EP0542846A1

EP0542846A1 - N-hydrocarbyl-4-substituted piperidines, their preparation and use as calcium blocking agents

Info

Publication number: EP0542846A1
Application number: EP91914558A
Authority: EP
Inventors: Thomas Henry Smithkline Beecham Brown; David Gwynn Smithkline Beecham Cooper
Original assignee: Smith Kline and French Laboratories Ltd
Current assignee: Smith Kline and French Laboratories Ltd
Priority date: 1990-08-06
Filing date: 1991-08-05
Publication date: 1993-05-26
Also published as: CN1061963A; MX9100513A; AP279A; MA22250A1; PT98574A; IL99073A0; AU8327191A; IE912759A1; WO1992002502A1; CA2088491A1; NZ239268A; KR930701402A; AP9100313A0; JPH06500093A; TW267164B

Abstract

Composés de la structure (I) dans laquelle R représente C1-8 alkyle(phényle)p, C2-8 alkényle(phényle)p, C2-8 alcényle(phényle)p, C3-8 cycloalkyle ou C1-8 alkyle C3-8 cycloalkyle; p est compris entre 0 et 2; n est compris entre 0 et 6; A représente une liaison, oxygène, soufre ou NR1; R1 représente hydrogène, C1-8 alkyle ou phényle C1-4 alkyle; m est compris entre 0 et 3; et Ar représente aryle ou hétéroaryle, chacun d'entre eux pouvant être éventuelement substitués, ainsi que leurs sels; procédés de préparation desdits composés (I), compositions pharmaceutiques qui les contiennent et leur utilisation thérapeutique, notamment comme agents de blocage du calcium.Compounds of structure (I) in which R represents C1-8 alkyl (phenyl) p, C2-8 alkenyl (phenyl) p, C2-8 alkenyl (phenyl) p, C3-8 cycloalkyl or C1-8 alkyl C3-8 cycloalkyl; p is between 0 and 2; n is between 0 and 6; A represents a bond, oxygen, sulfur or NR1; R1 represents hydrogen, C1-8 alkyl or phenyl C1-4 alkyl; m is between 0 and 3; and Ar represents aryl or heteroaryl, each of which may be optionally substituted, as well as their salts; processes for the preparation of said compounds (I), pharmaceutical compositions containing them and their therapeutic use, in particular as calcium blocking agents.

Description

N-HYDROCARBYL-4-SUBSTITUTED PIPERIDINES,

THEIR PREPARATION AND USE

AS CALCIUM BLOCKING AGENTS

The present invention relates to 4-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);

(I)

in which

R is C_1-8alkyl (phenyl)p, C_2-8alkenyl (phenyl)p,

C_2-8alkynyl (phenyl) p, C_3-8cycloalkyl or

C_1-8alkylC_3-8cycloalkyl;

p is 0 to 2 ;

n is 0 to 6 ;

A is a bond, oxygen, sulphur or NR¹;

R¹ is hydrogen, C_1-8alkyl or phenylC_1-4alkyl;

m is 0 to 3; and

Ar is aryl or heteroaryl, each of which may be

optionally substituted;

and salts thereof. Suitably, R is C_1-8alkyl(phenyl)p, C_2-8alkenyl-(phenyl)p, C_2-8alkynyl(phenyl)p, C_3-8cycloalkyl or

C_1-8alky1C_3-8cycloalkyl.

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 C_1-8galkyl(phenyl)p in which p is 0 or 1, i.e. C_1-8alkyl, such as n-pentyl, or phenylC_1-8alkyl such as phenylpropyl, or R is C_2-8alkenyl(phenyl)p where p is 1, such as cinnamyl.

Suitably, n is 0 to 6; preferably n is 0 to 3; most preferably n is 2 or 3.

Suitably, m is 0 to 3; preferably m 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 2 and m is preferably 0.

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 10 carbon atoms, such as, for example, phenyl, naphthyl and

tetrahydronaphthyl. Preferred are optionally

substituted phenyl rings.

Suitable substituted phenyl rings include, for example, phenyl rings substituted by a C_1-2alkylenedioxy group such as a 3,4-methylenedioxy group or by 1 to 3 substituents selected from halogen, C_1-4alkoxy,

nitro, SC_1-4alkyl, NR²R² (in which each R² group

can be H or C_1-4alkyl), OCF₃, C_1-6alkyl, trifluoromethyl, CN, optionally substituted phenyl, optionally substituted phenylC_1-4alkyl and optionally substituted phenylC_1-4alkoxy. Preferred are phenyl rings substituted by one or two substituents, in

particular, by a single halogen, trifluoromethyl, unsubstituted phenyl or unsubstituted phenylC_1-4alkoxy group; or by two chlorine atoms, in particular in the 3 and 4 positions of the ring. Suitable optionally substituted phenylC_1-4alkyl groups include, for example benzyl. Suitable optionally substituted phenylC_1-4alkoxy groups include, for

example benzyloxy groups. Suitable substituents for said optionally

substituted phenyl, phenylC_1-4alkyl and

phenylC_1-4alkoxy groups include for example halogen, C_1-4alkyl, C_1-4alkoxy, nitro and trifluoromethyl groups.

Suitable heteroaryl rings include, for example, unsaturated monocyclic and unsaturated or partially saturated bicyclic ring systems of up to 10 carbon atoms containing lat "least one heteroatom, such as pyridyl, thienyl, quinolinyl, tetrahydroquxnolxnyl 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 include, for example, 1 to 3 substituents selected from halogen, C_1-4alkyl and C_1-4alkoxy.

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 nonpharmaceutically acceptable salts may be used for example as intermediates and are included within the scope of this invention.

Particular compounds of the invention include : 4-[2-(4-trifluoromethylphenoxy)ethyl]-1-pentylpiperidine oxalate,

4-[2-(3-trifluoromethylphenoxy)ethyl]-1-pentylpiperidine hydrochloride,

4-[2-(4-fluorophenoxy)ethyl]-1-pentylpiperidine

hydrochloride,

4-[2-(3,4-methylenedioxyphenoxy)ethyl]-1-pentylpiperidine hydrochloride

4-(2-phenoxyethyl)-1-pentylpiperidine hydrochloride

4-[2-(4-phenylphenoxy)ethyl]-1-pentylpiperidine

hydrochloride,

4-[2-(4-benzyloxyphenoxy)ethyl]-1-pentylpiperidine

hydrochloride,

4-[2-(4-fluorophenoxy)ethyl]-1-cinnamylpiperidine oxalate,

4-(4-fluorobenzyloxy)-1-pentylpiperidine oxalate

4-[2-(3,4-dichlorophenoxy)ethyl]-1-pentylpiperidine hydrochloride,

4-[2-(4-benzylphenoxy)ethyl]-1-pentylpiperidine oxalate,

4-[2-(3,4-dichlorophenoxy)ethyl]-1-cinnamylpiperidine oxalate,

4-[2-(4-fluorophenoxy)ethyl]-1-(3-phenylpropylpiperidine hydrochloride,

4-[2-(4-fluorophenoxy)ethyl]-1-heptylpiperidine

hydrochloride,

1-(3,3-diphenylpropyl)-4-[2-(4-fluorophenoxy)ethyl]-piperidine oxalate, 4-[2-(3,4-dichlorothiophenoxy)ethyl]-1-pentylpiperidine hydrochloride,

4-[2-(4-tert-butylphenoxy)ethyl]-1-pentylpiperidine hydrochloride,

4-[2-(4-iso-propylphenoxy)ethyl]-1-pentylpiperidine hydrochloride,

4-[2-(3,4-dichlorophenoxy)ethyl]-1-(3-phenylpropyl)- piperidine hydrochloride, and

1-cyclopropylmethyl-4-[2-(4-fluorophenoxy)ethyl]- piperidine oxalate.

