followed by a strong acid. e.g. concentrated sulphuric acid, resulting in the aldehyde wherein n is 1. Alternatively the aldehyde may be converted to the corresponding cyanomethyl derivative as described in EPA 363085 followed by acid hydrolysis, conversion to the N-methyl-N-methoxycarboxamide and reduction. These procedures may also be used to form higher homologues. 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. Suitable resolving agents include optically active acids such as R-(-)- or S-(+)-mandelic acid or. Alternatively a mixture of diastereomeric amides may be prepared by reacting a mixture of enantiomers of formula (I) with an optically active reagent such as S(+)-α- methoxyphenylacetic acid, in the form of a reactive derivative such as an acid chloride. The mixture of amides may be separated by conventional methods and then converted into the resolved amines by hydrolysis. An ischaemic event such as stroke results in disruption of the blood supply to the brain, depriving it of essential oxygen. A cascade of biochemical reactions ensues, a consequence of which is to permit the influx of calcium ions into the brain cells (neurons) via so-called Voltage Operated Calcium Channels (VOCCs) causing cell death. It is believed that agents which inhibit such calcium influx will minimise cell death and hence increase the potential for recovery. 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 ischaemia including for example stroke, anoxia, and traumatic head injury. They may also be of use in the treatment of migraine, visceral pain, epilepsy, 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. 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 the brain cells of mammals which comprises administering to a subject in need thereof 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 ischaemia including for example stroke, anoxia or traumatic head injury which comprises administering to a subject in need thereof, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The invention also provides a method of treatment of migraine, visceral pain, epilepsy, 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. The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition or disease related to the accumulation of calcium in the brain cells of a mammal. Compounds of the present invention will preferably be of use in the treatment of ischaemic stroke. For use in medicine, the compounds of the present invention are usually administered in a standard pharmaceutical composition. The present invention therefore provides in a further aspect pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. The compounds of the invention may be administered by any convenient method for example by oral, parenteral, buccal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly. The compounds of formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids 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 carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule. Compounds of the invention may also be administered parenterally, by bolus injection or continuous infusion. Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration. Both liquid and solid compositions may contain other excipients known in the pharmaceutical art, such as a cyclodextrin or a solubilising agent such as Cremophor. 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 the formula (I) or a pharmaceutically acceptable salt thereof calculated as the 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 the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day. Alternatively the compounds of the invention may be administered by continuous intravenous infusion, preferably at a dose of up to 400mg per day. Thus, the total daily dosage by oral administration will be in the range 1 to 2000 mg and the total daily dosage by parenteral administration will be in the range 0.1 to 400 mg. