NZ239267A

NZ239267A - 3-substituted piperidine derivatives and pharmaceutical compositions

Info

Publication number: NZ239267A
Application number: NZ239267A
Authority: NZ
Inventors: Thomas Henry Brown; David Gwyn Cooper
Original assignee: Smith Kline French Lab
Priority date: 1990-08-06
Filing date: 1991-08-05
Publication date: 1994-05-26
Also published as: AP9100314A0; MA22251A1; AU649468B2; AP236A; EP0542844A1; IE912760A1; AU8324391A; MX9100517A; WO1992002501A1; CN1062349A; CA2088490A1; IL99074A0; TW239860B; PT98575A; JPH06500092A

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £39267 # « 239 2 67 Priority Date{i .(pJ.'.P,. /?A?/ Complete Specification Fiisd: MOM fa, &rtPH&!h.. !M>! && !ut*s: Publication Dc:c: ..?. § . P.O. Journcl, No: NEW ZEALAND PATENTS ACT, 1953 No,: -5AUGi99f Date: > COMPLETE SPECIFICATION COMPOUNDS ■> ■N .* ■•• •' ->> ^ O / '-•? P t _.J -- We, SMITH KLINE & FRENCH LABORATORIES LIMITED, a British Company, of Mundells, Welwyn Garden City, Hertfordshire AL7 1EY, England, hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement - 1 - (followed by page la) 10 15 20 35 t ! _ vy 1 a - ^ 7 ■ ~i COMPOUNDS 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 N k 25 in which R is Cs-salkyi(phenyl)p, C2-8alkenyl(phenyl)pr C2-8alkynyl(phenyl)p, C3_8cycloalkyl or 30 Ci-salkylCs-scycloalkyl; p is 0 to 1; n is 0 to 6, and m is 0 to 3 provided that m and n are not both zero; A is a bond, oxygen, sulphur or NR*, where R1 is hydrogen, Cj-galkyl or phenylCi-^alkyl; and Ar is optionally substituted phenyl, ^ and salts thereof. * *3 / MAR 1994 *; ■ r i v* 2\ ^ Suitably, R is C5 _ 8 a1ky1(pheny1)p , C2_8alkenyl( phenyl )p, C2_8alkynyl( phenyl )p, C3_8cycloalkyl or _8alkylC3_8cycloalkyl. It will be understood that the alkylcycloalkyl, alkylphenyl, alkenylphenyl and alkynylphenyl groups are linked to the piperidine nitrogen atom via the alkyl, alkenyl and alkynyl moieties respectively. Preferably, R is C5_8alkyl(phenyl)p, in which p is 0 or 1, i.e. C5_8alkyl, such as n-pentyl, or R is C2_8alkenyl(phenyl)p wherein p is 1, such as cinnamyl. Suitably, n is 0 to 6; preferably n is 0 to 3; most preferably n is 1. Suitably, m is 0 to 3; preferably n is 0 or 1; most preferably m is 0. Suitably, A is a bond, oxygen, sulphur or NR1; preferably A is oxygen or sulphur; most preferably A is oxygen. When A is oxygen n is preferably l and m is preferably 0. Suitably, Ar is optionally substituted phenyl. Suitable substituted phenyl rings include, for 3 1 MAR 1994 * 1 0 1 5 25 30 35 "i - •% _ . V & - 3 - • •••* y " example, phenyl rings substituted by a C1_2alkylene-dioxy group such as a 3,4-methylenedioxy group or by l to 3 substituents selected from halogen, C1_4alkoxy/ nitro, SCj^alkyl, NR2R2 (in which each R2 group can be H or C1_4alkyl), OCF3, C-^galkyl, trifluoromethyl, CN, optionally substituted phenyl, optionally substituted phenylC1_4alkyl and optionally substituted phenylC1_4alkoxy. Preferred are phenyl rings substituted by one or two substituents, in particular, by a single halogen, trifluoromethyl, unsubstituted phenyl or unsubstituted phenylC1_4alkoxy group; or by two chloro atoms especially in the 3- and 4-positions of the phenyl ring. Suitable optionally substituted phenylC1_4alkyl 20 groups include, for example benzyl. Suitable optionally substituted phenylC1_4alkoxy groups include, for example benzyloxy groups. Suitable substituents for said optionally substituted phenyl, phenylC1_4alkyl and phenylC1_4alkoxy groups include for example halogen, C1_4alkyl, C1_4alkoxy, nitro and trifluoromethyl groups. £ N /* o\ y * 3-ITWRWlst V " 7 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 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, 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, 1 -pentyl-3-(3-trifluoromethylphenoxymethyl)piperidine hydrochloride, 1-pentyl-3 - (3-phenylphenoxymethyl)piperidine oxalate, 1-pentyl-3-(2-phenylphenoxymethyl)piperidine oxalate, 1-pentyl-3-(4-phenylphenoxymethyl)piperidine 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 3 1 oxalate, + 3- (4-iso-propylphenoxymethyl) -1-pentylpiperidine o c , sl r ** hydrochloride, and 3—(3,4-dichlorophenylaminomethy1)-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 mixtvires of 039 239 2 - 5 - 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. 