AP279A - 4 substituted piperidine derivatives, processes for their preparation pharmaceutical compositions containing them and their use in therapy. - Google Patents

Abstract

Compounds of structure (I) in which R is C1-8alkyl (phenyl) p, C2-8akenyl (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; n 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

COMPOUNDS

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):

R in which

R is C^.galkyl(phenyl)p, C₂ _₈alkenyl(phenyl)p, C₂_₈alkynyl(phenyl)p, C₃_₈cycloalkyl or

C₁_galkylC₃_gCycloalkyl;

p is 0 to 2;
n	is	0	to 6;
A	is	a	bond, oxygen, sulphur or NR^;

R¹ is hydrogen, C^.galkyl or phenylC₁_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 Cj.galkyi(phenyl)p, C₂_₈alkenyl(phenyl)p, C₂__galkynyl(phenyl)p, C₃_₈cycloalkyl or C₁_₈alkylC₃_₈cycloalkyl.

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

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

Preferably R is C₁_₃alkyl(phenyl)p in which p is 0 or l,

i.e. C^.galkyl, such as n-pentyl, or phenylC\_₈alkyl such as phenylpropyl, or R is C₂_₈alkenyl(phenyl)p where p is 1, such as cinnamyl.

Suitably, n is 0 to 6; preferably n is 0 to 3; most 10 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 C₁_₂alkylenedioxy group such as a 3,4-methylenedioxy group or by 1 to 3 substituents selected from halogen, Cj^alkoxy, nitro, SC₁_₄alkyl, NR²R² (in which each R² group can be H or C₁_₄alkyl) , OCF₃, C^^alkyl,

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- 3 trifluoromethyl, CN, optionally substituted phenyl, optionally substituted phenylCj_₄alkyl and optionally substituted phenylC₁_₄aikoxy. 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 phenylC₁_₄alkyl groups include, for example benzyl. Suitable optionally substituted pheny1C._₄alkoxy groups include, for example benzyloxy groups.

Suitable substituents for said optionally substituted phenyl, phenylC₁_₄alkyl and phenylCj_₄alkoxy groups include for example halogen, C₁_₄alkyl, C₁_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 at least one heteroatom, such as pyridyl, thienyl, quinolinyl, tetrahydroquinolinyl and imidazolyl rings. The heteroaryl ring can be linked to the remainder of structure (I) via a carbon atom or via a hetero atom, e.g. a nitrogen atom.

Suitable substituents for said heteroaryl rings include, for example, 1 to 3 substituents selected from halogen, C₁_₄alkyl and Cj_₄alkoxy.

Alkyl groups present in the compounds of structure (I) , alone or as part of another group, can be straight or branched.

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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-methylenedicxyphenoxy)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,

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- 5 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 l-cyclopropylmethyl-4-[2-(4-fluorophenoxy) ethyl]10 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):

(^cH₂)n^AlH

(II)

BAD ORIGINAL

AP Ο Ο Ο 2 7 9

ΣΣ34 3

as described fcr -true rh a ccr.pcund cf scrcc and Ar are as describe IS 3. _ β <3 V J. Γ. O' CTO up * (b) fcr ccrpourds cf structure (I) in which A is 0, NR¹, reaction of a compound of structure (III):

or

• I

».1 in which n and R are as described for structure and

L¹ is a group displaceable by a nucleophile, with a

2G ccspouna or scrucrure nA~ (C*C }-^Ar where r. and .tr . ι are as described fcr structure ,1) arc A is as described fcr structure (1Z‘; cr (c) for compounds of structure (I) *.._r reduction cf a compound of structure (:

is NR-

AP Ο Ο Ο 2 7 9 :::-,) ^n;r-,'C(CH_?) ,_.Ar or - (CH-) ίν fR-} < CH<-Ar, ar.d n, m, R ar.d Ar are as described fcr structure (I) ;

(d; fcr compounds cf structure (I) ir which A is a herd, reaction cf a compound of structure (V) :

(f^H2' η-ί-η (V) (vherein R, L¹, n and m are as hereinbefore defined) with a compound of structure X*.-.r in which A_r is as described fcr structure (1'. and X- is an alkali metal;

