CA2088490A1

CA2088490A1 - 3-substituted piperidine derivatives

Info

Publication number: CA2088490A1
Application number: CA002088490A
Authority: CA
Inventors: Thomas Henry Brown; David Gwyn Cooper
Original assignee: Individual
Current assignee: Smith Kline and French Laboratories Ltd
Priority date: 1990-08-06
Filing date: 1991-08-05
Publication date: 1992-02-07
Also published as: AP9100314A0; PT98575A; CN1062349A; MX9100517A; EP0542844A1; AP236A; TW239860B; MA22251A1; WO1992002501A1; AU8324391A; NZ239267A; AU649468B2; JPH06500092A; IL99074A0; IE912760A1

Abstract

Compounds of structure (I) in which R is C1-8alkyl(phenyl)p, C2-8alkenyl(phenyl)p, C2-8alkynyl(phenyl)p, C3-8cycloalkyl or C1-8alkylC3-8cycloalkyl; p is 0 to 2; n is 0 to 6; A is a bond, oxygen, sulphur or NR1; R1 is hydrogen, C1-8alkyl or phenylC1-4alkyl; m is 0 to 3; and Ar is aryl or heteroaryl, each of which may be optionally substituted, and salts thereof;
processes for preparing compounds (I), pharmaceutical compositions containing them and their use in medicine, in particular as calcium blocking agents.

Description

W O 92/02501 ~ ~ 3 3 ~ ~ o P(~r/GB91/01339 The present invention relates to 3-substituted piperidine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
The present invention therefore provides, in a first aspect, compounds of structure (I):

(CH2)nA~CH2)mAr ~ J (I) N

R

in which R is Cl_8alkyl(phenyl)p, C2_8alkenyl(phenyl)p, C2_8alkynyl~phenyl)p, C3_8cycloalkyl or cl-8alkylc3-8cycloalkyl;
p is 0 to 2;
n is 0 to 6;
A is a bond, oxygen, sulphur or NRl;
Rl is hydrogen, Cl_8alkyl or phenylCl_4alkyl;
m is 0 to 3; and Ar is aryl or heteroaryl, each of which may be optionally substituted, and salts thereof.

2 ~ 9 0 - 2 -Suitably, R is Cl_8alkyl(phenyl)p, C2_8alkenyl-(phenyl)p, C2_8alkynyl(phenyl)p, C3_8cycloalkyl or Cl-8alkYlC3 _gCycloalkyl .

It will be understood that the alkylcycloalXyl, alkylphenyl, alkenylphenyl and alkynylphenyl groups are linked to the piperidine nitrogen atom via the alkyl, alkenyl and alkynyl moieties respectively.

Preferably R is Cl_8alkyl(phenyl)p in which p is 0 or l, i.e. Cl_8al~yl, such as n-pentyl, or phenylCl_8alkyl such as phenylpropyl, or R is C2_8alkenyl(phenyl)p wherein p is l, such as cinnamyl.

lS Suitably, n is 0 to 6; preferably n is 0 to 3; most preferably n is l.

Suitably, m is 0 to 3; preferably m is 0 or l; most pre~erably m i5 O.
Suitably, A is a bond, oxygen, sulphur or NRl;
pre~erably A is oxygen or sulphur; most preferably A is oxygen. When A is oxygen n is preferably l and m is preferably O.
Suitably, Ar is optionally substituted aryl or heteroaryl; preferably Ar is optionally substituted aryl.

Suitable aryl groups include, for example, unsaturated monocyclic and unsaturated or partially saturated bicyclic ring systems of up to lO carbon atoms, such as, for example, phenyl, naphthyl and tetrahydronaphthyl. Preferred are optionally substituted phenyl rings.
Suitable substituted phenyl rings include, for WO92/0~01 (~ PCT/GB91/01339 example, phenyl :- ngs substituted by a Cl_2alkylene-dioxy group such ~s a 3,4-methylenedioxy group or by l to 3 substituents selected from halogen, Cl_4alkoxy, nitro, SCl_4alkyl, NR2R2 ~in which each R2 group 5 can be H or cl_4alkyl), OCF3~ Cl-6alkYl~
trifluoromethyl, CN, optionally substituted phenyl, optionally substituted phenylCl_4alkyl and optionally substituted phenylCl_4alkoxy. Preferred are phenyl rings substituted by one or two substituents, in particular, by a single halogen, trifluoromethyl, unsubstituted phenyl or unsubstituted phenylCl_4alkoxy group; or by two chloro atoms especially in the 3- and 4-positions of the phenyl ring.

Suitable optionally substituted phenylCl_4aIkyl groups include, for example benzyl. Suitable optionally substituted phenylCl_4alkoxy groups include, for example benzyloxy groups.

Suitable substituents for said optionally substituted phenyl, phenylCl_4alkyl and phenylCl_4alkoxy groups include for example halogen, Cl_4alkyl, Cl_4aLkoxy, nitro and trifluoromethyl groups.

Suitable heteroaryl rings include, for example, unsaturated monocyclic and unsaturated or partially saturated bicyclic ring systems of up to lO carbon atoms containing at least one heteroatom, such as pyridyl, thienyl, quinolinyl, tetrahydroquinolinyl and imidazolyl rings. The heteroaryl ring can be linked to the remainder of structure (I) via a carbon atom or via a hetero atom, e.g. a nitrogen atom.

Suitable substituents for said heteroaryl rings 3~ include, for example, l to 3 substituents selected from halogen, Cl_4alkyl and Cl_4alkoxy.