5 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 10 compound of structure (I) which comprises: (a) for compounds of structure (I) in which A is 0, S or NR1, reaction of a compound of structure (II): 15 20 £H2>nAH (II) N & 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 25 structure (I) , and L is a leaving group; (b) for compounds of structure (I) in which A is 0, s or NR1, reaction of a compound of structure (III): 30 )39 239 2 67 - 6 - ^CH2^n (III) N I R in which n and R are as described for structure (I) and 10 L1 is a group displaceable by a nucleophile, with a compound of structure HA1(CH2)DJAr where m and Ar are as described for structure (I) and A1 is as described for structure (II); or 15 (c) for compounds of structure (I) in which A is NR1, reduction of a compound of structure (IV) : 20 25 (IV) in which R4 represents the group 30 -(CH2)nH(R1)C(CH2)m.1ir or -(CH2)^ClUR1) (CHjljjftr, 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) : ? n o - 7 - (GH )n+Tn L 2 n+m 10 N< R (V) 15 20 wherein R, L1, m and n are as hereinbefore defined, with a compound of structure X-'-Ar 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) : (CH2>ni(CH2»»*r 25 i (VI) 30 wherein A, Ar, m and n are as hereinbefore defined, by reaction with a compound RL2, wherein L2 is a leaving group; 35 (f) reduction of a compound of formula (VII) : ■t % 31 MAR WW S « n S | \l - 8 - ^ L ; O f. y -J (CH2)nA(CH2)mAr (VII) ■N- COR" 10 wherein R5 is C4_7alkyl (phenyl )p , C2_7alkenyl(phenyl)p, C2_7alkynyl(phenyl)p or C1_7alkylc3_8cycloalkyl and A, Ar, m and n are as hereinbefore defined ; 15 (g) reduction of a compound of structure (VIII): 20 (CH2)nA(CH2)mAr • N- I R (VIII) 30 25 wherein R, A, Ar m and n are as hereinbefore defined and X© 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, 35 optionally in the presence of a base. When a , fluoro-substituted aryl compound F-Ar is employp^I^w v *3i war »»»;;, ' ° ^ f: I 039 239 2 67 - 9 - 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 5 as CF3 or N02. The reaction between a compound of structure (III) and a compound of structure HA1(CH2)mAr can take place under conditions which depend on the nature of L1 10 and A. For example when L1 is hydroxy, m is 0 and A1 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, l). 15 Alternatively the leaving group L1 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. 20 The reduction of a compound 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 25 (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 30 a compound of structure X-'-Ar 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 35 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 39 239 2 67 - 10 - 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 5 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 10 aluminium hydride. Reduction of a compound of formula (VIII) may be effected for example by hydrogenation, using a noble metal catalyst such as platinum, palladium or platinum 15 oxide, suitably in a solvent such as an alcohol eg. ethanol. The compounds of structure (II) can be prepared from the corresponding compounds in which R is hydrogen, by 20 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 25 ethyl ketone, or a C1_4alkanol such as ethanol, in the presence of a base, such as potassium carbonate, or dimethyIformamide in the presence of an iodoalkane. The corresponding compounds of structure (II) in 30 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. 35 Alternatively, the compounds of structure (II) in which A1 is oxygen can be prepared by reduction of a compound of structure (IX): 039 - 11 - 239 2 67 R in which R and n are as described for structure (I) and 10 X" is a counter ion. Compounds of structure (III) wherein L1 is OH can be prepared as described for compounds of structure (II), and compounds of structure (III) wherein L1 is a 15 halogen atom, or a mesyloxy or tosyloxy group can be prepared from the corresponding alcohol in conventional manner. Compounds of structure (IV) wherein R4 is a group 20 O - (CH2) nN (R ) C (CH2)m_iAr can be prepared by reacting a compound of structure (II) wherein A1 represents NR1 with an acylating agent corresponding to the group -(CH2)mAr, for example an acid chloride 25 C10C(CH2)m_1Ar. Compounds of structure (IV) wherein R4 is a group O -(CH2)n_1CN(R1) (CH2)mAr may be prepared for 30 example by reaction of a corresponding compound wherein R4 represents -(CH2)n_1C02H or an activated derivative thereof such as an acid halide, ester or anhydride, with an amine of formula HNfR1) (CH2)m Ar. It will be appreciated that when the acid itself is 35 employed, reaction with the amine should be effected in 0039 10 - 12 - 239 2 67 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 A1 is oxygen. Compounds of structure (V) 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 15 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, methoxycarbony1, ethoxycarbonyl, or benzyloxycarbonyl. 20 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 25 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 30 appropriate acid derivative for example an acid chloride, or anhydride. 35 A compound of structure (VIII) may be prepared using the general methods described in processes (a) to (e) above. r39 239 2 6 7 - 13 - 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 5 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 10 conditions and diseases related to an accumulation of calcium in the brain cells of mammals, in particular humans. For example, the compounds are expected to be of use in the treatment of anoxia, ischaemia including for example stroke, migraine, epilepsy, traumatic head 15 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. 