It will be appreciated that the compounds of

structure (I) may contain one or more asymmetric

centres. Such compounds will exist as optical isomers (enantiomers). Both the pure enantiomers, racemic mixtures (50% of each enantiomer) and unequal mixtures of the two are included within the scope of the invention. Further, all diastereomeric forms possible (pure

enantiomers and mixtures thereof) are within the scope of the invention.

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 NR¹, reaction of a compound of structure (II):

(ID

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

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, n and m 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) :

wherein R⁵ is C_1-7alkyl (phenyl)p, C_2-7alkenyl(phenyl)p, C_2-7alkynyl(phenyl)p or C_1-7alkylC_3-8cycloalkyl;

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

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, optionally in the presence of a base. When a

fluoro-substituted aryl F-Ar is employed in 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 dimethyl formamide. Preferably the aryl group is substituted by an activating group such as CF₃ or NO₂. 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 and A. For example when L¹ is hydroxy, m is O 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, 1).

Alternatively the leaving group L¹ may be for example a halogen atom or a sulphonyloxy group eg. methanesulphonyloxy or p-toluenesulphonyloxy. In this case the reaction may be effected in the presence or absence of solvent at a temperature in the range 0 to 200°C

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 (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 structure X¹Ar 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 sulphonyloxy group such as methanesulphonyloxy or p-toluene sulphonyloxy. 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 for example by hydrogenation, using a noble metal catalyst such as platinum, palladium or platinum oxide, suitably in a solvent such as an alcohol eg.

ethanol.

The compounds of 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 C_1-4alkanol 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 4-hydroxyalkylpyridine.

Alternatively, compounds of structure (II) in which A¹ is oxygen can be prepared by reduction of a compound of structure (IX): (IX)

in which R and n are as described for structure (I) and 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

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 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

ClOC(CH₂)_m-1Ar.

Compounds of structure (IV) wherein R⁴ is a group may be prepared for

example by reaction of a corresponding compound wherein

R⁴ represents -(CH₂)_n-1CO₂H or an activated

derivative thereof such as an acid halide, ester or anhydride, with an amine of formula HN(R¹) (CH₂)_m

Ar. It will be appreciated that when the acid itself is employed, reaction with the amine should be effected in the presence of a coupling agent. The carboxylic acid may itself be prepared for example by oxidation of the corresponding alcohol, ie. a compound of 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 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. In addition compounds of structure (VIII) wherein A represents a bond may be prepared from 4-methyl pyridine (picoline) by reaction with a compound of formula L(CH₂)q Ar wherein L and Ar are as hereinbefore defined and q is (m+n-1), in the presence of a strong base such as sodium amide in liquid ammonia or an alkyl lithium. The resulting substituted pyridine is then reacted with a compound RL², as hereinbefore defined, to give a quaternary pyridinium compound of formula (VIII). Reduction of this compound according to process (g) provides a convenient method of preparing compounds of structure (I) wherein A represents a bond.

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

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 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. 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 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 administering to a subject in need thereof, an effective amount of a compound of structure (I) or a pharmaceutically acceptable salt thereof. The invention also provides the use of a compound of structure (I) or a pharmaceutically

acceptable salt thereof in the manufacture of a

medicament for the treatment of the aforementioned conditions or diseases. 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 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

pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.

A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.

A composition in the form of a tablet can be

prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.

Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose. A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable

pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.

Compounds of the invention may also be administered parenterally, by bolus injection or continuous infusion. Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptabl salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol,

polyvinyl pyrrolidone, lecithin, arachis oil or

sesame oil. Alternatively, the solution can be

lyophilised and then reconstituted with a suitable solvent just prior to administration.

Preferably the composition is in unit dose form such 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 a compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base.

The daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, eg. 5 to 200 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 60 mg, eg. 1 to 40 mg of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day. Alternatively the compounds of the invention may be administered by continuous intravenous infusion, preferably at a dose of up to 100mg per day.

Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more.

DATA

Ca²⁺ Current Measurement Cell preparations

Sensory neurons from dorsal root ganglia were dissociated from 1 day old rat pups (Forda et al.

Developmental Brain Research, 22 (1985), 55-65). Cells were plated out onto glass coverslips and used within 3 days to permit effective voltage clamp of Ca²⁺ currents.

Solutions

The pipette (internal solution) contained in mM: CsCl, 130; HEPES, 10; EGTA, 10; MgCl₂, 4; ATP, 2;

buffered to pH 7.2 with CsOH.

Cells were bathed in a normal Tyrodes solution before establishment of whole cell recording when the bathing solution was changed to one allowing isolation of 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 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 24°C.

Whole cell currents were recorded using List EPC-7 amplifiers and stored, digitised for later analysis using PC based software similar to that described previously (Benham & Tsien, Journal of Physiology (1988), 404, 767-784).

RESULTS

Ca²⁺ currents

Peak voltage gated Ca²⁺ channel currents of up to 10 nA from dorsal root ganglion neurons were recorded using 10 mM Ba²⁺ as charge carrier. Currents were evoked from a holding potential of -80 mV to a test potential of 0 or +10 mV every 15 seconds. This test potential was at the peak of the current voltage

relationship and assessing block at this point reduced any errors due to drifting holding potential. Some cells showed slow rundown of current as is commonly seen when recording Ca²⁺ currents. The rundown rate was measured in control conditions and extrapolated through the time of drug application to derive a control value to relate the drug affected current to. Block by 20 μM drug was assessed 3 minutes after drug application.

Compounds of the invention gave percentage

inhibition of plateau Ca²⁺ current in the range 30 to 100%

TOXICOLOGY

The compound of Example 9 did not show any adverse toxicological effects when administered to rats at a dose of 10 mg/kg, i.v. PHARMACEUTICAL FORMULATIONS

1. Formulation for intravenous infusion 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 alcohol 0 - 10 ml water to 100 ml

2. Formulation for bolus injection

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 mg/tablet

Compound of structure (I) 25 lactose 153 starch 33 crospovidone 12 microcrystalline cellulose 30 magnesium stearate 2

255 EXAMPLES

Intermediate Preparations

(i) 4-(2-Hydroxyethyl)-1-pentylpiperidine

A mixture of 4-(2-hydroxyethyl)piperidine (20g), 1-bromopentane (19.2g), potassium carbonate (21.42g) and ethanol (400ml) was heated at reflux for 3 days. The solution was filtered, and the solvent was removed under reduced pressure. The residue was treated with acetone, filtered, and the solvent was removed to give the title compound as an oil (30.2g) which was used without further purification.

(ii) 4-(2-Hydroxyethyl)-1-cinnamylpiperidine

A mixture of 4-(2-hydroxyethyl)piperidine (16.4g),

cmnamyl bromide (25.0g), potassium carbonate (17.55g) and ethanol (350ml) was heated at reflux for 3 days. The solution was filtered, and the solvent removed under reduced pressure. The residue was chromatographed on silica gel eluted with methanol/dichloromethane to give the title compound (12.0g) as an inpure solid which was used without further purification. (iii) 4-(3-Hydroxypropyl)-1-pentylpyridinium bromide

A solution of 4-(3-hydroxypropyl)pyridine (27.43g), 1- bromopentane (37.76g) and acetone (50ml) was refluxed for 24 hours, cooled and poured into diethylether (200ml). The oil which precipitated was collected by decantation then washed by decantation with diethylether (5 X 100ml) and dried at 50°C 0.1mmHg to give the title compound which was used without further purification.

(iv) 4-(3-Hydroxypropyl)-1-pentylpiperidine

A mixture of 4-(3-hydroxypropyl)-1-pentylpyridinium bromide (8.65g), platinum oxide (0.5g) and ethanol (120ml) was stirred under an atmosphere of hydrogen for 3 hours. The mixture was filtered and the solvent removed. The residue was dissolved in dilute sodium hydroxide (70ml) and extracted with dichloromethane (3 x 75ml). The extracts were combined, dried over magnesium sulphate and the solvent was removed to give the title compound as an oil (4.68g). v) 4-Hydroxymethyl-1-pentylpyridinium bromide A solution of 4-hydroxymethylpyridine (25g), 1-bromopentane (43.2g) and acetone (50ml) was refluxed for 24 hours, cooled and poured into diethylether (200ml).