W092/0~01 2 B ~ ~ ~ 9 ~ PCTJGBgl/01339 Alkyl groups present in the compounds of structure (I), alone or as part of another group, can be straight or branched.
It will be appreciated that ~or 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, oxalate, or similar pharmaceutically acceptable inorganic or organic acid addition salts. Other non-pharmaceutically acceptable salts may be used for example as intermediates and are included within the scope of this invention.
Particular compounds of the invention include:
3-(4-fluorophenoxymethyl)-1-pentylpiperidine oxalate, 3-(3,4-methylenedioxyphenoxymethyl)-1-pentylpiperidine hydrochloride, 3-(3-tri~luoromethylphenoxymethyl)-1-pentylpiperidine hydrochloride, 3-(3-phenylphenoxymethyl)-1-pentylpiperidine oxalate, 3-(2-phenylphenoxymethyl)-1-pentylpiperidine oxalate, 3-(4-phenylphenoxymethyl)-1-pentylpiperidine oxalate, 3-(2-benzylphenoxymethyl)-1-pentylpiperidine oxalate, 3-(4-benzylphenoxymethyl)-1-pentylpiperidine hydrochloride, 3-(4-benzyloxyphenoxymethyl)-1-pentylpiperidine hydrochloride, l-cinnamyl-3-(3,4-dichlorophenoxymethyl)piperidine oxalate, 3-(4-iso-propylphenoxymethyl)-1-pentylpiperidine hydrochloride, and 3-(3,4-dichlorophenylaminomethyl)-1-pentylpiperidine dihydrochloride.
It will be appreciated that the compounds of structure (I) may contain one or more asymmetric centres, in particular at the 3-position of the piperidine ring.
Such compounds will exist as optical isomers (enantiomers). Both the pure enantiomers, racemic mixtures (50% of each enantiomer) and unequal mixtures of 2 ~
WO92/0~01 PCT/GB91/01339 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.

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 structure (I) which comprises:

(a) for compounds of structure (I) in which A is O, S or NRl, reaction of a compound of structure (II):

~ 2)nA ~
R (II) in which R and n are as described for structure (I) and Al is o, S or NRl, with a compound of structure L(CH2)mAr in which m and Ar are as described for structure (I), and L is a leaving group;

(b) for compounds of structure (I) in which A is O, S or NRl, reaction of a compound of structure (III):

WO92/0~01 2 0 8 ~ ~ 9 PCT~GB91/01339 ,~CH2 ) nLl (III) R

in which n and R are as described for structure (I) and Ll is a group displaceable by a nucleophile, with a compound of structure HAl(CH2)mAr where m and Ar are as described for structure (I) and Al is as described for structure (II); or (c) for compounds of structure (I) in which A is NRl, reduction of a compound of structure (IV) :

~ ,,-N (IV) R

in which R4 represents the group O
(c~2)nN(Rl)c(cH2)m-lAr or ~(CH2)n-1CN(Rl)(CH2)~Ar' and n, m, R and Ar are as described for structure (I);

(d) for compounds of structure (I) in which A is a bond, reaction of a compound of structure (V) :
.

WO92/02501 , 2 ~ 3 3 ~ 9 0 PCT/GBgl/0l339 ( 2)n+m L
~ / (V) R

(wherein R, Ll, m and n are as hereinbefore defined).

with a compound of structure XlAr in which Ar is as described for structure (I), and Xl is an alkali metal;

(8) introduction o~ the group R into a co~pound of formula (VI) :

(CH2)nA(CH2)mAr ,'^~ /
(VI) by reaction with a compound RL2, wherein L2 is a leaving group;

(f) Reduction of a compound of formula (VII) :

2 ~

(CH2)nA(CH2)mAr J (VII) COR

wherein R5 is Cl_7alkyl(phenyl)p, C2_7alkenyl(phenyl)p, C2 7alkynyl(phenyl)p or Cl_7alkylC3_8cycloalkyl;

tg) Reduction of a compound of structure (VIII):

~ (CH2)n~tCH2)mAr I (VIII) N~ J
R

wherein R, A, Ar m and n are as hereinbefore defined and ~ is a counter ion;
and optionally thereafter forming a salt.

In process (a) the reaction between a compound of structure (II) and a compound L(CH2)mAr can take place under conditions which depend on the nature of the group L. For example, when L is halogen or a sulphonic acid residue such as a tosylate or mesylate, the reaction is carried out under standard conditions in a solvent, optionally in the presence of a base. When a fluoro-substituted aryl compound F-Ar is employed in WO92/0~01 ~ 8 ~ ~ 9 0 PCT/GB91/01339 _ g _ process (a), the reaction is effected in the presence of a strong base such as sodium hydride, and in an inert organic solvent such as dimethylformamide. Preferably the aryl group is substituted by an activating group such as CF3 or N02.

The reaction between a compound of structure (III) and a compound of structure HAl(CH2)mAr can take place under conditions which depend on the nature of and A. For example when Ll is hydroxy, m is 0 and Al 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 Ll 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 200C.
The reduction of a c~ound of structure (IV) can be effected by methods known in the art, for example using a reducing agent such as lithium aluminium hydride.
Conveniently a compound of structure (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 structure (V) and a compound of struc--~re Xl~r can take place under standard conditions known to those skilled in the art for the formation of carbon-carbon bonds.

The reaction of a compound of structure (VI) with RL2 according to process (e) may be effected in conventional manner, for example in an organic solvent, such as dimethyl formamide. The leaving group L2 may be for example a halide such as bromide or chloride, an acyloxy group such as acetoxy or chloroacetoxy or a WO92/02501 , PCT/GB91/01339 2~8l~9~

sulphonyloxy group such as methanesulphonyloxy or p-toluenesulphonyloxy. When L2 is a halide the reaction is preferably carried out in the presence of a weak base such as potassium carbonate, and when L2 is sulphonyloxy, a strong base such as sodium hydride or potassium t-butoxide may be employed.

Reduction of a compound of formula (VII) may be effected using standard reducing agents such as lithium aluminium hydride.

Reduction of a compound of formula ~VIII) may be effected ~or 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.

The compounds o~ structure (II) can be prepared from the corresponding compounds in which R is hydrogen, by alkylation under standard conditions. For example, compounds of structure (II) in which R is n-pentyl can be prepared from the corresponding precursor in which R is hydrogen by reaction with an n-pentylhalide such as n-pentyl bromide in a suitable solvent, such as methyl ethyl ketone, or a Cl_4alkanol such as ethanol, in the presence of a base, such as potassium carbonate, or dimethylformamide in the presence of an iodoalkane.