20 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 25 amount of a compound of structure (I) or a pharmaceutically acceptable salt thereof. In addition, the present invention also provides a method of treatment 2039 239267 - 14 - 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 5 addiction withdrawal such as ethanol addiction withdrawal, which comprises administering to a subject in need thereof, an effective amount of a compound of structure (I) or a pharmaceutically acceptable salt thereof. 10 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 15 compositions comprising a compound of structure (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. The compounds of structure (I) and their 20 pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges. 25 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 30 suspending agent, preservative, flavouring or colouring agent. A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) 35 routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, 039 oin o £m "0 -tj &m - 15 - starch, lactose, sucrose and cellulose. A composition in the form of a capsule can be prepared using routine encapsulation procedures. For 5 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, 10 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 15 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, 20 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 25 as a tablet or capsule. 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 30 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, 35 preferably between 1 mg and 250 mg, eg. 5 to 200 mg or an intravenous, subcutaneous, or intramuscular dose of 2039 239 2 67 - 16 - 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 lOOmg per day. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more. 2039 239 2 67 - 17 - DATA Ca2+ Current Measurement 5 Cell preparations Sensory neurons from dorsal root ganglia were dissociated from 1 day old rat pups (Forda et al, Developmental Brain Research, 22 (1985), 55-65). Cells were plated out onto glass coverslips and used within 3 10 days to permit effective voltage clamp of Ca2+ currents. Solutions The pipette (internal solution) contained in mM: CsCl, 130; HEPES, 10; EGTA, 10; MgCl2, 4; ATP, 2; 15 buffered to pH 7.2 with CsOH. Cells were bathed in a normal Tyrodes solution before establishment of whole cell recording when the bathing solution was changed to one allowing isolation of 20 Ca2+ currents. The external solution for recording Ca2+ channel currents contained in mM: BaCl2, 10; TEA-C1, 130; glucose, 10; HEPES, 10; MgCl2, 1; buffered to pH 7.3 25 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 30 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 24°C. 35 Whole cell currents were recorded using List EPC-7 amplifiers and stored, digitised for later analysis using 23 9 2 - 18 - PC based software similar to that described previously (Benham & Tsien, Journal of Physiology (1988), 404. 767-784). 5 RESULTS Ca2+ currents Peak voltage gated Ca2+ channel currents of up to 10 nA from dorsal root ganglion neurons were recorded 10 using 10 mM Ba2+ as charge carrier. Currents were evoked from a holding potential of -80 mV to a test potential of 0 or +10 mV every 15 seconds. This test potential was at the peak of the current voltage relationship and assessing block at this point reduced 15 any errors due to drifting holding potential. Some cells showed slow rundown of current as is commonly seen when recording Ca2+ currents. The rundown rate was measured in control conditions and extrapolated through the time of drug application to derive a control value to 20 relate the drug affected current to. Block by 20 jiM drug was assessed 3 minutes after drug application. Compounds of the invention gave percentage inhibition of plateau Ca2+ current in the range 30 to 25 100%. 30 22039 239 2 67 20 25 18A - PHARMACEUTICAL FORMULATIONS 1. Formulation for intravenous infusion 5 Compound of structure (I) 0.1-60 mg Sodium hydroxide/hydrochloric acid to pH ca 7 polyethylene glycol 0 - 30 ml propylene glycol 0 - 30 ml 10 alcohol 0 - 10 ml water to 100 ml 2. Formulation for bolus injection 15 Compound of structure (I) 0.1 - 60 mg sodium hydroxide or hydrochloric acid to pH ca 7 polyethylene glycol 0 - 2.5 ml alcohol 0 - 2.5 ml water to 5 ml A toxicity adjusting agent eg. sodium chloride, dextrose or mannitol may also be added. 