CA2088491A1 - N-hydrocarbyl-4-substituted piperidines, their preparation and use as calcium blocking agents - Google Patents

Abstract

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

Description

~ V ~ Y l W O 92/02502 1 P ~ tGB91/01340 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):

( CH2 ) nA ( CN2 ) mAr ~ (I) R

in which R is Cl_8alkyl(phenyl)p, C2_8alkenyl(phenyllp, C2_8alXynyl(phenyl)p, C3_8cycloalkyl or Cl_8alkylC3_8cycloalkyl;
p is 0 to 2;
n is 0 to 6;
A is a bond, oxygen, sulphur or NRl;
Rl is hydrogen, Cl_8alXyl or phenylCl_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 Cl_8alkyl(phenyl)p, C2_8alkenyl-(phenyl)p, C2_8alkynyl(phenyl)p, C3_8cycloalkyl or Cl_8alXylC3_8cycloalkyl.

It will be understood that the alkylcycloalkyl, alkylphenyl, alkenylphenyl and alkynylphenyl groups are SUBSTlTlJTE 8HEET

W092/02502 2 a ~ PCT/GB9t/Ot340

- 2 -linked to the piperidine nitrogen atom via the alkyl, alkenyl and alkynyl moieties respectively.

Preferably R is C1_8alkyl(phenyl)p in which p is 0 or l, i.e. C1_8alkyl, such as n-pentyl, or phenylCl_8alkyl such as phenylpropyl, or R is C2_8alkenyl(phenyl)p where p is 1, such as cinnamyl.

Suitably, n is O to 6; preferably n is O 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 O.

Suitably, A is a bond, oxygen, sulphur or NRl;
preferably A is oxygen or sulphur; most preferably A is oxygen. When A is oxygen n is preferably 2 and m is pre~erably O.

Suitably, Ar is optionally substituted aryl or heteroaryl; preferably Ar is optionally substituted aryl.

Suitable aryl groups include, for example, unsaturated monocyclic and unsaturated or partially saturated bicycIic ring systems of up to lO carbon atoms, such as, for example, phenyl, naphthyl and tetrahydronaphthyl. Preferred are optionally substituted phenyl rings.
Suitable substituted phenyl rings include, for example, phenyl rings substituted by a C1_2alkylene-dioxy group such as a 3,4-methylenedioxy group or by 1 to

3 substituents selected from halogen, C1_4alkoxy, nitro, SC1_4alkyl, NR2R2 (in which each R2 group can be H or c1_4alkyl), OCF3~ C1-6alkYl' SVBSTITIJTE SHEFT

W092/02502 PCT/GB9t/0l340 2~3~

trifluoromethyl, CN, optionally substituted phenyl, optionally substituted phenylC1_4alkyl and optionally substituted phenylCl_4alkoxy. Preferred are phenyl rings substituted by one or two substituents, in particular, by a single halogen, trifluoromethyl, unsubstituted phenyl or unsubstituted phenylCl_4alkoxy group; or by two chlorine atoms, in particular in the 3 and 4 positions of the ring.

Suitable optionally substituted phenylC1_4alkyl groups include, for example benzyl. Suitable optionally substituted phenylCl_4aLkoxy groups include, for example benzyloxy groups.

Suitable substituents for said optionally substituted phenyl, phenylC1_4alkyl and phenylCl_4alkoxy groups include for example halogen, Cl_4alkyl, Cl_4alkoxy, nitro and tri~luoro~ethyl groups.
Suitable heteroaryl rings include, for example, unsaturated monocyclic and unsaturated or partially saturated bicyclic ring systems of up to 10 carbon atoms containing ~t least one heteroatom, such as pyridyl, thienyl, quinolinyl, tetrahydroquinolinyl and imidazolyl rings. The heteroaryl ring can be linked to the remainder of structure ~I) via a carbon atom or via a hetero atom, e.g. a nitrogen atom.

Suitable substituents for said heteroaryl rings include, for example, 1 to 3 substituents selected from halogen, cl_4alkyl and cl-4alkoxy Alkyl groups present in the compounds of structure (I), alone or as part of another group, can be straight or branched.

SUBSTIT~JTE 5HEET

2a~91 - 4 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 :

4-[2-(4-trifluoromethylphenoxy)ethyl~-l-pentylpiperidine oxalate, 4-t2-(3-trifluoromethylphenoxy)ethyl]-1-pentylpiperidine hydrochloride, 4-t2-(4-~luorophenoxy)ethyl~ pentylpiperidine hydrochloride, 4-t2-(3~4-methylenedioxyphenoxy)ethyl]-l-pentylpiperidine hydrochloride 4-(2-phenoxyethyl)-l-pentylpiperidine hydrochloride 4-t2-(4-phenylph~oxy)ethyl~-l-pentylpiperidine hydrochloride, 4-t2-(4-benzyloxyphenoxy~ethyl]-l-pentylpiperidine hydrochloride, 4-[2-(4-fluorophenoxy)ethyl]-l-cinnamylpiperidine oxalate, 4-(4-fluorobenzyloxy)-l-pentylpiperidine oxalate 4-[2-(3,4-dichlorophenoxy)ethyl]-l-pentylpiperidine hydrochloride, 4-t2-(4-benzylphenoxy)ethyl]-l-pentylpiperidine oxalate, 4-[2-(3,4-dichlorophenoxy)ethyl]-l-cinnamylpiperidine oxalate, 4-[2-(4-fluorophenoxy)ethyl]-l-(3-phenylpropylpiperidine hydrochloride, 4-[2-(4-fluorophenoxy)ethyl~-l-heptylpiperidine hydrochloride, l-(3,3-diphenylpropyl)-4-[2-(4-fluorophenoxy)ethyl]-piperidine oxalate, SUBSTlTlJTE 8HE~T

092/02502 PCT/GB9t/013402 ~ 91 4-t2-(3,4-dichlorothiophenoxy)ethyl]-1-pentylpiperidine hydrochloride, 4-~2-(4-tert-butylphenoxy)ethyl]-1-pentylpiperidine hydrochloride, 4-t2-(4-iso-propylphenoxy)ethyl]-1-pentylpiperidine hydrochloride, 4-~2-(3,4-dichlorophenoxy)ethyl]-1-(3-phenylpropyl)-piperidine hydrochloride, and l-cyclopropylmethyl-4-~2-(4-fluorophenoxy)ethyl]-piperidine oxalate.