The corresponding compounds of structure (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 3-hydroxy-alkylpyridine.

Alternatively, the compounds of structure (II) in which Al is oxygen can be prepared by reduction of a compound of structure (IX):

W092/0250l 2 ~ 9 ~ PCTtGBg1/0l339 2 ) nOH
~ J (IX) S ~N X
R

in which R and n are as described for structure (I) and X~ is a counter ion.

Compounds of structure (III) wherein Ll is OH can be prepared as described for compounds of structure (II), and compounds o~ structure (III) wherein Ll is a halogen atom, or a mesyloxy or tosyloxy group can be prepared fr the corresponding alcohol in conventional manner.

Compounds of structure (IV) wherein R4 is a group o -(CH2)nN(Rl)C(CH2)m_lAr can be prepared by reacting a compound of structure (II) wherein Al represents NRl with an acylating agent corresponding to the group -(CH2)mAr, for example an acid chloride cloc(cH2)m-lAr-Compounds of structure (IV) wherein R4 is a group o -(CH2)n_lCN(Rl)(CH2)mAr may be prepared for example by reaction of a corresponding compound wherein R4 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 WO92/0~01 PCT/GB9t/01339 2~4~

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 structure (II) wherein Al is oxygen.

Compounds of structure (Y) may be prepared in analogous manner to compounds of structure (III); where necessary the chain length may be increased using methods well known in the art.
Compounds of structure (VI) may be prepared for example according to any of processes (a) to (d) above, using intermediates analogous to structures (II) to (IV) wherein R is replaced by an N-protecting group, which is subsequently removed by methods well known in the art.
Suitable protecting groups include aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl and acyl groups such as acetyl, trifluoroacetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, or benzyloxycarbonyl.
An 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 where the N-protecting group is aralkyl, the compound is of structure (I) and this reaction sequence thus provides a means of converting one compound of formula (I) into a different compound of formula (I).

A compound of formula (VII) may be prepared by reaction of a compound of formula (VI) with an appropriate acid derivative for example an acid chloride, or anhydride.

A compound of structure (VIII) may be prepared using the general methods described in processes (a) to (e) above.
.

W092/0~01 PCT/GB91/01339 2~d9~

When compounds of structure (I) are obtained as mixtures of enantiomers, these may be separated by conventional methods such as crystallisation in the presence of a resolving agent, or chromatography, for example using a chiral HPLC column.

The compounds of the invention have been found to exhibit high calcium influx blocking activity and as such are expected to be of use in therapy in treating lo 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 ~or example stroke, migraine, epilepsy, traumatic head in~ury, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory 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 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 structure (I) or a pharmaceutically acceptable salt thereof. In addition, the present invention also provides a method of treatment W092/02501 ~ ~ PCT/GB91/0133g of anoxia, ischaemia including for example stroke, migraine, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory disorders, and drug addiction withdrawal such as ethanol addiction withdrawal, which comprises administeriny to a subject in need thereof, an effective amount of a compound of structure (I) or a pharmaceutically acceptable salt thereo~.
In therapeutic use, the compounds of the present invention are usually administered in a standard pharmaceutical composition. The present invention therefore provides in a further aspect pharmaceutical lS compositions comprising a compound of structure (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

The compounds o~ structure (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions~or-em~lsions, 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, WO92/02501 2 ~ 3 ~ ~ 9 ~ PCT/GB91/01339 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 agueous 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.

Preferably the composition is in unit dose form such as a tablet or capsule.

Each dosage unit for oral administration contains preferably from l to 250 mg (and for parenteral administration contains preferably from O.l to 60 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the ~ree bac-.

The daily dosage regimen for an adult patient may be, for example, an oral dose of between l ~g and 500 mg, preferably between l mg and 250 mg, eg. 5 to 200 mg or an intravenous, subcutaneous, or intramuscular dose of W092/0 01 ~ ~ 9 ~ PCT/GB91/01339 between O.l mg and lO0 mg, preferably between O.l 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 l to 4 times per day. Alternatively the compounds of the invention may be administered by continuou~ intravenous infusion, preferably at a dose of up to lOOmg per day.
Suitably the co~pounds will be administered for a period of continuous therapy, for examp}e for a week or more.

W092/0~01 2 ~ 9 0 PCT/GB9l/01339 DATA

Ca~+ 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 qlass coverslips and used within 3 days to permit e~fective voltage clamp o~ Ca2+ currents.

Solutions The pipette (internal solution) contained in mM:
CsCl, 130; HEPES, 10; EGTA, 10; MgC12, 4; ATP, 2;
buffered to pH 7.2 with CsOH~

Cells were bathed in a normal ~yrodes solut~on be~ore establishment o~ whole cell record~ng when the bathing solution was changed to one allowing isolation of Ca2+ currents.

The external solution-~or recording Ca2+ channel currents contained in mM: BaC12, lo; TEA-Cl, 130;
glucose, 10; HEPES, 10; NgC12, 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 the drug concentration used the vehicle (0.1%) had no significant effect on Ca2+
currents.

All experiments were performed at 21 to 24C.
Whole cell currents were recorded using List EPC-7 amplifiers and stored, digitised for later analysis using W092~0~ ~ ~ 9 ~ PCT/GB91/01339 PC based software similar to that described previously (Benham ~ Tsien, Journal of Physiology (1988), 404, 767-784).

RESULTS

Ca2+ currents Peak voltage gated Ca2+ channel currents of up to 10 nA ~rom dorsal root ganglion neurons were recorded using 10 mM Ba2+ as charge carrier. Currents were evoked ~rom arholding potential of -80 mV to a test potential of 0 or +10 mV every 15 seconds. This test potential was at the peak of the current voltage relationship and assessing block at this point reduced any errors due to dri~ting holding potential. Some cells showed slow rundown o~ current as is commonly seen when recording ca2+ currents. The rundown rate was measured in control conditions and extrapolated through the time o~ drug application to derive a control value to relate the drug a~fected current to. Block by 20 ~M
drug was assessed 3 minutes a~ter drug application.