3. Tablet for oral administration mq/tablet Compound of structure (I) 25 lactose 153 starch 33 30 crospovidone 12 microcrystalline cellulose 30 magnesium stearate 2 255 239 2 67 22039 - 19 - EXAMPLES Intermediate Preparations 5 (i) 3-(Hvdroxymethvl)-1-pentvlpiperidine A mixture of 3-(hydroxymethyl)piperidine (20g), 1-bromopentane (26.28g), potassium carbonate (24g) and 10 ethanol (400ml) was heated at reflux for 4 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 was distilled under reduced pressure to give the title 15 compound as an oil. (24.63g, b.p. 103-104°C 0 0.3mmHg.) (ii) 3-(Hvdroxymethvl)-1-propylpiperidine A mixture of 3-(hydroxymethyl)piperidine (20g), 1-20 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 25 distilled under reduced pressure to give the title compound as an oil. (18.21 g, b.p. 101-103°C 0 0.2mmHg.) (iii) l-Cinnamvl-3-(hvdroxymethvl) piperidine 30 A mixture of 3-(hydroxymethyl)piperidine (28g), cinnamyl bromide (47.91g), potassium carbonate (33.6g) and ethanol 239 2 67 22039 - 20 - (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 5 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-Methanesulphonvloxymethvl-l-pentvlpiperidine hydrochloride Methanesulphonyl chloride (5.8ml) in dichloromethane (20ml) was added to a solution of 3-hydroxymethyl-l-15 pentylpiperidine (lOg) in dichloromethane (20ml). The mixture was stirred for 18 hours, treated with hydrogen chloride in ether and recrystallised from ethylacetate to give the title compound (13.2g) m.p. 99-101°C 20 (v) 3-(3-Hvdroxypropvl)-1-pentvlpyridinium 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). 25 The oil which precipitated was collected by decantation then washed by decantation with diethyl ether (5 X 100ml) and dried at 50°C (O.lmmHg) to give the title compound (42g)which was used without further purification. 30 (vi) 3-(3-Hvdroxypropvl)-1-pentvlpiperidine 239 2 67 22039 - 21 - 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 5 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.Og). 10 Example 1 3-(4-Fluorophenoxvmethyl)-1-pentylpiperidine oxalate 15 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 (10ml). The resulting solution was stirred at room temperature for 18 20 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 (50ml) and treated with oxalic acid (0.62g). The precipitate was collected by filtration and 25 recrystallised (methanol/ethyl acetate) to give the title compound (1.21g), m.p. 126 - 128°C. Found: C, 61.17; H, 7.79; N, 3.78; F 4.71%. (C17H26FN0-C2H2°4-3H20) requires: C, 60.80; H, 7.60; 30 N, 3.70; F, 5.06%. 22 Example 2 3-(3.4-Methvlenedioxyphenoxvmethvl)-1-pentvlpiperidine hydrochloride 5 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 (10ml). 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 acetate) to give the title compound (l.Olg), m.p. 183 - 184°C. Found: C, 63.27; H, 8.22; N, 4.17; CI, 10.37%. 20 (C^gH27N03.HC1) requires: C, 63.25; H, 8.20; N, 4.10; CI, 10.40%. Example 3 25 1 -Pentvl-3-(3-phenvlphenoxvmethyl)piperidine 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 30 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 % / 4 O' 10 30 * \S 22039 .? Q - 23 - chromatographed on silica gel eluted with methanol/dichloromethane. The resulting oil (l.lg) was dissolved in ethyl acetate (50ml) and treated with oxalic acid (1.lequivalents). The precipitate was collected by filtration and recrystallised (methanol/ethyl acetate) to give the title compound (0.8g), m.p. 148 - 149°C. Found: C, 70.46; H, 7.80; N, 3.24%. <C23H31N0*C2H2°4> requires: C, 70.23; H, 7.78; N, 3.28% Example 4 1-Pentyl-3-(2-phenvlphenoxvmethvl)piperidine oxalate 15 A solution of 3-(hydroxymethyl)-1-pentylpiperidine (2.0g), 2-phenylphenol (1.70g) and triphenylphosphine (2.62g) in tetrahydrofuran (50ml) was treated with diethyl azodicarboxylate (1.74g) in tetrahydrofuran (10ml). The resulting solution was stirred at room temperature for 18 20 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 25 acetate) to give the title compound (1.10g), m.p. 99 - 101°C. Found: C, 70.00; H, 7.97; N, 3.28% (C23H31NO.C2H2O4) requires: C, 70.23; H, 7.78; N, 3.28% £*T C j.'v * f*3 1 MARI99tr -I * «s 2 3 9 2 6 7 22039 - 24 - Example 5 3-(4-Benzvloxvphenoxvmethvl)-1-pentvlpiperidine hydrochloride 5 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 (10ml). 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 and treated with hydrogen chloride in diethyl ether. The precipitate 15 was collected by filtration and recrystallised (methanol/ethyl acetate) to give the title compound (0.5g), m.p. 149 - 150°C. Found: C, 71.56; H, 8.71; N, 3.43; CI, 8.57% 20 (C24H33NO2.HCI) requires: C, 71.35; H, 8.48; N, 3.47; CI, 8.78% Example 6 25 3-(4-Benzvlphenoxvmethvl)-1-pentvlpiperidine hydrochloride The title compound was prepared in a similar manner to example 5 starting from 3-(hydroxymethyl)-1-pentylpiperidine (2.0g), 4-hydroxydiphenylmethane (1.84g), 30 triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride gave 25 a white solid which was recrystallised from methanol/ethyl acetate (0.51g), m.p. 169 - 171°C. Found: C, 74.38; H, 8.96; N, 3.68; CI, 8.22% (C24H33NO.HCI) requires: C, 74.30; H, 8.83; N, 3.61; CI, 9.16% Example 7 1 -Pentyl-3-(3-trifluoromethvlphenoxvmethvl)piperidine hydrochloride The title compound was prepared in a similar manner to example 5 starting from 3-(hydroxymethyl)-1-pentylpiperidine (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. 