The oil which precipitated was collected by decantation then washed by decantation with pentane (5 X 100ml) and dried at 50°C 0.1mmHg to give the title compound which was used without further purification. (vi) 4-Hydroxymethyl-1-pentylpiperidine

A mixture of 4-(3-hydroxypropyl)-1-pentylpyridinium bromide (5.2g), platinum oxide (0.4g) and ethanol (100ml) was stirred under an atmosphere of hydrogen for 3 hours. The mixture was filtered and the solvent removed. The residue was dissolved in dilute sodium hydroxide (70ml) and extracted with dichloromethane (3 x 75ml). The extracts were combined, dried over magnesium sulphate and the solvent was removed. The residue was chromatographed on silica gel eluted with methanol/ammonia/dichloromethane to give the title compound as an oil (1.35g).

(vii) 4-Hvdroxy-l-pentylpiperidine

A mixture of 4-hydroxypiperidine (25g), 1-bromopentane (37.33g), potassium carbonate (34.13g) and ethanol (400ml) was heated at reflux for 3 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.

(18.00g, b.p. 100 °C @ 0.6 mmHg.) (viii) 4-(2-Hydroxyethyl)-1-propylpiperidine

A mixture of 4-(2-hydroxyethyl)piperidine (5g), 1-bromopropane (4.87g), potassium carbonate (5.5g) and ethanol (100ml) was heated at reflux for 1 day. The solution was filtered, and the solvent was removed under reduced pressure. The residue was treated with acetone, filtered, and the solvent was removed to give the title compound as an oil (5.1g) which was used without further purification.

(ix) 4-(2-Hydroxyethyl)-1-(3-phenyl)propylpiperidine

A mixture of 4-(2-hydroxyethyl)piperidine (10g), 1-bromo- 3-(phenyl)propane (15.8g), potassium carbonate (10.69g) and ethanol (200ml) was heated at reflux for 24 hours. The solution was filtered, and the solvent was removed under reduced pressure. The residue was treated with acetone, filtered, the solvent removed and the residue distilled, to give the title compound as an oil (14.52g) (b.p. 141°C @ 0.2mmHg) (x) 4-(2-Hydroxyethyl)-1-heptylpiperidine

A mixture of 4-(2-hydroxyethyl)piperidine (20g), 1-bromoheptane (27.73g), potassium carbonate (21.39g) and ethanol (400ml) was heated at reflux for 24 hours. The solution was filtered, and the solvent was removed under reduced pressure. The residue was treated with acetone, filtered, the solvent was removed and the residue

distilled, to give the title compound as an oil (10.01g) (b.p. 110°C @ 0.1mmHg)

(xi) 4-(2-Hydroxyethyl)-1-(2-ethyl)butylpiperidine

A mixture of 4-(2-hydroxyethyl)piperidine (20g), 1-bromo-2-ethylbutane (17.9g), potassium carbonate (26g) and ethanol (400ml) was heated at reflux for 4 days. The solution was filtered, and the solvent was removed under reduced pressure. The residue was distilled, to give the title compound as an oil (29.61g) (b.p. 102°C @ 0.3mmHg)

(xii) 1-Cyclohexylmethyl-4-(2-hydroxyethyl)piperidine

A mixture of 4-(2-hydroxyethyl)piperidine (20g),

cyclohexylmethyl bromide (27.41g), potassium carbonate (26g) and ethanol (400ml) was heated at reflux for 4 days. The solution was filtered, and the solvent was removed under reduced pressure. The residue was distilled, to give the title compound as an oil (27g) (b.p. 165°C @ 0.5mmHg)

(xiii) 4-(2-hydroxyethyl)-1-(3-methylbutyl)piperidine

A mixture of 4-(2-hydroxyethyl)piperidine (20g), 1-bromo-3-methylbutane (25.57g), potassium carbonate (26g) and ethanol (400ml) was heated at reflux for 4 days. The solution was filtered, and the solvent was removed under reduced pressure. The residue was distilled to give the title compound as an oil (23.21g) (b.p. 98°C @ 0.1mmHg)

(xiv) 1-Benzyl-4-(2-hydroxyethyl)piperidine A mixture of 4-(2-hydroxyethyl)piperidine (5g), benzyl bromide (6.15g), potassium carbonate (5.35g) and ethanol (50ml) was heated at reflux for 24 hours. The mixture was poured into water (200ml) and extracted with diethylether. The organic phase was dried over sodium sulphate,

filtered, and the solvent was removed under reduced pressure. The residue was distilled, to give the title compound as an oil (5.13g) (b.p. 120-130°C @ 0.1mmHg) (xv) 4-[2-(4-Fluorophenyl)ethyl]-pyridine

4-Picoline (30g) was added over 30 minutes to a suspension of sodium amide (12.56g) in liquid ammonia (150ml) and the resulting mixture was stirred for 1.5 hours. 4-Fluorobenzyl chloride (40ml) was then added over 15 minutes and the mixture was stirred for 3-hours. Ammonium chloride (50g) was added and the solvent was allowed to evaporate. The residue was dissolved in chloroform

(300ml) and dilute sodium hydroxide (300ml) and the organic phase was separated, dried over magnesium sulphate and the solvent was removed. The residue was

recrystallised from petroleum ether to give the title compound as white needles (25.3g), m.p. 69-70.5°C

(xvi) 4-[2-(4-Fluorophenyl)ethyl]-1-pentylpyridinium bromide A mixture of 4-[2-(4-fluorophenyl)ethyl)pyridine (5g), 1-bromopentane (7.0g) and acetone (10ml) was heated at reflux for 18 hours. The solvent was removed under reduced pressure and the residue was recrystallised from ethyl acetate / methanol to give the title compound

(7.32g), m.p. 130 - 131°C.

(xvii) 4-[2-(4-Fluorophenoxy)ethyl]-piperidine

hydrochloride A mixture of 1-benzyl-4-[2-(4-fluorophenoxy)ethyl]piperidine (1.50g), 10% palladium on carbon (0.6g) and ethanol (120ml) was shaken under an atmosphere of hydrogen at 50 p.s.i for 24 hours. The mixture was filtered and the residue washed with ethanol. The filtrates were combined, the solvent removed and the residue was treated with hydrogen chloride in ether to give a solid. Recrystallisation from ethyl acetate gave the title compound (0.45g), m.p. 122 -123°C.

Found: C, 59.58; H, 7.37; N, 5.35; Cl, 13.33%

(C₁₃H₁₈FNO.HCl) requires: C, 60.11; H, 7.37; N, 5.39; Cl, 13.65%

Example 1

4-[2-(4-Fluorophenoxy)ethyl]-1-pentylpiperidine

hydrochloride

A solution of 4-(2-hydroxyethyl)-1-pentylpiperidine

(2.0g), 4-fluorophenol (1.12g) 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 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 ethereal hydrogen chloride, the precipitate was collected by filtration and recrystallised (methanol/ethyl acetate) to give the title compound (1.1g), m.p. 167-169 °C. Found: C, 65.45; H, 8.90; N, 4.16; Cl, 10.75; F 5.76%. (C₁₈H₂₈FNO.HCl) requires: C, 65.54; H, 8.86; N, 4.25;

Cl, 10.75; F, 5.77%. Example 2

4-[2-(3,4-Methylenedioxyphenoxy)ethyl]-1-pentylpiperidine hydrochloride

A solution of 4-(2-hydroxyethyl)-1-pentylpiperidine

(2.0g), sesamol (1.39g) 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 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 ethereal hydrogen chloride. The precipitate was collected by filtration and recrystallised (methanol/ethyl acetate) to give the title compound (0.45g), m.p. 134 - 136°C. Found: C, 64.12; H, 8.52; N, 4.03; Cl, 10.00%.