It will be appreciated that the compounds ofstructure (I) may contain one or more asymmetric centres. Such compounds will exist as optical isomers (enantiomers). Both the pure enantiomers, racemic mixture~ (50% of each enantiomer) and unequal mixtures of the two are included within the scope o~ the invention.
Further, all diastereo~eric forms possible (pure enantiomers and ~ixtures thereof) are within the scope of the invention.

~ he compounds of the present in~ention can be prepared by processes analogoùs to ~hose 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 N21, reaction of a compound of structure (II):

( CH2 ) nAlH

(II) N

R

SUBSTlTUl E SHEET

2~ 191 in which R and n are as described for structure (I)and Al is O, S or NRl, with a compound of structure L(CH2)mAr in which m and Ar are as described for structure (I), and L is a leaving group;
s (b) for compounds of structure (I) in which A is O, S or NRl, reaction of a compound of structure (III):

(CH2)nL

1 1 (III) in which n and R are as described or structure (I) and Ll is a group displaceable by a nucleophile, with a compound of structure HAl(CH2)mAr where m and Ar are as described for structure (I) and Al is as described for structure (II); or (c) for compounds of structure (I) in which i is NRl, reduction of a compound of structure (IV) :

~ (IV) N
R
in which R4 represents the group SUBSTITUTE SHEET

W092/02502 PCT~GB91/01340 -(cH2)nN(Rl~c(cH2)m-lAr or ~(CH2)n-lCN(R )(CH2jmAr~
and n, m, R and Ar are as described for structure (I);

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

(~2)n+m L
~ (V) R
(wherein R, Ll, n and m are as hereinbefore defined) with a compound of structure XlAr in which Ar is as described for structure (I), and Xl is an alkali metal;

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

(CH2)nA(CH2)mAr ~ (VI) I

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

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

SUBSTIT~TE SHEET

W092/02S02 2 ~ 3 ~ ~ 91 PCT/GB91/013~0 (IC~2)nA(CH2)mAr ~ (VII) ~ N J

COR

wherein R5 is Cl_7alkyl(phenyl)p, C2_7alkenyl(phenyl)p, C2_7alkynyl(phenyl)p or Cl_7aLkylC3_8cycloalkyl;
(g) Reduction of a compound of structure (VIII):

(CH2)nA(CH2)mAr ~ (VIII) wherein R, A, Ar m and n are as hereinbefore defined and is a counter ion;

and optionally thereafter forming a salt.
In process (a) the reaction between a compound of structure (II) and a compound L(CH2)mAr can take place under conditions which depend on the nature of the group L. For example, when L is halogen or a sulphonic acid residue such as a tosylate or mesylate, the reaction is carried out under standard conditions in a solvent, optionally in the presence of a base. When a fluoro-substituted aryl F-Ar is employed in process (a), the reaction is effected in the presence of a strong base SUBSTITUTE SHEET

W092/02502 2 ~ 9 1 PCT/GB91/01340 _ g _ such as sodium hydride, and in an inert organic solvent such as dimethyl formamide. Prefera~ly the aryl group is substituted by an activating group such as CF3 or N02.

The reaction between a compound of structure (III) and a compound of structure HA1(C~2)mAr can take place under conditions which depend on the nature of L1 and A. For example when L1 is hydroxy, m is 0 and Al is oxygen or sulphur, the reaction is carried out in the presence of diethyl azodicarboxylate and triphenyl phosphine. Such a reaction is known as the Mitsunobu reaction (as described in Synthesis 1981, 1).
Alternatively the leaving group Ll may be for example a halogen atom or a sulphonyloxy group eg. methane-sulphonyloxy or p-toluenesulphonyloxy. In this case the reaction may be effected in the presence or absence of solvent at a temperature in the range 0 to 200C

The reduction o~ a compound of structure (I~) can be e fected 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) 2S 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 SUBSTITUTE SHEET

2 ~

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 s~ructure (II) can be prepared from the corresponding compounds in which R i5 hydrogen, by alkylation under standard conditions. For example, compounds o~ structure ~II) in which R is n-pentyl can be prepared from the corresponding precursor in which R is hydrogen by reaction with an n-pentylhalide such as n-pentyl bromide in a suitable solvent, such as methyl ethyl ketone, or a Cl_4alkanol such as ethanol, in the presence of a base, such as potassium carbonate, or dimethylformamide in the presence of an iodoalkane.

The corresponding compounds of structure (II) in which R is hydrogen are available commercially, known in the literature or can be prepared by standard techniques;
for example by reduction of the corresponding 4-hydroxy-alkylpyridine.

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

SUBSTlTlJTE 5HEET

WOg2/02502 2 ~ 3 ~ ~ 9 1 PCT/G891/01340 (CH2)nOH
(IX) 1 0 x~

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

Compounds of structure (III) wherein Ll is OH can be prepared as described for compounds of structure (II), and compounds of structure (III) wherein L~ 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 ~4 is a group -(CH2)nN(Rl)CtCH2)m_lAr can be prepared by reacting a compound of structure (II) wherein Al represents NRl with an acylating agent corresponding to the group -(CH2)mAr, for example an acid chloride Cloc(cH2)m-lAr~

Compounds of structure (rv) wherein R4 is a group -(CH2)n_lCN(Rl)(CH2)mAr may be prepared for example by reaction of a corresponding compound wherein R4 represents -(CH2)n_lCO2H or an activated derivative thereof such as an ^id halide, ester or anhydride, with an amine of formula HN(Rl)(CH2)m Ar. It will be appreciated that when the acid itself is employed, reaction with the amine should be effected in SUBSTITIJTE SHEET

W092/02502 PCT/GBgl/01340 2~

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 neceæsary 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 hydro~ysis. 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 Sl,lBSTlTlJTE SHEET

W092/02502 ~ 3 ~ ~ 9; PCTtGB91/01340 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-l), in the presence of a strong base such as sodium amide in liquid ammonia or an alkyl S lithium. The resulting substituted pyridine is then reacted with a compound RL2, as hereinbefore defined, to give a quaternary pyridinium compound of f ormula (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 o~ 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 addic-ion 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 SUBSTITIJ~E SHEET

W~92/025~ PCT/GB91/01340 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 t~ereof and a pharmaceutically acceptable carrier or excipient.

