The present invention relates to cyclic secondary amine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy. In our International Applications No's WO92/02501 , WO92/02502, WO92/22527 and WO93/15052 we describe various cyclic secondary amine derivatives as intermediates and their use as calcium channel antagonists is described in our International Application No. WO94/13291. We have now found a small group of related novel compounds which exhibit particularly useful therapeutic activity 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 O(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 ;

R ¹ is hydrogen, Cj.galkyl orphenylCj^alkyl; and Ar is a group

where X is -SO ₂ - or - CH.-) _^ --, Y< a3nd Zr m ^x ay ^→ eaGch be hydrogen, fluorine, chlorine, bromine, C, ^alkyl, C, .alkoxy or trifluoromethyl; or a salt thereof. 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, and such use of the compounds forms an important aspect of this invention. In the compounds of formula (I) W preferably represents (CH )4 or (CH ₂ )5

The group -(CH ₂ ) _n A(CH ) _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 (CH2) _n A(CH ₂ ) _m contains at least one atom. In general, the length of the chain -(CH ₂ ) _n A(CH ) _rn 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 preferably 2 and m may be zero.

A is preferably oxygen or a bond, most preferably oxygen. Preferably W is -(CH )5- and the substituent -(CH2) _n A(CH ₂ ) _rn Ar is α to the ring nitrogen atom. In a preferred class of compounds A is oxygen, n is 1 or 2 and m is zero.

A particularly preferred group of compounds according to the present invention is that of formula (IA):

Formula (IA)

wherein X,Y and Z are as hereinbefore defined for Formula (I) and n is 1 or 2, and salts thereof.

In compounds of formulae (I) and (IA) the group

- ^χ 3 is preferably in the 4-position relative to the -(CH ) _n A(CH ₂ ) _m - group.

Preferably Y is fluoro or chloro and Z is hydrogen or both Y and Z are hydrogen. When Y is fluoro or chloro it is preferably in the 4-position relative to the X group.

Alkyl groups present in the compounds of formula (I), alone or as part of another group, can be straight or branched. Thus a Cμgalkyl 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 .-ec-pentyl. It will be appreciated that the group

-C(CH ₃ ) ₂ - ^^ ^Y

is a specific example of optionally substituted phenyl Cι_4alkyl compounds described in co-pending International Application No. PCT/EP93/03473.

Compounds of formula (I) wherein W is -(CH ₂ )5 and the group -(CH ₂ ) _n A(CH ) _m Ar is α to the piperidine nitrogen atom are particularly preferred. Preferably A is oxygen, n is 1 or 2 and m is zero.

Particular compounds according to the invention include: (±)2- [2- { 4-(4-fluorophenylsulphone)phenoxy } ethyl]piperidine,

(±)2-[2-(4- { 1 -methyl- 1 -(4-fluorophenyl)ethyl } phenoxy)ethyl] piperidine (±)2-[2-{4-(3-fluorophenylsulphone)phenoxy}ethyl]piperidine , (±)2-[2-(4-{ l-methyl-l-(3-fluorophenyl)ethyl)phenoxy)ethyl] piperidine (±)2-[2-{4-(4-chlorophenylsulphone)phenoxy}ethyl]piperidine , (±)2-[2-(4-{ 1 -methyl- l-(4-chlorophenyl)ethyl}phenoxy)ethyl] piperidine (±)2-[2-{4-(phenylsulphone)phenoxy}ethyl]piperidine, (±)2-[2-(4- { 1 -methyl- 1 -phenylethyl } phenoxy)ethyl]piperidine and salts thereof.

It is believed that compounds of the invention will have a relatively simple pharmacokinetic profile and extended durations of action in vivo. It is further believed that the compounds of the invention are particularly advantageous because they are resistant to metabolic degradation. The present compounds are also characterised by having improved solubility.

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 all such isomers and mixtures thereof.