Compounds o~ the invention gave percentage inhibition o~ plateau Ca2+ current in the range 30 to 100%.

W092/0~01 2 ~ ~ 3 ~ 9 0 PCT/GB91/01339 PHARMACEUTICAL FORMULATIONS

l. Formulation for intravenous infusion Compound of structure (I) O.l - 60 mg Sodium hydroxide/hydrochloric acid to pH ca 7 polyethylene glycol O - 30 ml propylene glycol O - 30 ml alcohol O - lO ml water to lOO ml 2. Formulation for bolus iniection Compound of structure ~I) O.l - 60 mg 15 sodium hydroxide or hydrochloric acid to pH ca 7 polyethylene glycol O - 2.5 ml alcohol O - 2.5 ml water to 5 ml A toxicity adjusting agent eg. sodium chloride, dextrose or mannitol may also be added.

3. Tablet for ora~ administration ma/tablet Compound of structure (I) 25 lactose lS3 starch 33 crospo~idone 12 microcrystalline cellulose 30 magnesium stearate 2 WO92/0~01 , PCT/GB9l/01339 2 ~

EXAMPLES

Intermediate PreParations (i) 3-(Hvdroxvmethvl)-l-PentvlPiPeridine A mixture of 3-~hydroxymethyl)piperidine (20g), 1-bromopentane (26.28g), potassium carbonate (24g) and ethanol ~400ml) was heated at reflux for 4 days. The solution was filtered, and the solvent removed under reduced prçssure. The residue was treated with acetone, filtered, the solvent removed and the resulting oil was distilled under reduced pre~sure to give the title compound as an o~ 24.63g, b.p. 103-104C @ 0.3mmHg.) (ii)3-(Hvdroxvmethvl)-l-ProPvlDiPeridine A mixture of 3-~hydroxymethyl)piperidine ~20g), 1-bromopropane (21.4g), potassium carbonate (24g) and ethanol (400ml) was heated at reflux for 1 days. The solution was filtered, and the solvent removed under reduced pressure. The residue was treated with acetone, filtered, the solvent removed and the resulting oil distilled under reduced pressure to give the title compound as an oil. (18.21 g, b.p. 101-103C Q 0.2mmHg.) (iii) l-Cinnamvl-3-(hvdroxYmethYl)~iPeridine A mixture of 3-(hydroxymethyl)piperidine (28g), cinnamyl bromide (47.91g), potassium carbonate (33.6g) and ethanol W092/02501 2 ~ PCT/GB9t/01339 ~300ml) was heated at reflux for 2 days. The solution was filtered, and the solvent removed under reduced pressure.
The residue was distilled under reduced pressure to give the title compound as an oil. (24.63g, b.p. 164-168 C @
0.3mmHg.) Found: C, 77.59; H, 9.18; N, 5.94%
(C15H21NO) requires: C, 77.88; H, 9.15; N, 6.05%

10 (iv) 3-Methanesul~honvloxvmethvl-l-PentvlPiPeridine hVdrochloride Methanesulphonyl chloride ~5.8ml) in dichloromethane ~20ml~ was added to a solution of 3-hydroxymethyl-1-pentylpiperidine (lOg) in dichloromethane (20ml). Themixture was stirred for 18 hours, treated with hydrogen chloride in ether and recrystallised from ethylacetate to give the title compound (13.2g) m.p. 99-101C

(v) 3-(3-HvdroxvProPvl)-l-PentvlPvridinium bromide A solution of 3-(3-hydroxypropyl)pyridine (20g), 1-bromopentane (22.05g) and acetone (250ml) was refluxed for 72 hours, cooled and poured into diethylether (200ml).
The oil which precipitated was collected by decantation then washed by decantation with diethyl ether (5 X lOOml) and dried at 50C (O.lmmHg) to give the title compound (42g)which was used without further purification.

(vi) 3-~3-HvdroxvProPvl)-l-pentvlpiPeridine W092/0250~j~t~ PCT/GB91/01339 A mixture of 3-(3-hydroxypropyl)-1-pentylpyridinium bromide ~42.g), platinum oxide (1.5g) and ethanol (350ml) was shaken under an atmosphere of hydrogen at 50 p.s.i.
for 1 hour. The mixture was filtered and the solvent S removed. The residue was dissolved in dilute sodium hydroxide (70ml) and extracted with dichloromethane (3 x 75ml). The organic extracts were combined, dried over magnesium sulphate and the solvent was removed to give the title compound as an oil (18.0g).

ExamPle 1 3-(4-FluoroPhenoxvmethYl)-l-PentvlPiperidine oxalate A solution of 3-(hydroxymethyl)-1-pentylpiperidine ~2.0g), 4-fluorophenol (1.21g) and triphenylphosphine (2.62g) in tetrahydrofuran (40ml) was treated with diethyl azodicarboxylate (1.74g) in tetrahydrofuran (lOml). The resulting solution was stirred at room temperature for 18 hours, the solvent was removed and the residue was chromatographed on silica gel eluted with methanol/dichloromethane. The resulting,,oil was dissolved in ethyl acetate (SOml) and treated with oxalic acid (0.62g). The precipitate was collected by filtration and recrystallised (methanol/ethyl acetate) to give the title compound (1.21g), m.p. 126 - 128C.

Found: C, 61.17; H, 7.79; N, 3.78; F 4.71%.
(C17H26FNO.C2H204.3H20) requires: C, 60.80; H, 7.60;
N, 3.70; F, 5.06%.

WO 92/02501 PCr/GB91/01339 xamPle 2 3- (3,4-MethYlenedioxYPhenoxvmethY~ -pentvlpiperidine hYdrochloride A solution of 3-(hydroxymethyl)-1-pentylpiperidine (2.0g), sesamol (1.49g) and triphenylphosphine (2.62g) in tetrahydrofuran (50ml) was treated with diethyl azodicarboxylate (1.74g) in tetrahydrofuran (lOml~. The 10 resulting solution was stirred at room temperature for 18 hours, the solvent removed and the residue chromatographed on silica gel eluted with methanol/dichloromethane. The resulting oil was dissolved in ethyl acetate (50ml) and treated with ethereal hydrogen chloride. The precipitate 15 was collected by filtration and recrystallised (methanol/ethyl acetatel to give the title compound (l.Olg), m.p. 183 - 184C.