The compounds of structure (I) and their pharmaceutically acceptable salts which are active when gi~en 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 o~ 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.

SUBSTlTlJTE S~IEET

W092/02502 2 ~ ~ 3 ~ ~1 PCTtGB91/01340 A composition in the form of a capsule can be prepared using routine encapsulation procedure~. 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, poly~inyl pyrrolidone, lecithin, arachis oil or s~same oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.

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

Each dosage unit for oral administration contains preferably from l to 250 mg (and for parenteral administration contains preferably from O.l to 60 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base.
The daily dosage regimen for an adult patient may be, for example, an oral dose of between l mg and 500 mg, preferably between l mg and 250 mg, eg.-S to 200 mg or an intravenous, subcutaneous, or intramuscular dose of between O.l mg and lO0 mg, preferably between O.l mg and 60 mg, eg. l to 40 mg of the compound of the formula (I) SU~3STIT~JTE SHEEI

2a~il3'~

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.

SUBSTlTlJTE SHEET

W092/02502 PCT/GB9t/0l~0 2C3~3~1 DATA

Ca2+ Current Measurement Cel~ Dre~arations 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;
buf~ered 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-Cl, 130; -glucose, 10; HEPES, 10; MgCl2, 1; buffered to pH 7.3 with T~ OH. Barium was used as the charge carrier as ~ this acsists in current isolation and calciu~ 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 Ca currents.

All experiments were performed at 21 to 24C.
Whole cell currents were recorded using ~ist EPC-7 amplifiers and stored, digitised for later analysis using SVBSTITlJTE SHEET

W092/02502 PCT/GB9ltO1~0 PC based software similar to that described previously (Benham & Tsien, Journal of Physiology (1988), 404, 767-784).

RESUITS

Ca2+ currents Peak voltage gated Ca2+ channel currents of up to l0 nA from dorsal root ganglion neurons were recorded using lO mM Ba2+ as charge carrier. Currents were evoked from a holding potential of -80 mV to a test potential of O or +lO mV every lS 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. ~he rundown rate was measured in control conditions and extrapolated through the time o~ drug application to derive a control value to relate the drug a~fected cùrrent to. Block by 20 ~M
drug was assessed 3 minutes a~ter drug application.

Compounds o~ the invent.cn save percentage inhi~ition of plateau Ca2+ current in the range 30 to 2S 100%

TOXICOLOGY

The compound of Example 9 did not show any adverse toxicological effects when administered to rats at a dose of l0 mg/kg, i.v.

SUBSTlTlJTE SHEET

W092/02502 2 ~ ~. 3 `~ 9 ~ PCT/GB91/01340 PHARMACEUTICAL FORMULATIONS

l. Formulation for intravenous infusion Compound of structure (I) 0.l - 60 mg Sodium hydroxide/hydrochloric acid to pH ca 7 polyethylene glycol 0 - 30 ml propylene glycol 0 - 30 ml alcohol 0 - l0 ml water to l00 ml 2. Formulation for bolus in~ection Compound of structure (I) 0.l - 60 mg sodlum hydroxide or hydrochloric acid to pH ca 7 polyethylené glycol 0 - 2.5 ml alcohol 0 - 2.5 ml wc er to 5 ml A toxicity adjusting agent eg. sodium chloride, dextrose or mannitol may also be added.

3. Tablet for oraI_administration mq/tablet Compound of structure (I) 25 lactose 153 starch 33 crospovidone 12 microcrystalline cellulose 30 magnesium stearate 2 SUBSTITUTE SHEET

W092/02502 PCT/GB91/Ot~O
æ~

EXAMPLES

Intermediate PreParations (i) 4-(2-Hvdroxvethvl)-l-PentvlPi~eridine A mixture of 4-(2-hydroxyethyl)piperidine (20g), 1-bromopentane (19.2g), potassium carbon~te (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-Hvdroxveth~l)-l-cinnamYlPiPeridine A mixture of 4-(2-hydroxyethyl)piperidine (16.4g), cinnamyl 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.

SUBSTITUTE SHEET

W092/02502 ~ ~ 3 ~ ~ 9 1 PCT/GB91/Ot~O

(iii) 4-(3-H iroxvProPvl)-l-~entvlPvridinium bromide A solution of 4-(3-hydroxypropyl)pyridine (27.43g), l-bromopentane ~37.76g) and acetone ~SOml) 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 lOOml) and dried at 50C O.lmmHg to give the title compound which was used without further purification.
~iv) 4-~3-HvdroxvDroPvl)-l-Dentvl~iDeridine A mixture of 4-~3-hydroxypropyl)-1-pentylpyridinium bromide (8.65g), platinum oxide ~O.Sg) 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 extractec with dichloromethane (3 x 75ml). The extracts were _ombined, dried over magnesium sulphate and the solvent was removed to give the title compound as an oil (4.68g).

v) 4-Hvdroxvmethvl-l-oentvlPvridinium bromide A solution of 4-hydroxymethylpyridine ~25g), 1-bromopentane ~43. g) 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 lOOml) and dried at 50C O.lmmHg to give the title compound which was used witnout further purification.

SUBSTITUl-E SHEET

~ a ~

~vi) 4-Hvdroxvmethv1-l-PentYlPiperidine A mixture of 4-~3-hydroxypropyl)-1-pentylpyridinium ~romide ~5.2g), platinum oxide ~0.4g) and éthanol (lOOml) 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-Hvdroxv-l-~entvl~Peridine 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-HvdroxYethvl)-1-ProDvlPi~eridine A mixture of 4-(2-hydroxyethyl3piperidine (5g), 1-bromopropane (4.87g), potassium carbonate (5.5g) and ethanol (lOOml) 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 SUBSTIT~JTE SHEEl 2 ~

compound as an oil (5.lg) which was used without further purification.