(C₁₉H₂₉NO₃.HCl) requires: C, 64.12; H, 8.50; N, 3.93;

Cl, 9.96%.

Example 3

4-(2-Phenoxyethyl)-1-pentylpiperidine hydrochloride

The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine

(2.0g), phenol (0.94g), 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 (0.88g), m.p. 158 - 159°C.

Found: C, 69.10; H, 9.80; N, 4.61; Cl, 11.34%

(C₁₈H₂₉NO.HCl) requires: C, 69.32; H, 9.69; N, 4.49;

Cl, 11.37%

Example 4 4-[2-(3-Trifluoromethylphenoxy)ethyl]-1-pentylpiperidine hydrochloride

(2.0g), α,α,α, trifluoro-m-cresol (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 (0.44g), m.p. 154°C.

Found: C, 59.51; H, 7.62; N, 3.80; Cl, 9.49%

(C₁₉H₂₈F₃NO.HCl) requires: C, 60.07; H, 7.69; N, 3.69;

Cl, 9.33% Example 5

4-[2-(4-Phenylphenoxy)ethyl]-1-pentylpiperidine

hydrochloride The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine

(2.0g), 4-phenylphenol (0.1.70g), 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

(0.4g), m.p. 205-206°C.

Found: C, 73.77 ; H, 8.88; N, 3.66; Cl, 9.14%

(C₂₄H₃₃NO.HCI) requires: C, 74.2; H, 8.8; N, 3.6;

Cl, 9.27% Example 6

4-[ 2-(4-Benzyloxyphenoxy)ethyl]-1-pentylpiperidine hydrochloride The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (1.0g), 4-benzyloxyphenol (1.00g), triphenylphosphine (1.31g) and diethyl azodicarboxylate (0,87g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from methanol/ethyl acetate (0.1g), m.p. 168 - 169°C.

Found: C, 70.42; H, 8.59; N, 3.50; Cl, 8.29%

(C₂₅H₃₅NO₂.HCl .0 .5H₂O) requires : C, 70 .31 ; H, 8 .73 ;

N, 3.28 ; Cl, 8.20%

Example 7

4- [2- (3-Dimethylaminophenoxy) ethyl ] -1-pentylpiperidine dioxalate The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (2.2g), 3-dimethylaminophenol (1.5g), triphenylphosphine (2.88g) and diethyl azodicarboxylate (1. 94g) . Treating the product with oxalic acid gave a white solid which was recrystallised from methanol/ethyl acetate (0.2g), m.p. 128-130°C.

Found: C, 57.82; H, 7.63; N, 5.62%

(C₂₀H₃₄N₂O.2C₂H₂O₄) requires: C, 57.83; H, 7.63; N, 5.62%

Example 8

4-[2-(4-Methoxyphenoxy)ethyl]-1-pentylpiperidine oxalate

The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (1.5g), 4-methoxyphenol (0.93g), triphenylphosphine

(1.97g) and diethyl azodicarboxylate (1.31g). Treating the product with oxalic acid gave a white solid which was recrystallised from methanol/ethyl acetate (0.53g), m.p. 119-121°C.

Found: C, 63.54;. H, 8.47; N, 3.69%

(C₁₉H₃₁NO₂.C₂H₂O₄) requires: C, 63.79; H, 8.35; N, 3.54%

Example 9

4- [2- (3 , 4-Dichlorophenoxy) ethyl] -1-pentylpiperidine hydrochloride The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine

(2.0g), 3,4-dichlorophenol (1.63g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.76g). Treating the product with hydrogen chloride gave the title compound as white prisms from methanol/ethyl acetate (1.02g), m.p. 177 - 178°C.

Found: C, 57.05; H, 7.43; N, 3.85; Cl, 27.93%

(C₁₈H₂₇Cl₂NO.HCl) requires: C, 56.78; H, 7.41; N, 3.68; Cl, 27.93%

Example 10 4-[2-(4-Cyanophenoxy)ethyl]-1-pentylpiperidine

hydrochloride

(2.0g), 4-cyanophenol (1.19g), 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 (0.95g), m.p. 173 - 174°C.

Found: C, 67.69; H, 8.84; N, 8.28; Cl, 10.85%

(C₁₉H₂₈N₂O.HCl) requires: C, 67.74; H, 8.68; N, 8.31;

Cl, 10.52% Example 11

4-[2-(4-Chlorophenoxy)ethyl]-1-pentylpiperidine

hydrochloride

(2.0g), 4-chlorophenol (1.30g), 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 (0.75g), m.p. 185 -186°C.

Found: C, 62.14; H, 8.48; N, 4.44; Cl, 20.63%

(C₁₈H₂₈ClNO.HCl) requires: C, 62.42; H, 8.44; N, 4.04;

Cl, 20.47%

Example 12 4-[2-(5,6,7,8-Tetrahydro-2-napthoxy)ethyl]-1-pentylpiperidine oxalate

(2.0g), 5,6,7,8-tetrahydro-2-napthol (1.48g),

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 (0.81g), m.p. 147°C.

Found: C, 68.88; H, 9.07; N, 3.40%

(C₂₂H₃₅NO.C₂H₂O₄) requires: C, 68.71; H, 8.89; N, 3.34% Example 13

4-[2-(5,6,7,8-Tetrahydro-1-napthoxy)ethyl]-1-pentylpiperidine oxalate

The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (2.0g), 5,6,7,8-tetrahydro-1-napthol (1.48g),

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 (1.14g), m.p. 162°C. Found: C, 68.03; H, 8.73; N, 3.40%

(C₂₂H₃₅NO.C₂H₂O₄.0.25H₂O) requires: C, 67.97; H, 8.84; N, 3.30%

Example 14

4-[2-(4-Nitro-3-trifluoromethylphenoxy)ethyl]-1-pentylpiperidine hydrochloride

The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (1.5g), 3-nitro-4-trifluoromethylphenol (1.44g),

triphenylphosphine (1.96g) and diethyl azodicarboxylate (1.19g). Treating the product with hydrogen chloride gave the title compound as a white solid from methanol/ethyl acetate (0.61g), m.p. 139 - 141°C.

Found: C, 53.80; H, 6.50; N, 6.45; Cl, 8.30% (C₁₉H₂₇F₃N₂O₃.HCl) requires: C, 53.71; H, 6. 64 ; N, 6.59; Cl, 8.34%

Example 15

4-[2-(3-Fluorophenoxy)ethyl]-1-pentylpiperidine

hydrochloride

(1.5g), 3-fluorophenol (0.84g), triphenylphosphine (1.97g) and diethyl azodicarboxylate (1.31g). Treating the product with hydrogen chloride gave the title compound as a white solid from methanol/ethyl acetate (1.21g),

m.p. 157-159°C.

Found: C, 65.27; H, 8.67; N, 4.61; Cl, 10.75%

(C₁₈H₂₈FNO.HCl) requires: C, 65.54; H, 8.86; N, 4.25;

Cl, 10.75%

Example 16

4-[2-(4-Methylphenoxy)ethyl]-1-pentylpiperidine

hydrochloride

(1.50g), p-cresol (0.81g), triphenylphosphine (1.96g) and diethyl azodicarboxylate (1.31g). Treating the product with hydrogen chloride gave the title compound as a white solid from methanol/ethyl acetate (1.09g),

m.p. 164 - 166°C. Found: C, 70.00; H, 9.69; N, 4.15; Cl, 10.82%

(C₁₉H₃₁NO.HCl) requires: C, 70.02; H, 9.90; N, 4.30;

Cl, 10.88%

Example 17

4-[2-(4-Benzylphenoxy)ethyl]-1-pentylpiperidine oxalate The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (1.50g), 4-benzylphenol (1.38g), triphenylphosphine

(1.96g) and diethyl azodicarboxylate (1.31g). Treating the product with oxalic acid gave the title compound as a white solid from methanol/ethyl acetate (0.377g),

m.p. 166 - 168°C.