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 preparing a compound of formula (I) which process 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* is O, S or NR*, and R^ 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 NRl, reaction of a compound of formula (HI):

Formula (III) in which W, n and R^ are as described above and L^ is a group displaceable by a nucleophile, with a compound of formula HA^(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^ represents the group -(CH ₂ ) _n N(Rl)C(O)(CH ₂ ) _m . ₁ Ar or -(CH ₂ ) _n . ₁ C(O)N(Rl)(CH ₂ ) _m Ar,

R^ ^a 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^, I_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^ is an alkali metal;

(e) For compounds where W is (CH ₂ )5 and A is O, S, NR* or a bond, reduction of a compound of formula (VI):

Formula (VI) wherein A, Ar m and n are as hereinbefore defined, R^ ^a 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 Formula (VII)

(wherein W, R^ and n are as hereinbefore defined) with a reagent serving to introduce the group (CH ₂ ) _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 ) _m . contains the moiety -CH ₂ -CH ₂ -; followed where necessary by removal of the N-protecting group R^, 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 dimethylsulphoxide or dimethylfoimamide. 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 HA^CH^π _j Ar (process b) can take place under conditions which depend on the nature of L ¹ and A ¹ . For example when L ¹ 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 (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 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 ₂ ) _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 ₂ ) _m contains the moiety -CH ₂ -CH ₂ - may be effected by catalytic reduction. Protecting groups R^ 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^ ^a 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^ or R^ ^a present in any of the above compounds (II) to (VII) as well as compounds (VIII) 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 R4 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^ is hydrogen are available commercially, known in the literature or can be prepared by standard techniques; for example by reduction of the corresponding hydroxyalkyl-pyridine. Alternatively, the compounds of formula (II) in which A is oxygen can be prepared by reduction of a compound of formula (VEQ):

Formula (VH1) in which W, R^ and n are as hereinbefore described. In this instance R^ 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^ is a group

-(CH ₂ ) _n N(Rl)C(O)(CH ₂ ) _m _ιAr can be prepared by reacting a compound of formula (II) wherein A represents NR with an acylating agent corresponding to the group -

(CH ₂ ) _m Ar, for example an acid chloride ClOC(CH ₂ ) _m _ιAr. Compounds of formula (IV) wherein R^ is a group

-(CH ₂ ) _n _ιC(O)N(R ¹ )(CH ₂ ) _m Ar may be prepared for example by reaction of a corresponding compound wherein R^ 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(R ¹ )(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* is oxygen.

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.

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 * 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 1 may be prepared from the corresponding compound wherein n is zero by various methods. For example the aldehyde wherein n is zero may be treated with (methoxymethyl) triphenylphosphonium chloride and potassium t-butoxide, followed by a strong acid, e.g. 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. 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, AEDS-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 caπier(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

Cd?+ 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

Specific compounds of the invention gave inhibition of plateau C ^ ⁺ current in the range 40-90% at 5μM of test compound in SCG preparations.

Pharmaceutical Formulations

The following represent typical pharmaceutical formulations according to the present invention, which may be prepared using standard methods.

TV 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, hydroxypropymethylcellulose

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-{l-MethyI-l-(4-fluorophenyl)ethyl}phenoxy)eth yl] piperidine- 1-carbox lie acid tert-butyl ester

Diethylazadicarboxylate, (2.47 mM, 0.43g) in dichloromethane (5ml) was added dropwise to triphenylphosphine (2.47 mM, 0.647g), 4-[l-(4-fluorophenyl)-l-methylethyl]phenol (2.47 mM, 0.57g), and 2-(2-hydroxyethyl)piperidine-l -carboxylic acid tert-butyl ester (2.47 mM, 0.566g) in dichloromethane (20ml) at 0°C under argon. The reaction mixture was stirred under these conditions for 1 hour before allowing the temperature to rise to room temperature and stirring continued for 2 days. The solvent was removed in vacua to afford a yellow oil which was subjected to column chromatography eluting with dichloromethane to afford the title compound as a clear oil. (Yield = 0.537g, 50%) iHNMR (250MHz, CDCI3) δ 1.39 (9H, s), 1.59 (6H, m), 1.63 (6H, m), 1.85 (1H, m), 2.21 (1H, m), 2.80 (1H, m), 3.95 (3H, m), 4.47 (1H, m), 6.76 (2H, m), 6.92 (2H, m), 7.12 (4H, m)