(ix) 4-(2-Hvdroxvethvl)-1-(3-~henvl)ProPvlPiPeridine A mixture of 4-(2-hydroxyethyl)piperidine (lOg), 1-bromo-3- ~henyl)propane (15.Bg), 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 th~ residue distilled, to give the title compound as an oil (14.52g) (b.p. 141C @ 0.2mmHg) (x) 4-(2-HvdroxYethvl)-1-hePtvlPiPeridine 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 ~lO.Olg) (b.p. 110C @ O.lmmHg) (xi) 4-~2-Hvdroxvethvl)-1-(2-ethvl)butvl~ieridine A mixture of 4-(2-hydroxyethyl)piperidine (20g), l-bromo-2-ethylbutane (17.9g), potassium carbonate (26g) and ethanol (4~0ml) was heated at reflux for 4 days. The solution was filtered, and the solvent was removed under SUBSTlTtJTE SHEET

WO 92/02502 PCT/GB9l/01340 ~,a~ 3'~ , reduced pressure. The residue was distilled, to give the title compound as an oil (29.61g) (b.p. 102C @ 0.3mm~g) (xii) l-CYclohexvlmethvl-4-(2-hvdroxvethvl)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.
$he 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. 165C Q
O.SmmHg) (xiii) 4-(2-hvdroxvethvl)-1-(3-methvlbutvl)~iPeridine A mixture of 4-(2-hydroxyethyl)piperidine (20g), l-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. 98C ~ O.lmmHg) (xiv) l-~enzvl-4-(2-hvdroxvethvl)Pi~eridine 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. 120-130C @ O.lmmHg) SUE~STlTlJTE SHEET

W092/02S02 PCT/GB91/Ot340 ~3~

(xv) 4-f2-(4-FluoroPhenvl)ethvll-Pvridine 4-Picoline ~30g) was added over 30 minutes to a suspension of sodium amide (12.56q) 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 (SOg) 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. 69-70.5C

(xvi) 4-~2-(4-FluoroPhenvl)ethYll-l-PentYlpyridinium bromide A mixture of 4-[2-(4-fluorophenyl)éthyl)pyridine (5g), 1-bromopentane (7.0g) and acetone (lOml) 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 compouna (7.32g), m.p. 130 - 131C.

(xvii) 4-~2-(4-FluoroPhenoxv)ethvll-~i~eridine hvdrochloride A mixture of l-benzyl-4-~2-(4-fluorophenoxy)ethyl~piperidine (1.50g), 10% palladium on car~on (0.6g) and ethanol (120ml) was shaken under an SUBSTITIJTE SHEET

W092/02502 PCT/GBg1/01340 2aC~

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 -123C.

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~

Exam~le 1 4-~2-(4-Fluoro~henoxv)ethYll-l-PentYlPi~eridine 1~ hvdrochloride A solution of 4-~2-hydroxyethyl)-1-pentylpiperidine (2.0q), 4-fluorophenol (1.12g) and triphenylphosphine (2.62g) in tetrahydrofuran ~40ml) was treated with die~hyi azodicarboxylate (1.74g) in tetrahydrofuran ~lOml). The resulting solution was stirred at room temperature for 18 hours, the solvent was removed and the residue was chromatographed on silica gel eluted with methanol/dichloromethane. The resulting oil was dissolved in ethyl acetate ~50ml) and treated with ethereal hydrogen chloride, the precipitate was collected by filtration and recrystallised (methanol/ethyl acetate) to give the title compound (l.lg), m.p. 167-169 C.

Found: C, 6S.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%.

SUBSTIT~JTE SHEET

W092to2S02 PCT/GB9l/Ol~
2 ~

Exam~le 2 4-~2-(3,4-MethvlenedioxvphenoxY)ethvll-l-~ent~lPi~eridine hvdrochloride 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 (lOml). The resulting solution was stirred at room temperature for 18 hours, the solvent was removed and the residue was chromatographed on silica gel eluted with methanol/dichloromethane. The resulting oil was dissolved in ethyl acetate (SOml) and treated with ethereal hydrogen chlor~de. The precipitate was collected by filtration and recrystallised (methanol/ethyl acetate~ to give the title compound (0.45g), m.p. 134 - 136C.

Found: C, 64.12; H, 8.S2; N, 4.03; Cl, 10.00%.
(ClgH29N03.HCl) requires: C, 64.12; H, 8.50; N, 3.93;
Cl, 9.96%.

Exam~ie 3 4-(2-Phenoxvethvl)-l-PentvlPi~eridine hvdrochloride 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 SUBSTITUTE SHEET

WO92/02sO2 PCT/GB91/013~

2 ~

recrystallised from methanol/ethyl acetate (0.8ag), m.p. 158 - 159C.

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%

Exam~le 4 4-r2-(3-TrifluoromethvlDhenoxv)ethvll-l-DentvlPiDeridine hvdrochloride The title compound was prepared in a similar manner to example 1 from 4-~2-hydroxyethyl)-1-pentylpiperidine (2.0g), ,a,a, 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. 154C.
Found: C, 59.51; H, 7.62; N, 3.80; Cl, 9.49$
(ClgH28F3NO.HCl) requires: C, 60.07; H, 7.69; N, 3.69;
Cl, 9.33%

Exam~le 5 4- r 2-(4-PhenvlDhenoxv)ethvll~ entvlDiDeridine 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 SUBSTITUTE SHEET

W092/02502 PCT/GB91/Ol~
2 `3 ~

~2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from methano}/ethyl acetate (0.4g), m.p. 205-206C.
s Found: C,73.77 ; H, 8.88; N,-3.66; Cl, 9.14%
(C24H33NO.HCl) requires: C, 74.2; H, 8.8; N, 3.6;
Cl, 9.27%

Exam~le 6 4-t2-(4-Benzvloxv~henoxv)ethvll~ entvlPiPeridine hvdrochlor~de The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (l.Og), 4-benzyloxyphenol (l.OOg), 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 (O.lg), m.p. 168 - 169C.

Found: C, 70.42; H, 8.59; N, 3.50; Cl, 8.29~
~C25H35N02.HCl,0,5H20) requires: C, 70.31; H, 8.73;
N, 3.28; Cl, 8.20%

Exam~le 7 4-~2-(3-DimethvlaminoPhenoxv)ethVll-l-DentVl~i~eridine dioxalate SUBSTITU'rE SHEET

2a~9~

The title compound was prepared in a similar manner tO
example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (2.2g), 3-dimethylaminophenol (l.Sg), 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. 128-130C.