165°C. Found: C, 59.04; H, 7.40; N, 3.91; CI, 9.67% (c18H26F3NO,HC^ requires: C, 59.0; H, 7.4; N, 3.8; CI, 9.7% Example 8 3-(4-Nitrophenoxvmethvl)-1-pentvlpiperidine hydrochloride 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 azodicaj *31MARW94; 22039 26 (1.74g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from methanol/ethyl acetate (0.13g), m.p. 220°C. Found: C, 59.22; H, 7.96; N, 8.08; CI, 10.31% (C17H26N2°3•hC1) requires: C, 59.55; H, 7.94; N, 8.17; CI, 10.35% Example 9 1-Pentvl-3-(4-phenvlphenoxvmethvl)piperidine oxalate The title compound was prepared in a similar manner to example 5 starting from 3-(hydroxymethyl)-1-pentylpiperidine (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 - 174°C. Found: C, 70.17; H, 7.74; N, 3.50% (C23h31NO,C2h2°4) requires: C, 70.23; H, 7.78; N, 3.28% Example 10 3-(2-Benzvlphenoxvmethvl)-1-pentvlpjperidine oxalate The title compound was prepared in a similar manner to example 5 starting from 3-hydroxymethyl-l-pentylpiperidine (2.0g), 2-hydroxydiphenylmethane (1.84g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with oxalic acid gave a (*3lW®W 239 2 6 7 22039 - 27 - white solid which was recrystallised from methanol/ethyl acetate (0.260g), m.p. 120°C. Found: C, 70.21; H, 7.99; N, 3.20% 5 (C24H33NO.C2H2O4.O.25H2O) requires: C, 69.94; H, 7.96; N, 3.14% Example 11 10 3- (4-Chlorophenoxvmethyl)-1-pentvlpiperidine oxalate The title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-l-pentylpiperidine (2.0g), 4-chlorophenol (1.28g), triphenylphosphine (2.62g) and 15 diethyl azodicarboxylate (1.74g). Treating the product with oxalic acid gave a white solid which was recrystallised from methanol/ethyl acetate (0.82g), m.p. 140°C. 20 Found: C, 59.27; H, 7.26; N, 3.80; CI, 8.93% ^17H26C1N0*^2H2°4^ requires: C, 59.14; H, 7.31; N, 3.63; CI, 9.19% 25 Example 12 3-(4-Cvanophenoxvmethyl)-1-pentvlpiperidine oxalate The title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-l-pentylpiperidine (2.0g), 30 4-cyanophenol (1.19g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with oxalic acid gave a white solid which was 239 2 22039 - 28 - recrystallised from methanol/ethyl acetate (0.79g), m.p. 104°C. Found: C, 63.83; H, 7.59; N, 7.47% 5 (C2gH2gN20.C2H204) requires: C, 63.81; H, 7.50; N, 7.44% Example 13 3-Phenoxvmethvl-l-pentvlpiperldine oxalate 10 The title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-l-pentylpiperidine (2.0g), phenol (0.94g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with 15 oxalic acid gave a white solid which was recrystallised from methanol/ethyl acetate (1.02g), m.p. 144.5°C. Found: C, 65.15; H, 8.43; N, 4.02% ^17H27N^,<"2Ii2®4^ requires: C, 64.93; H, 8.32; N, 3.99% 20 Example 14 3- (4-Fluorobenzvloxvmethvl)-1-pentvlpiperidine oxalate 25 A solution of 3-hydroxymethyl-l-pentylpiperidine (3.0g) in dimethyIformamide (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 30 (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 239 2 67 22039 - 29 - solvent was removed and the residue chromatographed on silica gel using methanol/dichloromethane as eluent. The resulting oil was dissolved in ethyl acetate and treated with oxalic acid (1.1 mole equivalent). The precipitate 5 was collected by filtration and recrystallised (methanol/ethyl acetate) to give the title compound (1.2g), m.p. 126 - 127°C. Found: C, 62.64; H, 7.97; N, 3.66%. 10 (C18H28FN0.C2H204) requires: C, 62.64; H, 7.89; N, 3.65% Example 15 3-(3,4-Methvlenedioxyphenoxvmethvl)-l-propvlpiperidine 15 hydrochloride 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 20 (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from methanol/ethyl acetate (0.30g), m.p. 154°C. 25 Found: C, 59.14; H, 7.63; N, 4.62; CI, 10.77% (C16H23NO3.HCI.O.5H2O) requires: C, 59.47; H, 7.74; N, 4.34; CI, 10.84% 239 2 67 22039 - 30 - Example 16 l-Cinnamyl-3-(3.4-dichlorophenoxymethvl)piperidine oxalate The title compound was prepared in a similar manner to 5 example 1 from l-cinnamyl-3-hydroxymethylpiperidine (2.00g), 3,4-dichlorophenol (1.41g), triphenylphosphine (2.27g) and diethyl azodicarboxylate (1.51g). Treating the product with oxalic acid in ethyl acetate gave a white solid which was recrystallised from ethyl acetate/methanol 10 to give the title compound as a white crystalline solid (1.27g), m.p.206°C. Found: C, 59.37; H, 5.46; N, 3.16; CI, 15.16% ^21H23C-L2N0,^2H2°4^ requires: C, 59.24; H, 5.40; N, 3.00; 15 CI, 15.16% Example 17 l-Cinnamvl-3-(4-fluorophenoxvmethvl)piperidine oxalate 20 The title compound was prepared in a similar manner to example 1 from l-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 25 solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (0.7g), m.p.l23°C. 30 Found: C, 66.51; H, 6.31; N, 3.44% (C21H24FN0,C2H2°4) requires: C, 66.49; H, 6.31; N, 3.37% 239 2 67 T » » 22039 - 31 - Example 18 3-(3. 