Found: C, 63.27; H, 8.22; N, 4.17; Cl, 10.37%.
(C18H27N03.HCl) requires: C, 63.25; H, 8.20; N, 4.10;
Cl, 10.40%.

ExamPle 3 25 3-(3-PhenYlPhenoxvmethvl)-l-PentYlpiperidine oxalate A solution of 3-(hydroxymethyl)-1-pentylpiperidine (2.0g), 3-phenylphenol (1.70g) and triphenylphosphine (2.62g) in tetrahydrofuran (40ml) was treated with diethyl azodicarboxylate (1.66g) in tetrahydrofuran (50ml). The resulting solution was stirred at room temperature for 18 hours, the solvent was removed and the residue was W092/0~01 ~ PCT/&B91/01339 chromatographed on silica gel eluted with methanol/dichloromethane. The resulting oil (l.lg) was dissolved in ethyl acetate (SOml) and treated with oxalic acid (l.lequivalents). The precipitate was collected by filtration and recrystallised (methanol/ethyl acetate) to give the title compound ~0.8g), m.p. 148 - 14~C.

Found: C, 70.46; H, 7.80; N, 3.24%.
~C23H31NO.C2H204~ requires: C, 70.23; H, 7.78; N, 3.28%
Exam~le 4 3-(2-PhenYlphenox~methvl)-l-PentYlPiPeridine oxalate ~5 A 801ution of 3-~hydroxymethyl)-1-pentylpiperidine (2.0g), 2-phenylphenol ~1.70g) and triphenylphosphine ~2.62g) in tetrahydrofuran ~SOml) was treated with diethyl azodicarboxylate ~1.74g) in tetrahydrofuran (lOml). The resulting solution was stirred at room temperature for 18 hours, the solvent removed and the residue chromatographed on silica gel eluted with methanol/dichloromethane. The resulting oil was dissolved in ethyl acetate (50ml) and treated with oxalic acid (0.9g). The precipitate was collected by filtration and recrystallised (methanol/ethyl acetate) to give the title compound (l.lOg), m.p. 99 - 101C.

Found: C, 70.00; H, 7.97; N, 3.28%
(C23H31NO.C2H204) requires: C, 70.23; H, 7.78; N, 3.28%

W092/0~01 , PCT/GB91~01339 2 3 ~ a ExamPle 5 3-(4-BenzvloxvPhenoxvmethvl)-l-PentYlPiperidine hvdrochloride A solution of 3-(hydroxymethyl)-1-pentylpiperidine (2.0g), 4-benzyloxyphenol ~2.0g) and triphenylphosphine ~2.62g) in tetrahydrofuran ~50ml) was treated with diethyl azodicarboxylate ~1.74g) in tetrahydrofuran (lOml). The resulting solution was stirred at room temperature for 18 hours, the solvent remo~ed and the residue chromatographed on silica gel eluted with methanol/dichloromethane. The resultlng oil was dissol~ed ~n ethyl acetate and treated with hydrogen chloride in diethyl ether. The precipitate was collected by f~ltratlon and recrystallised ~methanol/ethyl acetate) to give the title compound (0.5g), m.p. 149 - 150C.

Found: C, 71.56; H, 8.71; N, 3.43; Cl, 8.57%
~C24H33N02.HCl) requires: C, 71.35; H, 8.48; N, 3.47;
Cl, 8.78%

ExamPle 6 3-(4-9enzvlPhenoxvmethYl)-l-PentvlPiperidine hvdrochloride The title compound was prepared in a similar manner to example 5 starting from 3-(hydroxymethyl)-1-pentylpiperidine ~2.0g), 4-hydroxydiphenylmethane (1.84g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride ga~e WO92/0~01 PCT~GB9t/01339 ~3~ 3 a white solid which was recrystallised from methanol/ethyl acetate (O.Slg), m.p. 169 - 171C.

Found: C, 74.38; H, 8.96; N, 3.68; Cl, 8.22%
~C24H33NO.HCl) requires: C, 74.30; H, 8.83; N, 3.61;
Cl, 9.16~

ExamPle 7 3-~3-TrifluoromethvlPhenoxvmethvl)-l-~entvlPiPeridine hvdrochloride The title compound was prepared in a similar manner to example 5 starting from 3-(hydroxymethyl)-1-pentylplperidine (1.85g), 3-trifluoromethylphenol (1.62g), triphenylphosphine ~2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from methanol/ethyl acetate (0.41g), m.p. 165C.
Found: C, 59.04; H, 7.40; N, 3.91; Cl, 9.67%
(C18H26F3NO.HCl) requires: C, 59.0; H, 7.4; N, 3.8;
Cl, 9.7%

ExamPle 8 3-(4-Nitrophenoxvmethvl)-l-PentvlPiPeridine hvdrochloride The title compound was prepared in a similar manner to example 5 starting from 3-(hydroxymethyl)-1-pentylpiperidine (1.85g), 4-nitrophenol (1.39g), triphenylphosphine ~2.62g) and diethyl azodicarboxylate W092/0250l PCT/GB9l/01339 23(3~d9~

~1.74g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from methanol/ethyl acetate (0.13g), m.p. 220C.