Found: C, 57.82; H, 7.63; N, 5.62%
(C20H34N20.2C2H204) requires: C, 57.83; H, 7.63; N, 5.62%

ExamPle 8 4-r2-(4-MethoxvPhenoxv)ethvl~ Dentvlpi~eridine oxalate The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (l.Sg), 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. 119-121C.

Found: C, 63.54; H, 8.47; N, 3.69%
(Cl9H31N2 c2H2o4) requires C, 63.79; H, 8.35; N, ExamDle 9 4-~2-(3,4-DichloroPhenoxv)ethvll-1-~entyl~i~eridine hvdrochloride SUBSTITUTE SHEET

WO92/02502 PCT/GB91/01~0 2 ~ 9 1 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 - 178C.

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 1 0 4-~2-~4-CvanoPhenoxv)ethv~ entvlplperidine hvdrochloride The title compound was prepared in a similar manner to example 1 from 4-~2-hydroxyethyl)-1-pentylpiperidine ~2.0g), 4-cyanophenol (l.lgg), 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 (0.9Sg), m.p. 173 - 174C.
Found: C, 67.69; H, 8.84; N, 8.28; Cl, 10.85~
(ClgH28N2O.HCl) requires: C, 67.74; H, 8.68; N, 8.31;
Cl, 10.52%

SUBSTlTlJl'E SHEET

49~

Example 11 4-t2-(4-Chlorophenoxv)ethYll-1-PentvlPiPeridine hvdrochloride The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (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 -186C.

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;
C1, 20.47%

ExamDle 12 4-~2-(5,6,7,8-Tetrahvdro-2-naDthoxv)ethvll-~-PentvlPiPeridine 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-2-napthol (1.48g), triphenylphosphine (2.62q) and diethyl àzodicarboxylate (1.74g). Treating the product with oxalic acid gave a white solid which was recrystallised from methanol/ethyl acetate (0.81g), m.p. 147C.
Found: C, 68.88; H, 9.07; N, 3.40%
(C22H35NO.C2H204) requires: C, 68.71; H, 8.B9i N, 3.34%

SVBSTITUTE SHEET

W092/02~02 PCT/GB9l/Ot~O
2 ~

ExamPle 13 4-r2-(5,6,7,8-Tetrah~dro-l-napthoxv)ethvll-l-5 Pentvl~iPeridine 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 tl.48g), triphenylphosphine (2.62g) and diethyl azodicarboxylate ~1.74gl. Treating the product with oxalic acid gave a white solid which was recrystallised from methanol/ethyl acetate (1.14g), m,p. 162C, ~S Found: C, 68.03; H, 8.73; N, 3.40~
(C22H35NO.C2H204Ø25H20) requires: C, 67.97; H, 8.84;
N, 3.30%

ExamDle 14 4-~2-(4-Nitro-3-trifluoromethYlPhenoxY)ethYll-l-PentvlPiPeridine hvdrochloride 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 - 141C.

Found: C, 53.80; H, 6.50; N, 6.45; Cl, 8.30%

SUBSTlTlJTE SHEET

W092/02502 PCT/GB91/01~0 2~8~

(ClgH27F3N203.HCl) requires: C, 53.71; H, 6.64; N, 6.59;
Cl, 8.34%

Exam~le 15 s 4-~2-(3-Fluoro~henoxv)eth~ l-pentvlDi~eridine hvdrochloride The title compound was prepared in a similar manner tO
example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (l.Sg), 3-fluorophenol (0.84g~, triphenylphosphine ~1.97g) and diethyl azodicarboxylate (1.31g). Treating the product with hydrogen chlorlde gave the title compound as a white solid from methanol/ethyl acetate ~1.21g), m.p. 157-159C.

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%
ExamDle 16 4-t2-(4-MethvlDhenoxv)ethvll-l-pentvl~i~eridine hvdrochloride The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (l.SOg), p-cresol (0.81g), triphenylphosPhine (1.96g) and diethyl azodicarboxylate (1.31g). Treating the product with hydrogen chloride gave the tltle compound as a white solid from methanol/ethyl acetate (1.09g), m.p. 164 - 166C.

SVBSTlTlJTE SHEET

~3~31 Found: C, 70.00; H, 9.69; N, 4.15; Cl, 10.82%
(ClgH31NO.HCl) re~uires: C, 70.02; H, 9.90; N, 4.30;
Cl, 10.88~ .

ExamPle 17 4-r2-(4-Benzvluhenoxv)ethvll-l-~entvl~i~eridine oxalate The tltle compound was prepared in a similar manner to example 1 from 4-~2-hydroxyethyl)-1-pentylpiperidine (1.50g), 4-benzylphenol ~1.38g), triphenylphosphine (1.95g~ and diethyl azod~carboxylate (1.31g). Treating the product with oxal~c ac~d gave the title compound as a ~5 wh~te solid from methanol/ethyl acetate (0.377g), m.p. 166 - 16BC.

Found: C, 70.86; H, 8.02; N, 3.07%
(C25H35NO.C2H204) requires: C, 71.18; H, 8.19; N, 3.07%
Exam~le 18 4-r2-(3-chloroPhenoxv)ethvll-l-~entvl~i~eridine hvdrochloride The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (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. lSl - 153C.

SUBSTlTlJTE SHEET

2a~8~9'~

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%
s ExamPle 1 9 4-8enzvl-1-pentvlpi~eridine hvdrochloride 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. 150C @ O.lmmHg) which was treated with hydrogen chloride to gave the title compound as a white solid from methanol/ethyl acetate (2.06g), m.p. 188 - 190C.

Found: C, 70.00; H, 9.69; N, 4.15; Cl, 10.82%
(ClgH31NO.HCl) requires: C, 70.02; H, 9.90; N, 4.30;
Cl, 10.88%

Exam~le 20 .
4- r2- (4-Fluorophenoxv)ethvll-l-cinnamvlPiPeridine oxalate A solution of 4-(2-hydroxyethyl)-i-Cinnamylpiperidine (2.94g), 4-fluorophenol (1.31g) and triphenylphosphine (3.15g) in tetrahydrofuran (50ml) was treated with diethyi azodicarboxylate (2.09g). The resulting solution was stirred at room temperature for 18 hours, the solven~

SUBSTITUTE SHEET

2 ~

removed and the residue chromatographed on silica gel eluted with methanol/dichloromethane. The resulting oil was dissolved in ethyl acetate (SOml) 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 (l.lOg), m.p. 180 C.