Found: C, 70.86; H, 8.02; N, 3.07%

(C₂₅H₃₅NO.C₂H₂O₄) requires: C, 71.18; H, 8.19; N, 3.07%

Example 18

4-[2-(3-chlorophenoxy)ethyl]-1-pentylpiperidine

hydrochloride

(1.50g), 3-chlorophenol (0.69g), triphenylphosphine

(1.96g) and diethyl azodicarboxylate (1.31g). Treating the product with hydrogen chloride gave the title compound as a white solid from methanol/ethyl acetate (0.37g), m.p. 151 - 153°C. Found: C, 62.13; H, 8.30; N, 4.05; Cl-, 10.20%

(C₁₈H₂₈ClNO.HCl) requires: C, 62.42; H, 8.44; N, 4.04; Cl-, 10.23%

Example 19

4-Benzyl-1-pentylpiperidine hydrochloride A mixture of 4-benzylpiperidine (3.0g), pentyl bromide (2.84g), potassium carbonate (4.72g) and ethanol (40ml) was heated at reflux for 48 hours. The solution was filtered, and the solvent removed under reduced pressure. The residue was distilled in a kugelrohr apparatusto give an oil (b.p. 150°C @ 0.1mmHg) which was treated with hydrogen chloride to gave the title compound as a white solid from methanol/ethyl acetate (2.06g),

m.p. 188 - 190°C. Found: C, 70.00; H, 9.69; N, 4.15; Cl, 10.82%

(C₁₉H₃₁NO.HCl) requires: C, 70.02; H, 9.90; N, 4.30;

Cl, 10.88%

Example 20

4-[2-(4-Fluorophenoxy)ethyl]-1-cinnamylpiperidine oxalate

A solution of 4-(2-hydroxyethyl)-1-cinnamylpiperidine (2.94g), 4-fluorophenol (1.31g) and triphenylphosphine (3.15g) in tetrahydrofuran (50ml) was treated with diethyl azodicarboxylate (2.09g). 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 (1.1 mole equivalents). The precipitate was collected by filtration and recrystallised (methanol/ethyl acetate) to give the title compound (1.10g), m.p. 180 °C.

Found: C, 67.14; H, 6.60; N, 3.56%.

(C₂₂H₂₆FNO.C₂H₂O₄) requires: C, 67.11; H, 6.57; N, 3.26%

Example 21

4-[2-(3,4-Dichlorophenoxy)ethyl]-1-cinnamylpiperidine oxalate

A solution of 4-(2-hydroxyethyl)-1-cinnamylpiperidine (2.02g), 3,4-dichlorophenol (1.34g) and triphenylphosphine (2.16g) in tetrahydrofuran (50ml) was treated with diethyl azodicarboxylate (1.44g). The resulting solution was stirred at room temperature for 18 hours, the solvent removed and the residue was dissolved in ethyl acetate and extracted with dilute hydrochloric acid. The aqueous extract was basified and extracted with ethyl acetate.

The resulting organic layer was dried over magnesium sulphate, filtered and the solvent was removed. The residue was dissolved in ethyl acetate (50ml) and treated with oxalic acid (1.1 mole equivalents). The precipitate was collected by filtration and recrystallised

(methanol/ethyl acetate) to give the title compound

(0.3g), m.p. 179 - 180°C.

Found: C, 60.07; H, 5.67; N, 2.92; Cl, 14.79%. (C₂₂H₂₅Cl₂NO.C₂H₂O₄) requires: C, 60.01; H, 5.67;

N, 2.92; Cl, 14.76%

Example 22

4-[3-(4-Fluorophenoxy)propyl]-1-pentylpiperidine

hydrochloride

The title compound was prepared in a similar manner to example 1 from 1-pentyl-4-(3-hydroxypropyl)piperidine

(2.0g), 4-fluorophenol (1.05g), triphenylphosphine (2.46g) and diethyl azodicarboxylate (1.63g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from methanol/ethyl acetate (1.32g), m.p. 148 - 150°C.

Found: C, 65.94; H, 9.29; N, 4.15; Cl, 10.32%

(C₁₉H₃₀FNO.HCl) requires: C, 66.36; H, 9.09; N, 4.07;

Cl, 10.31%

Example 23

4-[3-(4-Benzyloxyphenoxy)propyl]-1-pentylpiperidine hydrochloride

The title compound was prepared in a similar manner to example 1 from 1-pentyl-4-(3-hydroxypropyl)piperidine (2.0g), 4-benzyloxyphenol (1.88g), triphenylphosphine (2.46g) and diethyl azodicarboxylate (1.48g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from acetonitrile (1.48g), m.p. 163 - 164°C. Found: C, 72.43; H, 8.91; N, 3.31; Cl, 8.06%

(C₂₆H₃₇NO₂.HCl) requires: C, 72.28; H, 8.86; N, 3.24;

Cl, 8.21%

Example 24

4-(4-Fluorophenoxy)methyl-1-pentylpiperidine hydrochloride The title compound was prepared in a similar manner to example 1 from 1-pentyl-4-hydroxymethylpiperidine (1.1g), 4-fluorophenol (0.69g), triphenylphosphine (1.63g) and diethyl azodicarboxylate (1.08g). Treating the product with oxalic acid gave a white solid which was

recrystallised from methanol/ethyl acetate (0.25g), m.p. 111 -112°C.

Found: C, 60.25; H, 7.56; N, 3.88%

(C₁₇H₂₆FNO.C₂H₂O₄.0.5H₂O) requires: C, 60.3; H, 7.72;

N, 3.70%

Example 25

4-(4-Fluorobenzyloxy)-1-pentylpiperidine oxalate

A solution of 4-hydroxy-1-pentylpiperidine (2.0g) in dimethylformamide (25 ml) was treated with sodium hydride (0.012 mole) and then stirred for 1 hour when 4-fluorobenzyl chloride (1.43 ml) was added and the mixture was stirred for 3 days. Water (100 ml) and

dichloromethane (100 ml) were added and the organic layer was separated, washed with water (2 x 100 ml), and dried over magnesium sulphate. The solvent removed and the residue was chromatographed on silica gel eluted with methanol/dichloromethane. 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 (0.2g), m.p. 124 - 125 °C.

Found: C, 61.71; H, 7.69; N, 3.94%.

(C₁₇H₂₆FNO.C₂H₂O₄) requires: C, 61.77; H, 7.64; N, 3.79%

Example 26

4-Benzyloxy-1-pentylpiperidine oxalate

Substitution of benzyl bromide (2.0g) for 4-fluorobenzyl chloride, in the procedure described in example 25, gave the title compound as a white solid on recrystallisation from methanol/ethyl acetate yield (0.2g),

m.p. 119 - 121°C.

Found: C, 64.63; H, 8.11; N, 4.14%

(C₁₇H₂₇NO.C₂H₂O₄) requires: C, 64.98; H, 8.32; N, 3.99% Example 27

4-(4-Fluorophenoxy)-1-pentylpiperidine oxalate

The title compound was prepared in a similar manner to example 1 from 4-hydroxy-1-pentylpiperidine (2.0g), 4-fluorophenol (1.31g), triphenylphosphine (3.15g) and diethyl azodicarboxylate (2.09g). Treating the product with oxalic acid gave a white solid which was

recrystallised from methanol/ethyl acetate (0.65g), m.p. 164°C. Found: C, 60.91; H, 7.56; N, 4.06%

(C₁₆H₂₄FNO.C₂H₂O₄) requires: C, 60.83; H, 7.37; N, 3.94%

Example 28 4-(3,4-Methylenedioxyphenoxy)-1-pentylpiperidine oxalate

The title compound was prepared in a similar manner to example 1 from 4-hydroxy-1-pentylpiperidine (2.0g), sesamol (1.66g), triphenylphosphine (3.15g) and diethyl azodicarboxylate (2.09g). Treating the product with oxalic acid gave a white solid which was recrystallised from methanol/ethyl acetate (0.65g), m.p. 164°C.