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more. If desired a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in combination or concurrently with one or more other therapeutic agents, for example a thrombolytic agent such as anistreplase, streptokinase or a tissue plasminogen activator, an excitatory amino acid antagonist such as an NMDA antagonists; a free radical inhibitor; or a calpain inhibitor. BIOLOGICAL DATA Ca^ + current can be measured in vitro using cell preparations of sensory neurons from dorsal root ganglia as described in WO92/02501 and WO92/02502, or sensory neurons from superior cervical ganglia as described in WO95/04027. RESULTS The specific compounds of the Examples gave percentage inhibition of plateau Ca2+ current in the range 35 to 85 % @ 5μM of test compound in the superior cervical ganglia preparations. Pharmaceutical Formulations The following represent typical pharmaceutical formulations according to the present invention, which may be prepared using standard methods. IV Infusion Compound of formula (I) 1-40 mg Buffer to pH ca 7 Solvent/complexing agent to 100 ml Bolus Injection Compound of formula (I) 1-40 mg Buffer to pH ca 7 Co-Solvent to 5 ml 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 Disintegrant * 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, hydroxypropymethy .cellulose Disintegrant : e.g. Sodium starch glycollate, crospovidone Lubricant : e.g. Magnesium stearate, sodium stearyl fumarate. Oral Suspension or Solution Compound 1 - 40 mg Suspending Agent or Solubiliser 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. Xanthan gum, microcrystalline cellulose Solubiliser : e.g. hydroxypropyl β cyclodextrin 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 The invention is further illustrated by the following non-limiting examples : Preparation 1 (±)2-[2-{4-(4-Chlorobenzoyl)phenoxy}ethyl]-l-tert-butoxycarbonyl piperidine N-BOC-2-ρiperidine ethanol (2.29g, lOmM), triphenyl phosphine (2.60g, lOmM) and 4- chloro-4'-hydroxybenzophenone (2.35g, lOmM) were dissolved with stirring under argon in dry dichloromethane (50ml). The mixture was cooled in an ice-bath and a solution of diethylazodicarboxylate (1.75g, lOmM) in dry CH 2 C1 2 (20ml) was added dropwise. The clear brown solution produced was allowed to slowly reach room temperature and stood under argon for sixty hours. The mixture was then concentrated to about half its original volume and chromatographed on silica gel using dichloromethane as eluent. This produced the title compound as a virtually colourless oil (2.85g) which crystallised on standing at room temperature overnight and was used without further purification. Example 1 (±)2-[2-{4-(4-Fluorobenzoyl)phenoxy}ethyl]piperidine hydrochloride A solution of 2-piperidine-ethanol (1.29g, lOmM) in dry DMSO (20ml) was treated with sodium hydride (0.36g of 80% dispersion in oil, 12mM) with stirring under argon at room temperature for two hours. A solution of 4,4'-difluorobenzophenone (2.62g, 12mM) in dry DMSO (20ml) was added dropwise when frothing was observed. Following addition, the mixture was allowed to stir for 30 minutes and then heated at 80°C (oil-bath temp) for 45 minutes. The mixture was cooled, quenched with glacial acetic acid (0.69ml, 12mM) and the resulting brown solution evaporated to dryness using xylene to azeotrope. The residue was equilibrated between aq. K 2 CO3 and ether, the aq. fraction re-extracted with ether (x 3) and the combined organic extracts washed (H 2 0, brine), dried (Na 2 Sθ4) anc ** evaporated to dryness. The residual light-brown oil (3.18g) was chromatographed on silica gel using CH 2 C1 2 as initial eluent followed by CH Cl 2 /2% MeOH, CH 2 Cl-2/5% MeOH and finally CH 2 Cl2/10% MeOH (MeOH contains 10% NH4OH) to give on evaporation a pale-green oil (1.66g). This was dissolved in ethyl acetate/methanol and ethereal HC1 added to the clear warm solution. The title compound was crystallised on slow cooling and was collected, washed with ether and dried. (1.45g), M.P.