Found: C, 67.14; H, 6.60; N, 3.56%.
(C22H26FNO.C2H204) requires: C, 67.11; H, 6.57; N, 3.26%
ExamDle 21 4-f2-(3,4-DichloroPhenoxv?ethvl1-1-cinnamvlPi~eridine oxalate A solution of 4-(2-hydroxyethyl)-1-cinnamylpiperidine (2.02g), 3,4-dichlorophenol (1.34g) and triphenylphosphine (2.16~) in tetrahydrofuran (50ml) was treated with diethyl azodicirboxylate (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 - 180C.

Found: C, 60.07; H, 5.67; N, 2.92; Cl, 14.79%.

S~JBC i ITtJTE 5HEET

WO 92/02502 PCr/GB9l/01340 ~, 3 3 ~

~C22H25C12NO.C2H204) requires: C, 60.01; H, 5.67;
N, 2.92; Cl, 14.76%

ExamPle 22 s 4-f3-~4-FluoroPhenoxv)ProPvll-l-Pentylpiperidine hvdrochloride The title compound was prepared in a similar manner to 10 example 1 f~om 1-pentyl-4-(3-hydroxypropyl)piperidine (2.0g), 4-fluorophenol (l.OSg), 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), 15 m.p. 148 - 150C.

Found: C, 65.94; H, 9.2g; N, 4.15; Cl, 10.32%
(ClgH30FNO.HCl) requires: C, 66.36; H, 9.09; N, 4.07;
Cl, 10.31%
ExamDle 23 4- r 3-(4-E~enzYloxvphenoxv)Propvll-l-Dentvl~i~eridine hvdrochloride 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 30 the product with hydrogen chloride gave a white solid which was recrystallised from acetonitrile (1.48g), m.p. 163 - 164C.

SUBSTlTlJTE SHEET

2~g/~3 ~

Found: C, 72.43; H, 8.91; N, 3.31; Cl, 8.06%
(c26H37No2.Hcl1 requires: C, 72.28; H, a.86; N, 3.24;
Cl, 8.21%

ExamPle 24 4-(4-FluoroPhenoxv)methvl-l-~entvlPiPeridine hvdrochloride ~he title compound was prepared in a similar manner to example 1 from 1-pentyl-4-hydroxymethylpiperidine tl.lg), 4-fluorophenol (0.69g), triphenylphosphine ~1.63g) and die~yl azodicarboxylate (1.08g). Treating the product wit.. oxalic acid ga~e a white sol~d which was recrystallised from methanol/ethyl acetate ~0.25g), m.p. 111 -112C.

Found: C, 60.25; H, 7.56; N, 3.88%
(Cl~H26FNO.C2H204Ø5H20) requires: C, 60.3; H, 7.72;
N, 3.70%

ExamPle 25 4-(4-Fluorobenzvlox~ -Dentyl~i~eridine 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 SUBSTITUTE SHEET

WO 92/02502 PCr/GB91/01340 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 5 equi~ralent). 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%

Exam~le 26 4-Benzvloxv-1-~entvl~i~eridine oxalate Substitut1on 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 ac~tate yield (0.2g), 20 m.p. 119 - 121C.

Found: C, 64.63; H, 8.11; N, 4.14%
(C17H27NO.C2H2O4) requires: C, 64.98; H, 8.32; N, 3.99%

Exam~le 27 4-(4-FluoroPhenoxv)-1-~entvl~iPeridine 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 producz SUBSTITUTE SI-IEET

WO 92/02502 PCr~GB91/0l340 with oxalic acid gave a white solid which was recrystallised from methanol/ethyl acetate (0.65g), m.p. 164C.

Found: C, 60.91; H, 7.56; ~, 4.06%
(C16H24FNO-C2H2O4) requires: C, 60.83; H, 7.37; N, 3.9496 Exam~le 28 4-(3,4-MethvlenedioxvPhenoxY)-l-~entYlDiPeridine 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. 164C.

Found: C, 59.76; H, 7.22; N, 3.72%
~C17H25NO3.C2H2O4) requires: C, 59.83; H, 7.14; N 3 67%

Exam~le 29 4-~2-~4-Fluoro~henoxv)ethvll-l-~ro~YlPiDeridine oxalate The title compound was prepared ~n 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. 109-112C.

SUBSTlTlJTE SHEET

~ a 3~

Found: C, 59.66; H, 7.46; N, 3.B0%
(C16H24FNO.C2H204ØSH2O) requires: C, 59.50; H, 7.43;
N, 3.~6%
S
ExamPle 30 4- r2- (4-FluoroPhenoxv)ethvl1~ 3-PhenvlProPvl)piperidine hvdrochloride ~0 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). Treat~ng the product with hydrogen chloride gave a white solid which was recrystallised from methanol/ethyl acetate (0.65g), m.p. 111-113C.

Found: C, 68.04; H, 7.72; N, 3.83, Cl, 9.11%
(C22H28FNO.HCl.O.SH20) requires: C, 68.23; H, 7.75;
N, 3.60; Cl, 9.04%

ExamPle 31 4-~2-(4-FluoroPhenoxv)ethv~ -heDtvlDiPeridine hvdrochloride 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 SUBSTITI.JTE SHEET

WO92/02S02 PCT/GB9l/Ot~0 ~33~91 which was recrystallised from methanol/ethyl acetate (l.lg), m.p. 139-141C.

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%

Exam~le 32 4-~2-(3,4-MethvlenedioxvPhenoxv)ethvll-l-hePtvlPiPeridine hvdrochloride 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 azod~carboxylate (1.74g). Treating the product with hydrogen chloride gave a white soild which was recrystallised from methanol/ethyl acetate 10.65g), m.p. 129-231~.
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-i2-(4-FluoroPhenoxv)ethvl1-1-(2-ethvl)butvlPiPeridine oxalate The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-(2-ethyl)butylpiperidine (2~97g)~ 4-~luorophenol (1.08g), SUBSTITUTE SHEET

2~83~

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. 13?-138C.