Found: C, 59.76; H, 7.22; N, 3.72%

(C₁₇H₂₅NO₃.C₂H₂O₄) requires: C, 59.83; H, 7.14; N, 3.67%

Example 29

4-[2-(4-Fluorophenoxy)ethyl]-1-propylpiperidine oxalate

The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-propylpiperidine (1.85g), 4-fluorophenol (1.12g), 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 (0.3g), m.p. 109-112°C. Found: C, 59. 66; H, 7 . 46; N, 3 . 80%

(C₁₆H₂₄FNO.C₂H₂O₄.0.5H₂O) requires: C, 59.50; H, 7.43; N, 3.86%

Example 30

4-[2-(4-Fluorophenoxy)ethyl]-1-(3-phenylpropyl)piperidine hydrochloride

The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-(3-phenylpropyl)piperidine (2.47g), 4-fluorophenol (1.12g), 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 (0.65g), m.p. 111-113°C.

Found: C, 68.04; H, 7.72; N, 3.83; Cl, 9.11%

(C₂₂H₂₈FNO.HCl.0.5H₂O) requires: C, 68.23; H, 7.75;

N, 3.60; Cl, 9.04%

Example 31 4-[2-(4-Fluorophenoxy)ethyl]-1-heptylpiperidine

hydrochloride

The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-heptylpiperidine

(2.27g), 4-fluorophenol (1.12g), 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 (1.1g), m.p. 139-141°C.

Found: C, 66.71; H, 9.32; N, 4.05; Cl, 10.08%

(C₂₀H₃₂FNO.HCl) requires: C, 67.10; H, 9.29; N, 3.91; Cl, 9.90%

Example 32 4-[2-(3,4-Methylenedioxyphenoxy)ethyl]-1-heptylpiperidine hydrochloride

The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-heptylpiperidine (2.27g), 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 (0.65g), m.p. 129-231°C.

Found: C, 65.61; H, 8.85; N, 3.71; Cl, 9.26%

(C₂₁H₃₃NO₃.HCl) requires: C, 65.69; H, 8.93; N, 3.65;

Cl, 9.23% Example 33

4-[2-(4-Fluorophenoxy)ethyl]-1-(2-ethyl)butylpiperidine oxalate The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-(2-ethyl)butylpiperidine (2.97g), 4-fluorophenol (1.08g), 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 (0.65g), m.p. 137-138°C.

Found: C, 63.24; H, 8.26; N, 3.58%

(C₁₉H₃₀FNO.C₂H₂O₄) requires: C, 63.46; H, 8.11; N, 3.52%

Example 34

4-[2- (3 ,4-Methylenedioxyphenoxy)ethyl]-1-(2-ethyl)butylpiperidine oxalate

The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-(2-ethyl)butylpiperidine (2.25g), sesamol (1.32g),

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 (1.25g), m.p. 133-134°C.

Found: C, 62.05; H, 7.88; N, 3.39%

(C₂₀H₃₁NO₃.C₂H₂O₄) requires: C, 62.39; H, 7.85; N, 3.31% Example 35

1-Cyclohexylmethyl-4-[2-(3,4-methylenedioxyphenoxy)ethyl]piperidine hydrochloride The title compound was prepared in a similar manner to example 1 from 1-cyclohexylmethyl-4-(2-hydroxyethyl)piperidine (2.25g), 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 (1.72g), m.p. 177-178°C.

Found: C, 66.01; H, 8.44; N, 3.85; Cl, 9.39%

(C₂₁H₃₁NO₃.HCl) requires: C, 66.04; H, 8.44; N, 3.67;

Cl, 9.28% Example 36

4-[2-(4-Fluorophenoxy)eihyl]-1-cyclohexylmethylpiperidine hydrochloride The title compound was prepared in a similar manner to example 1 from 1-cyclohexylmethyl-4-(2-hydroxyethyl)piperidine (2.25g), 4-fluorophenol (1.08g), 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 (0.98g), m.p. 178 - 180°C.

Found: C, 67.68; H, 8.85; N, 4.12; Cl, 9.87%

(C₂₀H₃₀FNO.HCl) requires: C, 67.68; H, 8.78; N, 3.94;

Cl, 9.96%

Example 37

1-(3-Methylbutyl)-4-[2-(3,4-methylenedioxyphenoxy)ethyl]piperidine hydrochloride The title compound was prepared in a similar manner to example 1 from 1-(3-methylbutyl)-4-(2-hydroxyethyl)- piperidine (2.0g), 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 (0.17g), m.p. 168-169°C.

Found: C, 63.95; H, 8.50; N, 4.05; Cl, 10.17%

(C₁₉H₂₉NO₃.HCl) requires: C, 64.12; H, 8.50; N, 3.94; Cl, 9.96%

Example 38 1-Benzyl-4-[2-(4-fluorophenoxy)ethyl]-1-piperidine hydrochloride

The title compound was prepared in a similar manner to example 1 from 1-benzyl-4-(2-hydroxyethyl)piperidine (3.83g), 4-fluorophenol (1.96g), triphenylphosphine

(4.61g) and diethyl azodicarboxylate (2.78g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from methanol/ethyl acetate (2.42g), m.p. 175 -176°C.

Found: C, 68.48; H, 7.22; N, 3.92; Cl, 10.07%

(C₂₀H₂₅FNO.HCl) requires: C, 68.66; H, 7.20; N, 4.00; Cl, 10.13% Example 39

4-[2-(4-Fluorophenoxy)ethyl]-1-(2-phenylethyl)-piperidine hydrochloride

A mixture of 4-[2-(4-fluorophenoxy)ethyl]-piperidine hydrochloride (0.57g) and sodium hydride (80% in oil) (0.146g) in dimethylformamide (10ml) was stirred under nitrogen until effervesence had subsided. 2-Phenylethyl bromide (0.3ml) was added and the mixture stirred for 48 hours. The mixture was poured into water (50ml) and extracted with ether. The ether phase was washed with dilute hydrochloric acid and the resulting precipitate collected by filtration. Recrystallisation from water gave the title compound (0.228g) m.p. 210-212°C

Found: C, 69.61; H, 7.48; N, 3.96; Cl, 9.77%

(C₂₁H₂₆FNO.HCl) requires: C, 69.12; H, 7.73; N, 3.84; Cl, 9.72%

Example 40

4-[2-(4-Fluorophenoxy)ethyl]-1-(4-phenylbutyl)-piperidine hydrochloride

The title compound was prepared in a similar manner to example 39 starting from 4-[2-(4-fluorophenoxy)ethyl]-piperidine hydrochloride (1.0g), sodium hydride (80% in oil) (0.3g) and 4-phenylbutyl chloride (0.649g) in dimethylformamide (20ml) and recrystallising the product from ethyl acetate/methanol, yield (0.39g), m.p. 166168°C. Found: C, 70.20; H, 8.00; N, 3.87; Cl, 8.91%

(C₂₃H₃₀FNO.HCl) requires: C, 70.48; H, 7.97; N, 3.57; Cl, 9.05% Example 41

1-(3,3-Diphenylpropyl)-4-[2-(4-fluorophenoxy)ethyl]- piperidine oxalate

A mixture of 4-[2-(4-fluorophenoxy)ethyl]-piperidine hydrochloride

(2.0g), 3,3-diphenylpropane-1-ylmethanesulphonate (2.23g) and sodium hydride (80% in oil) (0.58g) in

dimethylformamide (40ml) was stirred at 60°C under

nitrogen for 48 hours. The mixture was poured into water (200ml) and extracted with ether. The ether phase was treated with dilute hydrochloric acid and an oil

precipitated. The oil was separated and dissolved in dichloromethane. The dichloromethane solution was washed with dilute sodium hydroxide solution, dried over sodium sulphate and the solvent removed. The residue was

dissolved in ethyl acetate and treated with oxalic acid when the title compound crystallised. Yield (0.963g), m.p. 160-161°C Found: C, 70.96; H, 6.75; N, 2.83%

(C₂₈H₃₂FNO.C₂H₂O₄) requires: C, 70.98; H, 6.90; N, 2.66%

Example 42 4- [2- (4-Fluorothiophenoxy) ethyl] -1-pentylpiperidine hydrochloride The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (2.00g), 4-fluorothiophenol (1.28g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from ethyl acetate to give the title compound as white plate crystals (0.33g), m.p.164165°C. Found: C, 62.41; H, 8.47; N, 4.09; Cl, 10.17%

(C₁₈H₂₈FNS.HCl) requires: C, 62.49; H, 8.45; N, 4.05; Cl, 10.25%

Example 43

4-[2-(3,4-Dichlorothiophenoxy)ethyl]-1-pentylpiperidine hydrochloride

The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (2.00g), 3,4-dichlorothiophenol (1.79g),

triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from ethyl acetate to give the title compound as a white crystalline solid (0.77g), m.p.158-159°C.