S Found: C, 59.22; H, 7.96; N, 8.08; Cl, 10.31%
(C17H26N203.HCl) requires: C, 59.55; H, 7.94; N, 8.17;
Cl, 10.35%

ExamPle 9 3-~4-PhenYlPhenoxvmethvl)-l-PentvlPi~eridine oxalate The title compound was prepared in a similar manner to example 5 starting from 3-~hydroxymethyl)-1-pentyl-piperidine (2.0g), 4-phenylphenol ~1.70g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with oxalic acid gave a white solid which was recrystallised from methanol/ethyl acetate (0.60g), m.p. 173.5 - 174C.
Found: C, 70.17; H, 7.74; N, 3.50%
(C23H31NO.C2H204) requires: C, 70.23; H, 7.78; N, 3.28%

ExamPle 10 3-(2-BenzYlPhenoxvmethYl)-l-Pentylpiperidine oxalate The title compound was prepared in a similar manner to example 5 starting from 3-hydroxymethyl-1-pentylpiperidine (2.0g), 2-hydroxydiphenylmethane (1.84g), - triphenylphosphine ~2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with oxalic acid gave a WO 92/02501 PCr/GB91/01339 2~ o white solid which was recrystallised from methanol/ethyl acetate ~0.260g), m.p. 120C.

Found: C, 70.21; H, 7.99; N, 3.20%
~C24H33NO.C2H204Ø25H20) requires: C, 69.94; H, 7.96;
N, 3.14%

ExamPle 1 1 10 3-(4-ChloroPhenoxvmethvl)-l-PentvlPiPeridine oxalate The title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-1-penty}piperidine (2.0g), 4-chlorophenol (1.28g), triphenylphosphine ~2.62g) and 15 dlethyl azodlcarboxylate ~1.74g). Treating the product wlth oxalic acid gave a white solid which was recrystallised from methanol/ethyl acetate ~0.82g), m.p. 140C.

Found: C, 59.27; H, 7.26; N, 3.80; Cl, 8.93%
~C17H26ClNO.C2H204) requires: C, 59.14; H, 7.31; N, 3.63;
Cl, 9.1996 Examl~le 12 3-(4-Cvano~henoxvmethYl)-l-~entvlPi~eridine oxalate The title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-1-pentylpiperidine ~2.0g), 4-cyanophenol ~1.19g), triphenylphosphine ~2.62g) and diethyl azodicarboxylate ~1.74gt. Treating the product with oxalic acid gave a white solid which was WO92/0~01 PCT/GB91/01339 9 ~

recrystallised from methanol/ethyl acetate (0.79g), m.p. 104C.

Found: C, 63.83; H, 7.59; N, 7.47%
(C18H26N2O~C2H2O4) requires: C, 63.81; H, 7.50; N, 7.44%

Exam~le 13 3-~henoxvmethvl-1-~entvlPi~eridine oxalate The title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-1-pentylpiperidine (2 Og), phenol (0.94g), triphenylphosphine (2.62g) and diethyL
azodlcarboxylate (1.74g). Treating the product with oxalic acid gave a white solid which was recrystallised from methanol/ethyl acetate (1.02g), m.p. 144.5C.

Found: C, 65.15; H, 8.43; N, 4.02%
~C17H27NO.C2H2O4) requires: C, 64.93; H, 8.32; N, 3.99%
ExamPle 14 3-(4-Fluorobenzvloxvmethvl)-1-PentvlPiPeridine oxalate A solution of 3-hydroxymethyl-1-pentylpiperidine (3.0g) in dimethylformamide (30 ml) was treated with sodium hydride (0.0162 mole) and then stirred for 0.5 hour when 4-fluorobenzyl chloride (2.35g) was added. The mixture was stirred for 2 days and the solvent removed. Water (100 ml) and dichloromethane (100 ml) were added and the organic layer was separated, washed with saturated sodium chloride (150 ml) and dried over magnesium sulphate. The W092/0~01 PCT/GB9l/01339 2~3~ 30 solvent was removed and the residue chromatographed on silica gel using methanol/d$chloromethane as eluent. The resulting oil was dissolved in ethyl acetate and treated with oxalic acid (1.1 mole equivalent). The precipitate was collected by filtration and recrystallised ~methanol/ethyl acetate) to give the title compound ~1.2g), m.p. 126 - 127C.

Found: C, 62.64; H, 7.97; N, 3.66%.
~C18H28FNO.C2H204) requires: C, 62.64; H, 7.89; N, 3.65%

ExamPle 15 3-~3,4-Meth~lenedioxvPhenoxYmethYl)-l-Propylpiperidine hYdrochlorlde The title compound was prepared in a similar manner to example 5 starting from 3-~hydroxymethyl)-1-propyl-piperidine ~1.57g), sesamol ~1.38g), triphenylphosphine ~2.62g~ and diethyl azodicarboxylate ~1.74g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from methanol/ethyl acetate ~0.39g), m.p. 154C.

Found: C, 59.14; H, 7.63; N, 4.62; Cl, 10.77%
~C16H23N03.HCl.O.SH20) requires: C, 59.47; H, 7.74;
N, 4.34; Cl, 10.84%

WO92/02501 2 ~ ~ ~ d ~ V PCTJGB9l/01339 ~xamPle 16 l-Cinnamvl-3-(3,4-dichloroPhenoxvmethvl)PiPeridine oxalate The title compound was prepared in a similar manner to example 1 from 1-cinnamyl-3-hydroxymethylpiperidine ~2.00g), 3,4-dichlorophenol (1.41g), triphenylphosphine (2.27g) and diethyl azodicarboxylate (l.Slg). Treating the product with oxalic acid in ethyl acetate gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (1.27g), m.p.206C.

Found: C, 59.37; H, 5.46; N, 3.16; Cl, 15.16~
(C21H23C12NO~C2H2O4) requires C, 59.24; H, 5.40; N, 3.00;
Cl, 15.16%

ExamPle 17 l-Cinnamvl-3-~4-fluoroPhenoxvmethvlt~iPeridine oxalate The title compound was prepared in a similar manner to example 1 from 1-cinnamyl-3-hydroxymethylpiperidine (2.00g), 4-fluorophenol (0.971g), triphenylphosphine (2.27g) and diethyl azodicarboxylate (1.51g). Treating the product with oxalic acid in ethyl acetate gave a white solid which was recrystallised ~rom ethyl acetate/methanol to give the title compound as a white crystalline solid (0.7g), m.p.123C.