4-Dichlorophenoxvmethvl)-1-pentvlpiperidine hydrochloride 5 The title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-l-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 10 was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (1.10g), m.p.188-190°C. Found: C, 55.92; H, 7.18; N, 3.86; CI", 9.64% 15 (C-^I^gC^NO.HCl) requires: C, 55.67; H, 7.15; N, 3.82; CI", 9.68% Example 19 20 3- (4-iso-Propylphenoxvmethvl) -1-pentvlpiperidine hydrochloride The title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-l-pentylpiperidine (2.00g), 25 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 give the title compound as a white crystalline solid (0.18g), 30 m.p.172-174°C. Found: C, 70.41; H, 9.95; N, 4.34% 239 2 67 22039 - 32 - (c20h33no-hc1) requires: C, 70.66; H, 10.08; N, 4.12% Example 20 5 3-(3-iso-Propylphenoxvmethvl)-1-pentvlpiperidine hydrochloride The title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-l-pentylpiperidine (1.5g), 3-iso-propylphenol (l.lg), triphenylphosphine (2.12g) and 10 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.138-140°C. 15 Found: C, 69.89; H, 9.91; N, 4.10; CI", 10.33% (C20H33^°-HC1•0•25 h2°) requires: C, 69.74; H, 9.95; N, 4.07; CI", 10.29% 20 Example 21 3-(3-tert-Butvlphenoxvmethvl)-1-pentvlpiperidine hydrochloride The title compound was prepared in a similar manner to 25 example 1 from 3-hydroxymethyl-l-pentylpiperidine (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.185-187°C. 239 2 67 22039 - 33 - Found: C, 71.39; H, 10.33; N, 4.09; CI, 9.92% (c21h35no-hc1) requires: C, 71.26; H, 10.25; N, 3.96; CI,10.02% 5 Example 22 3-(4-Fluorobenzvlaminomethvl)-1-pentvlpiperidine dihvdrochloride 10 A mixture of 4-fluorobenzylamine (2.4 9g) and 3- methanesulphonyloxymethyl-l-pentylpiperidine hydrochloride (2g) was heated at 150°C for 2.5 hours. The mixture was dissolved in dichloromethane and the dichloromethane solution washed with dilute sodium hydroxide solution, 15 dried over sodium sulphate and the solvent removed. The residue was chromatographed on silica gel with dichloromethane - methanol as eluent and treated with hydrogen chloride in ether to give a solid. Recrystallisation from ethyl acetate gave the title 20 compound (0.92g), m.p. 207-209°C. Found: C, 58.12; H, 8.55; N, 7.67; CI, 19.41% (C^gl^gF^^HCl. 0.3^0) requires: C, 58.26; H, 8.57; N, 7.54; CI, 19.09% 25 Example 23 3-(4-Fluorophenvlaminomethvl)-1-pentvlpiperidine dihvdrochloride 30 Substituting 4-fluoroaniline for 4-fluorobenzylamine (9.12g) in example 22 gave the title compound (0.593g) as a white microcrystaline solid, m.p. 196-198°C 239 2 6 7 22039 - 34 - Found: C, 56.77; H, 8.12; N, 7.83; CI, 19.63% (C17H27FN2,2HC1'°-5H20) requires: C, 56.66; H, 8.39; N, 7.77; CI, 19.68% 5 Example 24 3-(3,4-Dichlorophenvlaminomethvl)-1-pentvlpiperidine dihvdrochloride 10 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. 185-187°C Found: C, 50.99; H, 7.02; N, 6.99% 15 (C^-yH2gCl2N2.2HC1) requires: C, 50.76; H, 7.02; N, 6.96% Example 25 20 3-(4-tert-Butvlphenoxvmethvl)-1-pentvlpiperidine hydrochloride The title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-l-pentylpiperidine (1.50g), 4-tert-butylphenol (1.22g), triphenylphosphine (2.12g) and 25 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.197-199°C. 30 Found: C, 70.98; H, 10.21; N, 4.00; CI, 9.82% 239 2 67 22039 - 35 - <c21h35N0*HC1> requires: C, 71.26; H, 10.25; N, 3.96; CI,10.02% Example 26 5 3-f3-(4-Fluorophenoxv)propyl!-1-pentvlpjperidine oxalate The title compound was prepared in a similar manner to example 1 from l-pentyl-3-(3-hydroxypropyl)piperidine (2.13g), 4-fluorophenol (1.12g), triphenylphosphine 10 (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with oxalic acid gave a white solid which was recrystallised from methanol/ethyl acetate (1.10g), m.p. 115 - 118°C. 15 Found: C, 63.53; H, 8.11; N, 3.80% (C1gH30FN°.c2h2°4) requires: C, 63.48; H, 8.06; N, 3.53% Example 27 20 3-T3-(3.4-Dichlorophenoxv)propyl 1 -1-pentvlpiperidine oxalate The title compound was prepared in a similar manner to example 1 from 1-penty1-3-(3-hydroxypropyl)piperidine (2.13g), 3,4-dichlorophenol (1.63g), triphenylphosphine 25 (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with oxalic acid gave a white solid which was recrystallised from methanol/ethyl acetate (0.5g), m.p. 127-130°C. 30 Found: C, 56.35; H, 6.90; N, 3.25% (C19H29CI2NO.C2H2O4) requires: C, 56.25; H, 6.97; N, 3.12% </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 239267 22039 - 36 - Example 28 a) (-)-3-(4-Benzvloxyphenoxvmethvl)-1-pentvlpiperidine b) (+)-3-(4-Benzvloxyphenoxvmethvl)-1-pentvlpiperidine 5 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. 10 chromatography column using ethanol/hexane as eluent. The two enantiomers were collected. The (-) enantiomer being eluted first. Yield (8.0mg) rotation (-1.38° 0 22°C in methanol). The second peak gave the (+) enantiomer, yield (7.2mg) rotation (+1.24° 0 22°C in methanol). 15 Example 29 3-(3,4-Dichlorobenzylaminomethvl)-1-pentvlpiperidine dihvdrochloride 20 Substituting 3,4-dichlorobenzylamine for 4- fluorobenzylamine (0.587g) in example 22 gave the title compound (0.4 6g) as a white microcrystaline solid, m.p. 254-256°C 25 Found: C, 51.55; H, 7.09; N, 6.73; CI, 16.85% (C18H28C12N2«2HC1) requires: C, 51.94; H, 7.26; N, 6.73; CI, 17.04% 239267 WHAT WE CLAIM IS:

1. A compound of structure (I) : ^\^'(CH2)nA(CH2)mAr in which R is C5_8alkyl(phenyl)p, C2-8alkenyl(phenyl)p/ C2-8alkynyl(phenyl)p, C3_8cycloalkyl or Ci_8alkylC3_8cycloalkyl; p is 0 to 1; n is 0 to 6, and m is 0 to 3 provided that m and n are not both zero; A is a bond, oxygen, sulphur or NR1, where R1 is hydrogen, C^-salkyl or phenylCi_4alkyl; and Ar is optionally substituted phenyl, or a salt thereof.

2. A compound according to claim 1 wherein R is C5_8alkyl, or phenyl(C2-8)alkenyl.

3. A compound according to claim 2 wherein R is n-pentyl.

4. A compound according to any of claims 1 to 3 in which A is oxygen.

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

6. A compound according to any of claims 1 to 5 wherein m is 0 or 1.

7. A compound according to any of claims 1 to 6 in--,.., ^-'V. H 7 which Ar is phenyl, optionally substituted by a • " ■'a \1^ 30 e o C) p ft - 38 - Ci_2alkylenedioxy group or by 1 to 3 substituents selected from halogen, Ci_4alkoxy, nitro, SCi_4alkyl, NR2r2 (in which each R2 group can be H or Ci_4alkyl), OCF3, C^-galkyl, trifluoromethyl, CN, optionally substituted phenyl, optionally substituted phenylCi_4alkyl and optionally substituted phenylCj^alkoxy.