Found: C, 54.41; H, 7.11; N, 3.48; Cl-, 8.89%

(C₁₈H₂₇Cl₂NS.HCl) requires: C, 54.48; H, 7.11; N, 3.53;

Cl-, 8.93% Example 44

1-Pentyl-4-(3-phenylpropyl)piperidine hydrochloride

A mixture of 4-(3-phenylpropyl)piperidine (5g), 1- bromopentane (7.42g), potassium carbonate (10g) and ethanol (125ml) was heated at reflux for 18 hours. The solution was filtered, and the solvent was removed under reduced pressure. The residue was dissolved in

dichloromethane and the dichloromethane solution washed with dilute sodium hydroxide solution, dried over sodium sulphate and the solvent removed. The residue was treated with hydrogen chloride in ether to give a solid.

Recrystallisation from ethyl acetate gave the title compound (4.19g), m.p. 188-189°C.

Found: C, 72.56; H, 10.29; N, 4 .58 ; Cl, 11 .44%

(C₁₉H₃₁N.HCl .0.25H₂O) requires : C, 72.56; H, 10.36; N, 4 . 45; Cl , 11 .27% Example 45

4-[2-(4-Fluorophenyl)ethyl]-1-pentylpiperidine

hydrobromide A mixture of 4-[2-(4-fluorophenyl)ethyl]-1-pentylpyridinium bromide (3.0g), platinum oxide (0.6g) and ethanol (100ml) was shaken under an atmosphere of hydrogen for 15 minutes. The mixture was filtered and the filtrate was evaporated to dryness. The residue was recrystallised from methanol/ethyl acetate to give the title compound, m.p. 173-174°C. Example 46

4-[2-(4-Nitrophenoxy)ethyl]-1-pentylpiperidine

hydrochloride

A mixture of 4-(2-hydroxyethyl)-1-pentylpiperidine (2.5g), sodium hydride (60% in oil) (0.42g) and dimethylformamide (20ml) was heated at 50°C for 1.5 hours. 1-Fluoro-4-nitrobenzene (2.14ml) was added and the mixture was stirred at 50° for 5 hours. The mixture was cooled, poured into water and extracted with dichloromethane. The dichloromethane extracts were dried over magnesium

sulphate and the solvent removed. The residue was

chromatographed on silica gel, with

methanol/dichloromethane as eluent, and the product was treated with hydrogen chloride to give a yellow solid which was recrystallised from ethyl acetate to give the title compound as a yellow crystalline solid (0.937g), m.p.l74-176°C. Found: C, 60.35; H, 8.15; N, 7.85; Cl-, 9.70%

(C₁₈H₂₈NO₃.HCl) requires: C, 60.58; H, 8.19; N, 7.85; Cl, 9.93%

Examole 47

4-[2-(2-Fluorophenoxy)ethyl]-1-pentylpiperidine

hydrochloride

(1.5g), 2-fluorophenol (0.84g), triphenylphosphine (1.96g) and diethyl azodicarboxylate (1.19ml). Treating the product with hydrogen chloride gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (0.87g), m.p.150-152°C. Found: C, 65.14; H, 8.87; N, 4.30; Cl-, 10.82%

(C₁₈H₂₈FNO.HCl) requires: C, 65.54; H, 8.86; N, 4.25; Cl, 10.75%

Example 48

4-[2-(4-tert-Butylphenoxy)ethyl]-1-pentylpiperidine hydrochloride

(1.5g), 4-tert-butylphenol (1.127g), triphenylphosphine (1.96g) and diethyl azodicarboxylate (1.19g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid

(1.23g), m.p.189-191°C.

Found: C, 71.67; H, 10.50; N, 3.88; Cl-, 9.68%

(C₂₂H₃₇NO.HCl) requires: C, 71.8; H, 10.41; N, 3.81; Cl, 9.63%

Example 49

1-Pentyl-4-[2-(4-trifluoromethoxyphenoxy)ethyl]piperidine hydrochloride

The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (1.5g), 4-trifluoromethoxyphenol (1.335g),

triphenylphosphine (1.96g) and diethyl azodicarboxylate

(1.19ml). Treating the product with hydrogen chloride gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (0.95g), m.p.154-156°C.

Found: C, 57.29; H, 7.31; N, 3.52; Cl-, 8.59%

(C₁₉H₂₈F₃NO₂.HCl) requires: C, 57.64; H, 7.38; N, 3.54; Cl, 8.96%

Example 50 4-[2-(4-iso-Propylphenoxy)ethyl]-1-pentylpiperidine hydrochloride

The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (1.5g), 4-isopropylphenol (1.02g), triphenylphosphine (1.96g) and diethyl azodicarboxylate (1.19ml). Treating the product with hydrogen chloride gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (1.21g), m.p.185-187°C.

Found: C, 71.35; H, 10.23; N, 4.05; Cl-, 10.08%

(C₂₁H₃₅NO.HCl) requires: C, 71.26; H, 10.25; N, 3.96; Cl, 10.02% Example 51

4-(2-(3-iso-Propylphenoxy)ethyl]-1-pentylpiperidine hydrochloride

The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyexhyl)-1-pentylpiperidine (1.5g), 3-isopropylphenol (1.02g), triphenylphosphine (1.96g) and diethyl azodicarboxylate (1.19ml). Treating the product with hydrogen chloride gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (0.5g), m.p.166-168°C.

Found: C, 71.40; H, 10.30; N, 3.97; Cl-, 10.00%

(C₂₁H₃₅NO.HCl) requires: C, 71.26; H, 10.25; N, 3.96; Cl, 10.02%

Example 52

4-[2-(3-tert-Butylphenoxy)ethyl]-1-pentylpiperidine hydrochloride

The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (1.5g), 3-tert-butylphenol (1.127g), triphenylphosphine (1.96g) and diethyl azodicarboxylate (1.19g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (0.80g), m.p.171-173°C.

Found: C, 71.80; H, 10.57; N, 3.88; Cl-, 9.67% (C₂₂H₃₇NO.HCl) requires: C, 71.8; H, 10.41; N, 3.81; Cl, 9.63%

Example 53

4-[2-(2-phenylphenoxy)ethyl]-1-pentylpiperidine

hydrochloride

(1.5g), 2-phenylphenol (1.28g), triphenylphosphine (1.96g) and diethyl azodicarboxylate (1.19g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (1.05g), m.p.175-177°C.

Example 54

1-Pentyl-4-[2-(4-trifluoromethylphenoxy)ethyl]-piperidine oxalate

A mixture of 4-(2-hydroxyethyl)-1-pentylpiperidine (2.0g), sodium hydride (60% in oil) (0.4g) and dimethylformamide (20ml) was refluxed 1.5 hours. 4-Fluorotrifluoromethylbenzene (1.64ml) was added and the mixture was refluxed for 18 hours. The mixture was cooled, poured into water and extracted with ether. The ether extracts were dried over magnesium sulphate and the solvent was removed. The residue was chromatographed on silica gel with methanol/dichloromethane as eluent and the product was treated with oxalic acid to give solid. This was recrystallised from ethyl acetate/methanol to give the title compound. (0.5g), m.p.101-103°C.