(e) intrcduct formula (VI) :

:n of the crcuo R intc a csrccur.d cf (VI) by reaction ••ith a ccr.ccuru leaving group;

.’herein L² is a (f) Reduction of a compound cf formula (VII) :

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COR' wherein R⁵ is C1_7alkyl(phenyl)p, C2_7alkenyl(phenyl)p, ¹⁰ C2_₇alkynyl(phenyl)p or C₁_₇alkylC₃_₈cycloalkyl;

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

H (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)_ffiAr 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

bad original

AP Ο Ο Ο 2 7 9

s uch	as	sodium hydriie, and in an inert	organic selven
such	as	dimethyl formamide. Preferably	the aryl croup
subst	* —	uted by an activating group such	as CT3 cr N02·

The reaction between a compound of structure (Ill;. :d a ccrpcurd of structure EA¹(CH₂)_mAr can take place under conditions which depend on the nature of iA and A. For example when lA is hydroxy, m is O and A¹ is oxygen cr 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 1931, l) . Alternatively the leaving group lA nay te for example a ar.:

halogen atom	C -Γ	a sulpho	nylo
su Iphc r.y loxy	or	p-toluen	esul
reaction may	te	effected	in
solvent at a	tern	nerature	in

cryloxy. _n tris case tn« ec in the presence or absence of

The reduction cf 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 cf structure (IV) can be prepared (for example as described below) and reduced in a 'one-pot' reaction, without isolation of compound (IV)

Tne react.cn oetweer. a cc:

. 1 , rur.d of structure a compound of structure X‘Ar car. take place under standard conditions known to these skilled in the art trbcn-carbcn bends.

(. · t and

The reaction of a compound of structure (V_) with Rlr according to process (e) may be effected m conventional manner, for example in an organic solvent, such as dimethyl formamide. The leaving group l? may be for example a halide such as bromide cr chloride, an acyloxy group such as acetoxy or chloroacetoxy cr a

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- 10 p-toluene sulphcnyicxy. When L² is a halide the

reaction is	preferably carried out in the creser.ce cf a
weak case s'	uch as potassium carbonate, and when I2 is
Sil _ρ?ΪΟΩν «C17	/, a strong base such as sodium hydride or
5 potassium m-	-butexide may b : employed.
Reduct:	ion of a compound of formula (VII) may be
effected us:	Lr.g standard reducing agents such as lithium

alum.inium hydride.

λ c S 31 ί	Lon cf a compound of formula (VIII) may be
effected fc:	: example by hydrogenation, using a noble

metal catalyst such as platinum, palladium cr platinum oxide, suitably in a solvent such as an alcohol eg.

ethane 1.

Ihe cc:	•.pounds of structure (II) can be prepared from
the ccrrespc	ending compounds in which R is hydrogen, by
alkylation u	:nder standard conditions. For example,
20 compounds oi	: structure (II) in which R is n-pentyl can be
prepared fro	:m the corresponding precursor in which R is
hydrogen by	reaction with an n-pentylhalide such as
n-pentyl bro	mode in a suitable solvent, such as methyl

ethyl ketene, or a C-.^alkanol such as ethanol, in the 25 presence cf a base, such as potassium carbonate, or

dimethylf orm	mmide in the presence cf an icdcalkane.
The cor	responding compounds of structure (II) in
which R is h	ydregen are available commercially, known in
30 the literate	re cr can be prepared by standard techniques;

fcr example by reduction of the corresponding 4-hydroxya1ky1pyr i d i ne.

Alternatively, compounds of structure (II; in which 35 A¹ is oxygen can te prepared by reduction of a compound of structure (IX):

_Ap 0 ο 0 2 7 9

214 3

I

R in which R and n ana as described fcr structure (I) and X^- is a counter ion.

Compounds of structure (III) wherein I¹ is CH can be prepared as described fcr compounds of structure (II) , and compounds cf structure (III) wherein L* is a halogen atom, cr a mesyloxy or tosylcxy group can be prepared from the corresponding alcohol in conventional cf structure hereir is a group

-(CH₂) -d?:7Λ) 1(CH_Z)prepared by reacting a compound cf structure (II; wherein A³reuresents NS¹ with an acylating agent corresponding tc the grouo - (Ch-,) _Ar, for examole an acid chloride Z1QC ;in-' Ar.