Found: C, 63.24; H, 8.26; N, 3.58%
(ClgH30FNO.C2H2O4) requires: C, 63.46; H, 8.11; N, 3.52%

ExamPle 34 4-~2-(3,4-MethvlenedioxvDhenoxv)ethvll-1-(2-ethvl)butvlPiperidine 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. 133-134C.

Found: C, 62.05; H, 7.88; N, 3 . 39%
(C20H31NO3.C2H2O4) requires: C, 62.39; H, 7.85; N, 3.31%

ExamPle 35 l-Cvclohexvlmethvl-4-r2-(3,4-methvlenedioxvPhenoxv)ethvllPiPeridine hvdrochloride The title compound was prepared in a similar manner ro example 1 from 1-cyclohexylmethyl-4-(2-hydroxyethyl)piperidine (2.25g), sesamol (1.38g), SUBSTITUTE SHEET

2~3~491 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. 177~178C.

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%

Exam~le 36 4-r2-(4-Fluorophenoxv)ethvll-l-cvclohexvlmethvlPiperidine hvdrochloride 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). ~reating the product with hydrogen chloride gave a white solid which was recrystallised from methanol/ethyl acetate (0.98g), m.p. 178 - 180C.

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-methYlene-dioxvPhenoxv)ethyllpiDeridine hvdrochloride SUBSTITUTE~ SHEET

w092/02502 PCT/GB91/Ot34~

~3~'~9~

The title compound was prepared in a similar manner to example 1 from l-(3-methylbutyl)-4-(2-hydroxyethyl)-piperidine (2.0g), sesamol (1.38g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating S the product with hydrogen chloride gave a white solid which was recrystallised from methanol/ethyl acetate (0.17g), m.p. 16B-169C.

Found: C, 63.95; H, 8.50; N, 4.05; Cl, 10.17%
(ClgH29N03.HCl) requires: C, 64.12; H, 8.50; N, 3.94;
Cl, 9.96%

Exam~le 38 1-Benzvl-4-f2-(4-fluoro~henoxv)ethvll-1-~iPeridine hvdrochloride 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), tripnenylphosphine (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 -176C.
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%

SUBSTITUTE SHEET

W092/02502 PCT/GB9l/01340 2 ~

ExamPle 39 4-~2-~4-Fluorophenoxv)ethYll-1-(2-Phenvlethvl)-PiPeridine hYdrochloride A mixture of 4-[2-(4-fluorophenoxy)ethyl]-piperidine hydrochloride (0.57g) and sodium hydride (80% in oil) (0.146g) in dimethylformamide (lOml) 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 w~th ether. The ether phase was washed with d~lute hydrochloric ac~d and the resulting precipitate collected by filtration. Recrystall~sation from water ~ave th¢ tltle compound (0.228g) m.p. 210-212C

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%
Exam~le 40 4-l2-(4-FluoroPhenoxv)ethvll-1-(4-~henvlbut~ i~eridine hvdrochloride The title compound was prepared in a similar manner to example 39 starting from 4-[2-(4-fluorophenoxy)ethyl]-piperidine hydrochloride (l.Og), 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. 166-168C.

SU STlTlJTE SHEET

WO 92/02502 PCI'/GB91/01340 2~8~

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-DiPhenvlProPvl)-4-r2-(4-fluoroDhenoxy)eth PiPeridine oxalate A mixture of 4-[2-(4-fluorophenoxy)ethyl]-piperidine hydrochloride (2.0g), 3,3-diphenylpropane-1-ylmethanesulphonate (2.Z3g) and sodium hydride ~80% in oil) (0.58g) in dlmethylformamide ~40ml) was stirred at 60C u~der 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.

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-FluorothioPhenoxv~ethvll-l-DentvlDiPeridine hvdrochloride SUBSTITVTE SHE~T

W092/02502 PCT/GB9l/01340 2 ~ 3 1 The title compound was prepared in a slmilar 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.169-165C.

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%

Exam~le 43 4-[2-(3,4-DichlorothioPhenoxv)ethY11-1-~entvlPiPeridine hvdrochloride The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (2.009), 3,4-dichlorothiophenol (1.79g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride save a white solid which was recrystallised from ethyl acetate to give the title compound as a white crystalline solid (0.77g), m.p.158-159C.

Found: C, 54.41; H, 7.11; N, 3.48; Cl , 8.89%
(C18H27C12NS.HCl) requires: C, 54.48; H, 7.11; N, 3.53;
Cl , 8.93%

SUBSTlTlJTE SHEET

~a8~

ExamPle 44 l-Pentvl-4-~3 ~h nYlProPyl)piDeridine hvdrochloride A mixture of 4-(3-phenylpropyl)piperidine (Sg), 1-bromopentane (7.42g), potassium carbonate (lOg) and ethanol (125ml) was heated at reflux for 1~ 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.
Recrystal~isat~ an from ethyl acetate gave the tltle compound (4.19g), m.p. 188-189C.
Found: C, 72.56; H, 10.29; N, 4.58; Cl, 11.44%
~ClgH31N.HClØ25~20) requires: C, 72.56; H, 10.36; N, 4.45; Cl, 11.27%

Exam~le 45 4-r2-(4-~luoro~hen~l)ethYll-l-~entvlPiPeridine hvdrobromide A mixture of 4-[2-(4-fluorophenyl)ethyl]-1-pentylpyridinium bromide (3.0g), platinum oxide (0.6g) and ethanol (lOOml) 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. 173-174C.

SIJBSTlTlJTE SHEFr 2 ~

ExamPle 46 4-f2-(4-NitroPhenoxv)ethvll-l-PentvlPiPeridine hvdrochloride S A mixture af 4-(2-hydroxyethyl)-1-pentylpiperidine (2.5g), sodium hydride (60% in oil) (0.42g) and dimethylformamide (20ml) was heated at 50C 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 chr matographed on silica gel, with mèthanol/dichloromethane as eluent,and the product was treated with hydrogen chlor~de 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.174-176C.

Found: C, 60.35; H, 8.15; N, 7.85; Cl , 9.70~
(C18H28N03.HCl) requires: C, 60.58; H, 8.19; N, 7.85; Cl, 9.93%

ExamDle 47 .
4-~2-(2-FluoroPhenoxv)ethvll-l-PentvlDiPeridine hvdrochloride The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (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.150-152C.