= 230-232°C C 20 H 22 FNO .HC1 requires: C, 66.0, H, 6.4, N, 3.9 Found: C, 65.9, H, 6.3, N, 3.9% Example 2 (±)2-[2-{4-(4-FluorobenzyI)phenoxy}ethyl]piperidine hydrochloride Substituting bis-(4-fluorophenyl)methane (2.45g, 12mM) for 4,4'-difluorobenzophenone in Example 1 and using identical reaction conditions except that oil-bath heating was continued for 16hrs, gave an oil (1.22g) following the chromatography step. This oil was dissolved in hot ethyl acetate and excess ethereal HC1 added. The title compound separated on cooling as white crystals which were collected, washed with ether and dried (1.29g), M.P. = 171-173°C. C 20 H 2 4FNO.HC1 requires: C, 68.7, H, 7.2, N, 4.0 Found: C, 68.2, H, 6.9, N, 4.1% Example 3 (±)2-[2-{4-(4-Fluorophenoxy)phenoxy}ethyI]piperidine hydrochloride Substituting bis-(4-fluorophenyl)ether (2.47g, 12mM) for 4,4-difluorobenzophenone in Example 1 and using identical reaction conditions except that oil-bath heating was continued for four hours gave an oil (1.1 g) following the chromatography step. Crystallisation proceeded in an identical manner to Example 2 and the title compound separated as white crystals (0.74g), M.P. = 153-155°C C 1 9H 22 FNO 2 .HCl requires: C, 64.9, H, 6.6, N, 4.0 Found: C, 64.8, H, 6.5, N, 4.2% Example 4 (±)2-[2-{4-(4-chlorobenzoyl)phenoxy}ethyl]piperidine The product of Preparation 1 (2.7g) was dissolved in dichloromethane (50ml) and the solution stirred at room temperature under argon. A solution of trifluoroacetic acid (3.5ml - excess) in dichloromethane (20ml) was added dropwise over 30 minutes. The solution produced (slightly yellow) was stirred under argon for a further two hours. The solution was then equilibrated with 10% NaOH solution (50ml), the aq. fraction re-extracted with CH2CI2 and the combined organic extracts washed (2xH 2 O, brine), dried (Na2SO4) and evaporated to give a colourless oil (2.09g). This material solidified on standing in the cold so it was washed with ether/hexane to give the title compound as the free base (0.6 lg, M.P. = 102-103°C) C2()H22ClNO 2 requires: C, 69.9, H, 6.5, N, 4.1 Found: C, 69.3, H, 6.5, N, 4.1% Examples 5 and 6 (+) 2-[2-{4-(4-Fluorobenzyl)phenoxy}ethyljpiperidine hydrochloride (-) 2-[2-{4-(4-Fluorobenzyl)phenoxy}ethyl]piperidine hydrochloride To a solution of S-(+)-α-methoxyphenylacetic acid (2.2g, 13.24mmol) in dichloromethane (90ml) was added thionyl chloride (18ml) and the mixture was heated at reflux temperature for 90 minutes. On cooling, the yellow solution was concentrated in vacua. The oily residue was dissolved in dichloromethane (90ml) and (±) 2-[2-{4-(4- fluorobenzy phenoxy} ethyljpiperidine (4.15g, 13.24mmol) added. To the resulting solution was added an aqueous 1M sodium hydroxide solution (90ml). The two phase mixture was rapidly stirred at room temperature for two hours. The layers were separated and the aqueous phase re-extracted with dichloromethane. The combined organic extracts were washed (2 xH 2 O), dried (Na2SO4) and evaporated to dryness to afford a 50:50 mixture of the two diastereomeric amides (6.0g). These were readily separated by column chromatography on silica gel using Et 2 O/40-60°C petrol as eluent. The faster eluting diastereomer (2.14g) was dissolved in dry tetrahydrofuran (150ml) and treated with potassium tert-butoxide (20g) and water (0.335ml). The mixture was stirred vigorously for 45 minutes. After filtering off the solid material the mixture was concentrated in vacua and the residue partitioned between diethyl ether and water. The organic fraction was washed (H2O, brine), dried (Na2SO4) and evaporated to dryness. The oily residue was dissolved in ethyl acetate and treated with excess ethereal HC1. The mixture was evaporated to dryness and treated with ether to give a white solid which was collected and washed with ether. The solid was finally crystallised from methanol/ethyl acetate to give white crystals (0.58g, M.P. 172-173°C) of the (-)-enantiomer of the title compound. Specific optical rotation = -7.5° (chloroform) C 2 oH 4FNO.HCl requires: C, 68.6, H, 7.2, N, 4.0 Found: C, 68.1, H, 7.0, N, 4.0% The hydrolysis procedure and work-up was repeated for the slower eluting diastereomeric amide (1.62g) to give the (- )-enantiomer of the title compound as a white, crystalline solid (0.34g, MP=172-173°C) Specific optical rotation = + 7.5° (chloroform) C 2 oH 24 FNO.HCl requires: C, 68.6, H, 7.2, N, 4.0 Found: C, 68.3, H, 7.1, N, 4.0%