Found: C, 57.76; H, 7.00; N, 3.27%

(C₁₉H₂₈F₃NO.C₂H₂O₄.0.1 H₂O) requires: C, 57.9; H, 6.9; N, 3.2%

Example 55 4-[2-(3,5 Dichlorophenoxy)ethyl]-1-pentylpiperidine hydrochloride

The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (2.0g), 3,5-dichlorophenol (1.63g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (l.lg), m.p.168-170°C.

Found: C, 56.80; H, 7.40; N, 3.64; Cl-, 9.33; Cl, 27.92% (C₁₈H₂₇Cl₂NO.HCl) requires: C, 56.78; H, 7.41; N, 3.68; Cl-, 9.30; Cl, 27.93%

Example 56

4- [2- (3 , 4-Dichlorophenoxy) ethyl] -1-heptylpiperidine hydrochloride

The title compound was prepared in a similar manner to example 1 from 4- (2-hydroxyethyl) -1-heptylpiperidine (2.27g) , 3, 4 dichlorophenol (1. 63g) , triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (0.7g), m.p.138-139°C.

Found: C, 58.87; H, 7.88; N, 3.50; Cl-, 8.68; Cl, 26.00% (C₂₀H₃₁Cl₂NO.HCl) requires: C, 58.76; H, 7.89; N, 3.43; Cl-, 8.68; Cl, 26,01%

Example 57

4-[2-(3,4-Dichlorophenoxy)ethyl]-1-(3-phenylpropyl)piperidine hydrochloride

The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-(3-phenylpropyl)-piperidine (2.47g), 3,4-dichlorophenol (1.63g),

triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from ethyl

acetate/methanol to give the title compound as a white crystalline solid (0.75g), m.p.137-138°C. Found: C, 61.24; H, 6.45; N, 3.36; Cl-, 8.7%

(C₂₂H₂₇Cl₂NO-HCl.0.1 H₂O) requires: C, 61.56; H, 6.34; N, 3.27; Cl, 8.30% Example 58

1-Cyclopropylmethyl-4-[2-(4-fluorophenoxy)ethyl]-piperidine oxalate

The title compound was prepared in a similar manner to example 41 from 4-[2-(4-fluorophenoxy)ethyl]-piperidine hydrochloride (2.0g), bromomethylcyclopropane (2.0ml) and sodium hydride (80% in oil) (0.58g) in dimethylformamide (40ml). Treating the product with oxalic acid in ethyl acetate gave a solid which was recrystallised from ethyl acetate to give the title compound. Yield, (0.963g) m.p. 129-132°C Found: C, 61.95; H, 7.05; N, 3.91%

(C₁₇H₂₄FNO.C₂H₂O₄) requires: C, 62.11; H, 7.13; N, 3.81%

Example 59

1-(3,3-Diphenylprop-2-enyl)-4-[2-(4-fluorophenoxy)ethyl]-piperidine 1-(3,3-Diphenylprop-2-enyl)-4-[2-(4-fluorophenoxy)ethyl]-piperidine oxalate Methanesulphonyl chloride ((0.46ml) was added to a solution of 1,1-diphenyl-2-hydroxymethylethylene (1.14g) in tetrahydrofuran (20ml). The mixture was stirred for 1 hour when 4-[2-(4-fluorophenoxy)ethyl]-piperidine (1.42g) and triethylamine (0.8ml) was added. The mixture was stirred under nitrogen for 48 hours then heated at reflux for 8 hours. The mixture was poured into water (200ml) and extracted with ether. The ether phase was dried over magnesium sulphate, filtered and the solvent removed. The residue was chromatographed on silica gel with

methanol/dichloromethane as eluent and the product was treated with oxalic acid to give solid. This was

recrystallised from ethyl acetate/methanol to give the title compound. (0.687g), m.p.174-176°C.

Found: C, 70.84; H, 6.34; N, 2.93%

(C₂₈H₃₀FNO.C₂H₂O₄) requires: C, 71.27; H, 6.38; N, 2.77%

Example 60

4-[2-(2-Benzylphenoxy)ethyl]-1-pentylpiperidine

hydrochloride

(1.5g), 2-hydroxydiphenyl methane (1.38g),

triphenylphosphine (1.96g) and diethyl azodicarboxylate (1.19g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from ethyl

acetate/methanol to give the title compound as a white crystalline solid (1.65g), m.p.119-120°C. Found: C, 73.32; H, 8.94; N, 3.61; Cl, 8.70%

(C₂₅H₃₅NO.HCl . 0.3H₂O) requires : C, 73.59; H, 8 . 89; N, 3. 43 ; Cl, 8 . 69%

Claims

Claims:

1. A compound of structure (I):

(I)

in which

R is C_1-8alkyl(phenyl)p, C_2-8alkenyl(phenyl)p,

C_2-8alkenyl(phenyl)p,

C_3-8cycloalkyl or C_1-8alkylC_3-8cycloalkyl;

p is 0 to 2;

n is 0 to 6;

A is a bond, oxygen, sulphur or NR¹;

R¹ is hydrogen, C_1-8alkyl or phenylC_1-4alkyl;

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 C_1-8 alkyl, phenyl(C_1-8)alkyl or

phenyl(C_2-8)-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 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:

4-[2-(4-trifluoromethylphenoxy)ethyl]-1-pentylpiperidine, 4-[2-(3-trifluoromethylphenoxy)ethyl]-1-pentylpiperidine, 4-[2-(4-fluorophenoxy)ethyl]-1-pentylpiperidine,

4-[2-(3,4-methylenedioxyphenoxy)ethyl]-1-pentylpiperidine,

4-(2-phenoxyethyl)-1-pentylpiperidine,

4-[2-(4-phenylphenoxy)ethyl]-1-pentylpiperidine,

4-[2-(4-benzyloxyphenoxy)ethyl]-1-pentylpiperidine,

4-[2-(4-fluorophenoxy)ethyl]-1-cinnamylpiperidine,

4-(4-fluorobenzyloxy)-1-pentylpiperidine,

4-[2-(3,4-dichlorophenoxy)ethyl]-1-pentylpiperidine,

4-[2-(4-benzylphenoxy)ethyl]-1-pentylpiperidine,

4-[2-(3,4-dichlorophenoxy)ethyl]-1-cinnamylpiperidine, 4-[2-(4-fluorophenoxy)ethyl]-1-(3-phenylpropylpiperidine, 4-[2-(4-fluorophenoxy)ethyl]-1-heprylpiperidine,

1-(3,3-diphenylpropyl)-4-[2-(4-fluorophenoxy)ethyl]-piperidine,

4-[2-(3,4-dichlorothiophenoxy)ethyl]-1-pentylpiperidine, 4-[2-(4-tert-butylphenoxy)ethyl]-1-pentylpiperidine,

4-[2-(4-iso-propylphenoxy)ethyl]-1-pentylpiperidine,

4-[2-(3,4-dichlorophenoxy)ethyl]-1-(3-phenylpropyl)-piperidine, or

1-cyclopropylmethyl-4-[2-(4-fluorophenoxy)ethyl]-piperidine; 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) :

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) :

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

and n, m, R and Ar are as described for structure (I);

(V)

(wherein R, L¹, n and m 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) :

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

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

wherein R⁵ is C_1-7alkyl(phenyl)p, C_2-7alkenyl(phenyl)p, C_2-7alkynyl(phenyl)p or C_1-7alkylC_3-8cycloalkyl;

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

wherein R, A, Ar m and n are as hereinbefore defined and

X- 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) as defined in any of claims 1 to 7, or a pharmaceutically acceptable salt thereof in the manufaccure of a medicament for the treatment of a condition caused or exacerbated by the accumulation of calcium in the brain cells of mammals.

12. Method of treating 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) as defined in any of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

13. Method according to claim 12 wherein the condition is stroke.

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