Preparation 2

(+)2-[2-(4-{l-Methyl-l-phenylethyl}phenoxy)ethyl]piperidi ne-l-carboxylic acid tert- butyl ester. Using the conditions described in Preparation 1, replacing 4-[l-(4-fluorophenyl)-l- methylethyl]phenol with 4-[l-methyl-l-phenylethyl]phenol (lOmM, 2.12g) and using corresponding molar proportions of the other reagents gave the title product as a clear colourless oil (4.13g) after column chromatography. !H NMR (250 MHz. CDCI3) δ 1.38 (9H, s), 1.60-1.70 (12H, m), 1.85 (1H, m), 2.20 (1H, m), 2.80 (1H, m), 3.90 (3H, m), 4.47 (1H, m), 6.75 (2H, m), 7.05 - 7.30 (7H, m)

Example 1

(±)2-[2-{4-(4-FIuorophenylsulphone)phenoxy}ethyl]piperid ine 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 bis-(4-fluorophenyl)sulphone (3.05g, 12mM) in dry DMSO (20ml) was added dropwise when frothing was observed. Following addition, the mixture was allowed to stir for 30 minutes. The mixture was 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 CO3 and ether, the aq. fraction re-extracted with ether (x3) and the combined organic extracts washed (H ₂ O,

brine), dried (Na ₂ SO4) and 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 ₂ Cl ₂ /2% MeOH, CH ₂ Cl ₂ /5% MeOH and finally CH ₂ C1 /10% MeOH (MeOH contains 10% NH4OH) to give on evaporation an oil (1.52g) which crystallised on standing. This was dissolved in hot ethyl acetate and excess ethereal HCl added; the title compound separated on cooling as white crystals which were collected, washed with ether and dried

(0.67g), M.P. = 179-181°C.

Ci9H ₂₂ FNO3S.HCl requires: C, 57.1, H, 5.8, N, 3.5 Found: C, 56.9, H, 5.7, N, 3.5%

Example 2

(±)2-[2-(4-{l-MethyI-l-(4-fluorophenyl}ethyl)phenoxy)eth yl] piperidine hydrochloride To a solution of (±)-2- [2-(4- { 1 -methyl- 1 -(4-fluorophenyl)ethyl } phenoxy) ethyl] piperidine- 1 -carboxylic acid tert-butyl ester (1.13mM, 0.5g) in dichloromethane (6ml) was added excess trifluoroacetic acid in dichloromethane (2ml) under argon, at room temperature. Stirring was continued for two hours. Sodium hydroxide (10%, 10ml) was added dropwise to the solution which was then extracted with dichloromethane (3 x 15ml). The combined organic layers were washed with water (20ml), brine (20ml) and dried over sodium sulphate. The solvent was removed in vacuo to afford a yellow oil which was converted to the hydrochloride salt with ethereal hydrogen chloride to afford the title compound as a white crystalline solid , m.p. = 160°C, (Yield = 0.37g, 82%) (recrystallised from methanol/ethyl acetate). ¹ HNMR (270MHZ, DMSO) δ: 1.45 (2H, m, J=14), 1.60 (6H, s), 1.72 (2H, m, J=14), 1.92 (2H, m), 2.12 (1H, m), 2.86 (1H, m), 3.20 (2H, m, J=14), 4.06 (2H, t, J=7), 6.85 (2H, d, 3=1), 7.02 - 7.27 (8H, m), 8.98 (2H, s) MS EI ⁺ data also obtained.

Example 3

(±)2-[2-(4-{l-methyl-l-phenylethyl}phenoxy)ethyl]piperid ine hydrochloride

Using the conditions described in Example 2, replacing the product of Preparation 1 with the product of Preparation 2 (9.45mM, 4.0g) and using corresponding molar proportions of the other reagents and solvents gave the title product as a white crystalline solid (2.3g, M.P. = 151-153°C) crystallised from methanol/ethyl acetate. C ₂ H ₂₉ NO. HCl requires: C, 73.4, H, 8.4, N, 3.9

Found: C, 73.4, H, 8.6, N, 4.1 %