Claims: Claims 1. A compound of formula (I): Formula (I) in which W is -(CH 2 ) 4 , (CH 2 ) 5 , -(CH 2 )2θ(CH 2 )2 or -(CH 2 ) 2 S(CH 2 ) 2 n is 0 to 6; m is 0 to 3; A is a bond, -CH=CH-, -C≡C-, oxygen, sulphur or NR ; R 1 is hydrogen, Cj.galkyl 0r phenylC1.4a.kyl; and Ar is a group where X is a bond, O, CH2, CO or OCH2 and Hal is fluoro or chloro; or a salt thereof. 2. A compound according to claim 1 wherein W represents (CH2)4, or (CH 2 ) 5 . 3. A compound according to claim 1 or claim 2 wherein the group -(CH 2 ) n A(CH 2 ) m Ar is α to the ring nitrogen atom. 4. A compound according to any of claims 1 to 3 wherein the length of the chain -(CH 2 ) n A(CH 2 ) m is from 2 to 6 atoms. 5. A compound according to any of claims 1 to 4 wherein A is oxygen or a bond. 6. A compound according to any of claims 1 to 5 in which X is O or CO. 7. A compound according to any of claims 1 to 6 wherein the compound has the formula (IA): Formula (IA) wherein n is 1 or 2, X is O or CO and Hal is as hereinbefore defined, or a salt thereof. 8. A compound according to any of claims 1 to 7 in which the group is in the 4-position relative to the -(CH2) n A(CH2)m- or -(CH2) n O- group. 10 9. A compound according to any of claims 1 to 8 in which Hal is in the 4- position relative to the X group. 10. A compound according to any of claims 1 to 9 in which Hal is fluoro. !5 11. A compound of claim 1 selected from: (±)2-[2-{4-(4-fluorobenzoyl)phenoxy}ethyljpiperidine (±)2-[2-{4-(4-fluorobenzyl)phenoxy}ethyljpiperidine (+) 2-[2- { 4-(4-fluorobenzyl)phenoxy } ethyljpiperidine (-) 2-[2-{4-(4-fluorobenzyl)phenoxy}ethyljpiperidine 0 (±)2-[2-{4-(4-fluorophenoxy)phenoxy}ethyl]piperidine (±)2- [2- { 4-(4-chlorobenzoyl)phenoxy } ethyljpiperidine (±)2-[2- { 4-(4-chlorobenzyl)phenoxy } ethyljpiperidine (±)2-[2-{4-(4-chlorophenoxy)phenoxy}ethyljpiperidine or a salt thereof. 5 12. Use of a compound of any of claims 1 to 11 or a pharmaceutically acceptable salt thereof as a therapeutic agent. 13. Use of a compound of any of claims 1 to 11 or a pharmaceutically 0 acceptable salt thereof in the manufacture of a medicament for the treatment of disorders where a calcium channel antagonist is indicated. 14. Use according to claim 13 wherein the disorder is a condition or disease related to an accumulation of calcium in the brain cells of mammals. 5 15. A pharmaceutical composition comprising a compound of any of claims 1 to 11 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. 16. A process for the preparation of a compound of any of claims 1 to 11 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 W and n are as described for formula (I), A 1 is O, S or NR 1 , and R 4 is an N-protecting group with a compound of formula L(CH2)mAr in which m and Ar are as described for formula (I), and L is a leaving group; (b) for compounds of formula (I) in which A is O, S or NR 1 , reaction of a compound of formula (HI): Formula (HI) in which W, n and R 4 are as described above and L 1 is a group displaceable by a nucleophile, with a compound of formula HA 1 (CH2) m Ar where m and Ar are as described for formula (I) and A 1 is as described for formula (II); or (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 -(CH 2 ) n N(R 1 )C(O)(CH 2 ) m . 1 Ar or -(CH 2 ) n . 1 C(O)N(R )(CH 2 ) m Ar, R 4a is hydrogen or an N-protecting group, and W, n, m, and Ar are as described above. (d) for compounds of formula (I) in which A is a bond, reaction of a compound of formula (V) : Formula (V) (wherein W, R 4 , L 1 , m and n are as hereinbefore defined); with a compound of formula X 1 Ar in which Ar is as described for formula (I), and X 1 is an alkali metal; (e) For compounds where W is (CH2)5 and A is O, S, NR 1 or a bond, reduction of a compound of formula (VI): Formula (VI) wherein A, Ar m and n are as hereinbefore defined, R 4a is hydrogen or an N-protecting group and X " is a counter ion; (f) For compounds wherein A is -CH=CH-, reaction of a compound of formula (VII) : R 4 Formula (VII) (wherein W, R 4 and n are as hereinbefore defined) with a reagent serving to introduce the group Ar; (g) Interconversion of one compound of formula (I) to a different compound of formula (I); followed where necessary by removal of the N-protecting group R 4 , and optionally thereafter forming a salt.

Inventors: BROWN THOMAS HENRY, COPPER DAVID GWYN, BROWN, THOMAS, HENRY, COPPER, DAVID, GWYN
Applicants: BROWN THOMAS HENRY, COPPER DAVID GWYN, SMITHKLINE BEECHAM PLC, BROWN, THOMAS, HENRY, COPPER, DAVID, GWYN
Application year: 1995
Main classification: C07D211
IPC codes: A61K31, A61P3, A61P9, A61P25, C07D211, C07D265, C07D279