Found: C, 66.51; H, 6.31; N, 3.44%
(C2lH24FNo~c2H2o4) requires: C, 66.49; H, 6.31; N, 3.37 W092/0~01 PCT/GB91/01339 2 ~

ExamPle 18 3-(3,4-Dichloro~henoxYmethYl)-l-PentYlpi~eridine hvdrochlorlde The title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-1-pentylpiperidine (2.00g), 3,4-dichlorophenol (1.63g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride in ether gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (l.lOg), m.p.188-190C.

Found: C, 55.92; H, 7.18; N, 3.86; Cl , 9.64%
~C17H25C12NO~HCl) requlres: C, 55.67; H, 7.15; N, 3.82;
Cl-, 9.68%

ExamPle 1 9 3-(4-iso-ProPYlPhenoxvmethYl)-l-pentvlpiperidine hvdrochloride The title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-1-pentylpiperidine (2.00g), 4-iso-propylphenol (1.36g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride in ether gave a white solid which was recrystallised from ethyl acetate/methanol to gi~e the title compound as a white crystalline solid (0.18g), m.p.172-174C.

Found: C, 70.41; H, 9.95; N, 4.34%

2 ~ 3 l~

(C20H33NO.HCl) requires: C, 70.66; H, 10.08; N, 4.12%

ExamPle 20 3-(3-iso-Pro~vlPhenoxvmethvl)-l-Pentvl~iPeridine hYdrochloride The title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-1-pentylpiperidine (1.5g), 3-iso-propylphenol (l.lg), triphenylphosphine (2.12g) and diethyl azodicarboxylate (1.41g). Treating the product with hydrogen chloride in ether gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (0.8g), m.p.138-140C.
Found: C,-69.89; H, 9.91; N, 4.io; Cl , 10.33%
(C2oH33NO.HClØ25 H2O) requires: C, 69.74; H, 9.95; N, 4.07; Cl-, 10.29 ExamPle 21 3-(3-tert-ButvlPhenoxvmethvl)-l-PentvlPiPeridine hvdrochloride The title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-1-penty}piperidine (1.50g), 3-tert-butylphenol (1.22g), triphenylphosphine (2.12g) and diethyl azodicarboxylate (1.41g). Treating the product with hydrogen chloride in ether gave a white solid which was recrystallised from ethyl acetate/methanol to give the - 30 title compound as a white crystalline solid (1.035g), m.p.185-187C.

Found: C, 71.39; H, 10.33; N, 4.09; Cl, 9.92%
~C21H35NO.HCl) requires: C, 71.26; H, 10.25; N, 3.96;
Cl,10.02%

ExamPle 22 3-(4-Fluorobenzvlaminomethvl)-PentvlPiPeridine dihvdrochloride A mixture of 4-fluorobenzylamine ~2.49g) and 3-methanesulphonyloxymethyl-l-pentylpiperidine hydrochloride (2g) was heated at 150C for 2.5 hours. The mixture was dissolved in dichloromethane and the dichloromethane solution washed with dilute sodium hydroxide solution, drled over sodium sulphate and the solvent removed. The residue was chromatographed on silica gel with d~chloromethane - methanol as eluent and treated with hydrogen chloride in ether to give a solid.
Recrystallisation from ethyl acetate gave the title compound (0.92g), m.p. 207-209C.

Found: C, 58.12; H, 8.55; N, 7.67; Cl, 19.41%
(C18H29FN2.2HClØ3H20) requires: C, 58.26; H, 8.57; N, 7.54; Cl, 19.09%
ExamPle 23 3-(4-FluoroPhenvlaminomethvl~-PentvlPiPeridine dihvdrochloride Substituting 4-fluoroaniline for 4-fluorobenzylamine (9.12g) in example 22 gave the title compound (0.593g) as a white microcrystaline solid. m.p. 196-198C

WO g2/02501 2 ~ 3 ~ PCr/GBgl/0133g Found: C, 56.77; H, 8.12; N, 7.83; Cl, 19.63%
(C17H27FN2.2HC1Ø5H20) requires: C, 56.66; H, 8.39; N, 7.77; Cl, 19.68%
Exam~le 24 3-(3,4-DichloroPhenYlaminomethvl)-PentvlPiPeridine dihvdrochloride Substituting 3,4-dichloroaniline for 4-fluorobenzylamine (4.04g) in example 22 gave the title compound (0.38g) as a white microcrystaline solid. m.p. 185-187C

Found: C, 50.99; H, 7.02; N, 6.99%
~C17H26C12N2.2HCl) requires: C, 50.76; H, 7.027 N, 6.96 ExamPle 25 3-(4-tert-ButvlPhenoxYmethvl)-1-PentvlPiPeridine hvdrochloride The title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-1-pentylpiperidine (l.SOg), 4-tert-butylphenol (1.22g), triphenylphosphine (2.12g) and diethyl azodicarboxylate (1.41g). Treating the product with hydrogen chloride in ether gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (0.205g), m.p.197-199C.
Found: C, 70.98; H, 10.21; N, 4.00; Cl, 9.82%

23~9~

tC21H35NO.HCl) requires: C, 71.26; H, 10.25; N, 3.96;
Cl,10.02%

~xamPle 26 3- r 3-(4-Fluoro~henoxv)ProPvll-l-PentvlPiperidine oxalate The title compound was prepared in a similar manner to example 1 from 1-pentyl-3-(3-hydroxypropyl)piperidine (2.13g), 4-fluorophenol tl.l2g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with oxalic acid gave a white solid which was recrystallised from methanol/ethyl acetate tl.lOg), m.p.
115 - 118C.

1~ Found: C, 63.53; H, 8.11; N, 3.80~
tClgH30FNO.C2H204) requires: C, 63.4B; H, 8.06; N, 3.53%

ExamPle 27 3-r3-(3,4-DichloroPhenoxv)~roPvll-l-pentylpiperidine oxalate The title compound was prepared in a similar manner to example 1 from 1-pentyl-3-t3-hydroxypropyl)piperidine t2.13g), 3,4-dichlorophenol tl.63g), triphenylphosphine ~2.62g) and diethyl azodicarboxylate tl.74g). Treating the product with oxalic acid gave a white solid which was recrystallised from methanol/ethyl acetate tO.Sg), m.p.
127-130C.