8. A compound according to any of claims 1 to 6 wherein Ar is phenyl optionally substituted by one or two substituents selected from a single halogen, trifluoromethyl, unsubstituted phenyl or unsubstituted phenyl Ci_4alkoxy group; or by two chloro atoms.

9. A compound according to any of claims 1 to 6 in which Ar is unsubstituted phenyl or phenyl substituted by fluoro, chloro, dichloro, trifluoromethyl, nitro, cyano, isopropyl, t-butyl, methylenedioxy, phenyl, benzyloxy or benzyl.

10. A compound according to any of claims 1 to 6 wherein Ar is phenyl substituted by optionally substituted phenyl, optionally substituted phenyl Ci_4alkyl or optionally substituted phenyl Ci_4alkoxy.

11. A compound according to claim 1 which is: 3- (4-fluorophenoxymethyl) -1-pentylpiperidine, 3- (3,4 -methy lenedioxyphenoxymethy 1) -1-pentylpiperidine, 1-pentyl-3-(3-trifluoromethylphenoxymethyl)piperidine, 1-pentyl-3-(3-phenylphenoxymethyl) piperidine, o. \ 1 -pentyl-3-(2-phenylphenoxymethyl)piperidine, jf XK.\ 1 -pentyl-3- (4-phenylphenoxymethyl) piperidine, ^31 W\!R f 3 - (2 -benzylphenoxymethyl) -1-pentylpiperidine, \ 3- (4-benzylphenoxymethyl) -l-pentylpiperidine, ' * *,,, <" '' 3 - (4 -benzy loxyphenoxymethy 1) -1-pentylpiperidine, l-cinnamyl-3-(3,4-dichlorophenoxymethyl) piperidine, 3- (4-iso-propylphenoxymethy 1) -1-pentylpiperidine; dr 3-(3,4-dichlorophenylaminomethyl) -1-pentylpiperidine; or a pharmaceutically acceptable salt thereof. ^ £ 5

12. A process for preparing a compound of structure (I) as defined in claim 1 which comprises: (a) for compounds of structure (I) in which A is 0, S or NR1, reaction of a compound of structure (II): 10 15 20 ;cH2)nAlH (ii) N-^ R in which R and n are as defined in claim 1 and A1 is 0, S or NR1, with a compound of structure L(CH2)mAr in which m and Ar are as defined in claim 1, and L is a leaving group; (b) for compounds of structure (I) in which A is 0, S or NR1, reaction of a compound of structure (III): 25 30 tCH2>nL (III) 35 in which n and R are as defined in claim 1 and L1 is a group displaceable by a nucleophile, with a compound of structure HA1(CH2)mAr where m and Ar are as defined in claim 1 and A1 is as hereinbefore defined; or £ 7 - 40 - ** 9 g $ (c) for compounds of structure (I) in which A is NR1, reduction of a compound of structure (IV) : 10 (IV) 15 in which R4 represents the group 20 0 o -(CH2)nN(R1)C(CH2)m_1Ar or -(CH2)n.1CN(R1)(CH2)mAr, and n, m, R and Ar are as defined in claim 1; (d) for compounds of structure (I) in which A is a bond, reaction of a compound of structure (V) : 25 N' :H2>n+m L (V) 30 wherein R, L1, m and n are as hereinbefore defined, 35 with a compound of structure X^Ar in which Ar is as defined in claim 1, and X1 is an alkali metal; -- j i mW" - f : . ■>' 15 - 41 - w .y (e) introduction of the group R into a compound of formula (VI) : 10 N I H ^CH2)nA(CH2)mAr (VI) 20 wherein A, Ar, m and n are as hereinbefore defined, by reaction with a compound RL2, wherein L2 is a leaving group; (f) reduction of a compound of formula (VII) : 25 30 CH2)nA(CH2)ffiAr (VII) COR 35 wherein R5 is C4_7alkyl (phenyl )p/ C2_7alkenyl (phenyl)p, C2_7alkynyl(phenyl)p or ChalkylC3_Qcycloalkyl and A, Ar, m and n are as hereinbefore defined; 6N r - 42 - (i<) ^ i? (g) reduction of a compound of structure (VIII): JB (VIII) wherein R, A, Ar,m and n are as hereinbefore defined and is a counter ion; and optionally thereafter forming a salt.

13. A pharmaceutical composition comprising a compound of structure (I) as claimed in any of claims 1 to 11 or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier or excipient.

14. A compound of structure (I) according to any of claims 1 to 11 or a pharmaceutically acceptable salt thereof for use in therapy.

15. Use of a compound of structure (I) according to any of claims 1 to 11 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.

16. A process for preparing a compound of structure (I) as defined in claim 1 substantially as hereinbefore described with reference to any one of the foregoing Examples 1 to 29. lluQ THiS 31 D.^YDfA^ '; A. J. PARK & SON PER AGENTS FOR THE APPLICANTS </div>