S 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%

ExamDle 48 4-f2-(4-tert-Butvl~henoxv)ethYll-l-Pentvl~i~eridine hvdrochloride The t~tle compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylp~perid~ne (1.5g), 4-tert-butylphenol (1.127g), triphenylphosphine (1.96g) and diethyl azod~carboxylate (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.l89-191C.

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%

Exam~le 49 l-Pentvl-4-~2-(4-trifluoromethoxv~henoxv)ethvllPi~eridine hvdrochloride The title compound was prepared in a similar manner to example 1 from 4-~2-hydroxyethyl)-1-pentylpiperidine SUE3STlTlJTE SHEET

W092/02502 PCT/GB9t/01340 ~ ~J ~

(1.5g), 4-trifluoromethoxyphenol (1.335g), triphenylphosphine (1.9-6g) 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 (O.95g), m.p.154-156C.

Found: C, 57.29; H, 7.31; N, 3.52; Cl , 8.59%
(C1gH28F3NO2.HC1) requires: C, 57.64; H, 7.38; N, 3.54;
Cl, 8.96%

Exam~le 50 4-~2-(4-iso-Pro~vlPhenoxv)ethvll-1-PentvlPiDeridine hvdrochloride The title compound was prepared in a similar manner to example 1 from 4-~2-hydroxyethyl)-1-pentyipiperidine (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.185-187C.
2~
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%

W092/02502 PCT/GB91/01~0 2 ~

Exam~le 51 4-~2-(3-iso-Pro~vl~henoxv)ethvll-1-PentYlPiPeridine hYdrochloride The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-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 gi~e the title compound as a white crystalline solid (O.Sg), m.p.l66-168C.

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-r2-(3-tert-ButvlPhenoxv)ethvll-~-~entvlDiDeridine hvdrochloride 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), ~riphenylphosphine (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.171-173C.

Found: C, 71.80; H, 10.57; N, 3.88; C1 , 9.67%

.

W092/02502 PCT/GB91/013~
2 ~

~C22H37NO.HC11 requires: C, 71.8; H, 10.41; N, 3.81; Cl, 9.63%

ExamPle 53 4-~2-(2-~henvl~henoxv)ethvll-1-PentvlPi~eridine hvdrochloride The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (l.Sg), 2-phenylphenol (1.28g), triphenylphosphine (1.96g) and diethyl azodicarboxylate (1.19g). Treating the product with hydrogen chloride gave a white salid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (1.05g), m.p.175-177C.

Exam~le 54 l-Pentvl-4-r2-(4-trifluoromethvl~henoxv)ethvll-~i~eridine 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-Fluoro-trifluoromethylbenzene (1.64ml) was added and the mixture was refluxed for 18 hours. The m~xture 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 SUBSTlTlJTE SHEET

9 ~

recrystallised from ethyl acetate/methanol to give the title compound. (O.Sg), m.p.101-103C.

Found: C, 57.76; H, 7.00; N, 3.27%
S (Cl9H28F3NO C2H204 0 1 H20) requires: C, 57.9; H, 6.9; N
3.2%

ExamPle 55 4-l2-(3,5 Dichloro~henoxv)ethvll-l-~entvlPiDeridine hvdrochloride 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). Treatlng 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.l68-170C.

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;
~l-, 9.30; Cl, 27. 93%
ExamDle 56 4-~2-(3,4-Dichloro~henoxv~ethvll-l-heDtvlDiDeridine hvdrochloride 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~d~1 12.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from ethyl acetate/methanol to gi~e the title compound as a white crystal}ine solid (0.7g), m.p.l38-139C.

Found: C, 58.87; H, 7.B8; N, 3.50; Cl , 8.68; Cl, 26.00%
(C20H31C12NO.HCl) requires: C, 58.76; H, 7.89; N, 3.43;
Cl-, 8.68; Cl, 26~01%
Exam~le 57 4-~2-(3,4-Dichloro~henoxv)ethvll-1-~3-phenvlPro~y~Lp-iperidine hvdrochloride 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.l37-138C.

Found: C, 61.24; H, 6.45; N, 3.36; Cl , 8.7%
(C22H27C12NO.HC1Ø1 H20) requires: C, 61.56; H, 6.34; N, 3.27; C1, 8.30%

SUBSTIT~JTE SHEET

Exam~le 58 1-Cyclo~ro~ylmethvl-4-~2-(4-fluoroPhenoxv)ethvll-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.

Found: C, 61.95; H, 7.05; N, 3.91%
(C17~24FNO.C2H2O4) requires: C, 62.11; H, 7.13; N, 8.81%

Exam~le 59 1-(3,3-Di~henvlpro~-2-envl)-4-t2-(4-fluoroDhenOxY)ethvll-Piperidine 1-(3,3-DiPhen~l~roP-2-envl)-4-~2-(4-fluorophenoxv)ethvll-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 SUBSTITUTE SHEET

W092/02502 PCT/GB9l/Ot~O

_ 59 _ 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. (0.6B7g), m.p.l74-176C.

Found: C, 70.84; H, 6.34; N, 2.93%
(C28H30FNO.C2H204) requires: C, 71.27; H, 6.38; N, 2.77 Exam~le 60 4 ~2-(2-3enzvlphenoxv)ethvll-l-PentvlPiPeridine hvdrochloride The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (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.ll9-120C.

Found: C, 73.32; H-, 8.94; N, 3.61; Cl, 8.70%
(C25H35NO.HClØ3H20) requires: C, 73.59; H, 8.89; N, 3.43; Cl, 8.69%

SUBSTITIJTE SHEET

Claims (14)

Claims:

1. A compound of structure (I):

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

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

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

4. A compound according to any of claims 1 to 3 wherein n is o 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-heptylpiperidine, 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):

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

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

(II) 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 N-R1, reduction of a compound of structure (IV) :

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

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

(V) (wherein R, L1, 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) :

(VII) wherein R5 is C1-alkyl(phenyl)p, C2-7alkenyl(phenyl)p, C2-7alkynyl(phenyl)p or C1-7alkylC3-8cycloalkyl;

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

(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 manufacture 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 (1) 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.