Found: C, 56.35; H, 6.90; N, 3.25%
tClgH2gC12NO.C2H204) requires: C, 56.25; H, 6.97; N, 3.12%

WO92/02501 2 ~ 8 3 ~ Pcr/GBgliol339 ExamPle 28 a) ~-)-3-(4-BenzYloxvPhenoxvmethYl)-l-pentvlPiPeridine b) ~ 3-~4-BenzvloxYPhenoxYmethYl)-l-~entvlplperidine The product from example 5 (55mg) was partitioned between diethyl ether and dilute sodium bicarbonate solution. The ether phase was separated, dried and the solvent removed.
The residue was chromatographed on a Chiralcel OJ h.p.l.c.
chromatography column using ethanol/hexane as eluent. The two enant, ~ers were collected. The (-) enantiomer being eluted first. Yield (8.0mg) rotation (-1.38 @ 22C in methanol). The second peak gave the (+) enantiomer, yield ~7.2mg) rotation ~1.24 @ 22C in methanol).
ExamPle 29 3-(3,4-DichlorobenzvlaminomethYl)-l-PentvlPiPeridine dihvdrochloride Substituting 3,4-dichlorobenzylamine for 4-fluorobenzylamine (0.587g) in example 22 gave the title compound (0.46g) as a white microcrystaline solid. m.p.

Found: C, 51.55; H, 7.09; N, 6.73; Cl, 16.85%
(C18H28C12N2.2HCl) requires: C, 51.94; H, 7.26; N, 6.73;
Cl, 17.04%

Claims

Claims:

1. A compound of structure (I):

(I) in which R is C1-8alkyl(phenyl)p, C2-8alkenyl(phenyl)p, C2-8alkynyl(phenyl)p, C3-8cycloalkyl or C1-8alkylC3-8cycloalkyl;
p is 0 to 2;
n is 0 to 6;
A is a bond, oxygen, sulphur or NR1;
R1 is hydrogen, C1-8alkyl or phenylC1-4alkyl;
m is 0 to 3; and Ar is aryl or heteroaryl, each of which may be optionally substituted, or a salt thereof.

2. A compound according to claim 1 wherein R is C1-8alkyl, phenyl(C1-8)alkyl or phenyl(C2-8)alkenyl.

3. A compound according to claim 1 or claim 2 in which A is oxygen.

4. A compound according to any of claims 1 to 3 wherein n is 0 to 3.

5. A compound according to any of claims 1 to 4 wherein m is 0 to 3.

6. A compound according to any of claims 1 to 5 in which Ar is optionally substituted phenyl.

7. A compound according to claim 1 which is:
3-(4-fluorophenoxymethyl)-1-pentylpiperidine, 3-(3,4-methylenedioxyphenoxymethyl)-1-pentylpiperidine, 3-(3-trifluoromethylphenoxymethyl)-1-pentylpiperidine, 3-(3-phenylphenoxymethyl)-1-pentylpiperidine, 3-(2-phenylphenoxymethyl)-1-pentylpiperidine, 3-(4-phenylphenoxymethyl)-1-pentylpiperidine, 3-(2-benzylphenoxymethyl)-1-pentylpiperidine, 3-(4-benzylphenoxymethyl)-1-pentylpiperidine, 3-(4-benzyloxyphenoxymethyl)-1-pentylpiperidine, 1-cinnamyl-3-(3,4-dichlorophenoxymethyl)piperidine, 3-(4-iso-propylphenoxymethyl)-1-pentylpiperidine; or 3-(3,4-dichlorophenylaminomethyl)-1-pentylpiperidine; or a pharmaceutically acceptable salt thereof.

8. A process for preparing a compound of structure (I) which comprises:

(a) for compounds of structure (I) in which A is O, S or NR1, reaction of a compound of structure (II):

(II) in which R and n are as described for structure (I) and A1 is o, S or NR1, with a compound of structure L(CH2)mAr in which m and Ar are as described for structure (I), and L is a leaving group;

(b) for compounds of structure (I) in which A is O, S or NR1, reaction of a compound of structure (III):

(III) in which n and R are as described for structure (I) and L1 is a group displaceable by a nucleophile, with a compound of structure HA1(CH2)mAr where m and Ar are as described for structure (I) and A1 is as described for structure (II); or (c) for compounds of structure (I) in which A is NR1, reduction of a compound of structure (IV) :

(IV) in which R4 represents the group or , and n, m, R and Ar are as described for structure (I);

(d) for compounds of structure (I) in which A is a bond, reaction of a compound of structure (V) :

(V) (wherein R, L1, m and n are as hereinbefore defined).

with a compound of structure X1Ar in which Ar is as described for structure (I), and X1 is an alkali metal;

(e) introduction of the group R into a compound of formula (VI) :

(VI) by reaction with a compound RL2, wherein L2 is a leaving group;

(f) Reduction of a compound of formula (VII) :

(VII) wherein R5 is C1-7alkyl(phenyl)p, C2-7alkenyl(phenyl)p, C2-7alkynyl(phenyl)p or C1-7aIkylC3-8cycloalkyl;

(g) Reduction of a compound of structure (VIII):

(VIII) wherein R, A, Ar m and n are as hereinbefore defined and ? is a counter ion;
and optionally thereafter forming a salt.

9. A pharmaceutical composition comprising a compound of structure (I) as claimed in any of claims 1 to 7 or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier.

10. A compound of structure (I) according to any of claims 1 to 7 or a pharmaceutically acceptable salt thereof for use in therapy.

11. Use of a compound of structure (I) according to any of claims 1 to 7 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of conditions caused or exacerbated by the accumulation of calcium in the brain cells of mammals.

12. A method of treatment of a condition 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 structure (I) according to any of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

13. A method according to claim 12 wherein the condition is stroke.

14. A method according to claim 12 or claim 13 wherein the mammal is a human.