Ccmoc ::!₂; _η-ι’^:; V¹! (CH.:

m* example by reaction cf R⁴ represents -(CH₂)_n__L derivative thereof such anhydriie, with an amir. Ar. It will be appreci employed, reaction with are

-herein R¹ s a group may be prepared for a corresponding compound wherein CO₂H or an activated . as an acid halide, ester or e of formula HN(R*)(CH₂)_m ated that when the acid itself is the amine should be effected in

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- 12 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 triphenyImethyl 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

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AP Ο Ο Ο 2 7 9 pyridine (picoli.ne) by reaction with a compound of formula L(CR-;c Ar wherein defined and a is (m+.n-l), in the presence of a ;rcn:

immcnia cr an a..<vl rase such as sccaum amide rn nqui lithium. The resulting substituted pyridine is then reacted with a compound RL² , as hereinbefore defined, to give a quaternary pyridinium. compound cf formula (VTTI;. Reduction of this compound according to process (g) provides a convenient method of ^preparing compounds cf structure (I) wherein A represents a bond.

The comocunds ci :ae exhibit high calcium influx blocking activity and as such are excectea ;e cf use in .eracv in creating conditions and diseases related to an accumulation of calcium in the brain cells of mammals, in particular humans. Fcr example, the compounds are expected tc be of use in the treatment of anoxia, ischaemia including fcr 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.

diseases caused or exacerbated by the accumulation of calcium in the brain calls of mammals which comprises administering to a subject in need thereof an effective amount cf a compound cf structure (i; cr a pharmaceutically acceptable salt thereof. Tn addition, the present invention also provides a method cf treatment of anoxia, ischaemia including for example stroke, migraine, epilepsy, traumatic head injury, ATTS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory disorders, and drug addiction withdrawal such as ethanol addiction badghiginal

AP 0 0 0 2 7 9 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.

AP 0 0 0 2 7 9

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) _Ap 0 0 0 2 7 9

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- 16 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.

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SATA

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 Ca^{2 +} 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 Ca^{2 +} 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 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

AP Ο Ο Ο 2 7 9 rus ior.

cid

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- 18 PC based software similar to that described previously (Benham 4 Tsien, Journal of Physiology (1988) , 404. 767-784).

RESULTS

Sa²* current?

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 μΜ 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.

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AP 0 0 0 2 7 9

- 19 EXAMPL

Intermediate Preparations (i) 4-(2-Hydrcxyethyl)-l-pentylpiperidine

A mixture of 4-(2-hydroxyethyl) piperidine (20g) , 1bromopentane (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-clr.r.amyipiperidine

A mixture of 4-(2-hydroxyethyl) piperidine (16.4g), cinr.amyl bromide (25.Og), 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/dichlorcmethane to give the title compound (12.Og) as an inpure solid which was used without further purification.

(iii) 4- (3-Hydroxypropyl)-l-pentyloyridinium bromide

A solution of 4-(3-hydroxypropyl) pyridine (27.43g), 1bromopentane (37.76g) and acetone (50ml) was refluxed for 24 hours, cooled and poured into diethylether (200ml).

BAD OR'^g'^NAL sr i

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The oil which precipitated was collected by decantation then washed by decantation with diethylether (5 X 100ml) and dried at 50°C O.lmmHg to give the title compound which was used without further purification.

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

A mixture of 4-(3-hydroxypropyl)-l-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-l-pentylpyridinium bromide

A solution of 4-hydroxymethylpyridine (25g), 1bromopentane (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 5C°C O.lmmHg to give the title compound which was used without further purification.

(vi) 4-Hydroxymethyl-1-pentylpiperidine

A mixture of 4-(3-hydroxypropyl)-l-pentylpyridinium bromide (5.2g), platinum oxide (0.4g) and ethanol (100ml) was stirred under an atmosphere of hydrogen for 3 hours.

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- 21 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-Hydroxy-1-pentylpiperidine

A mixture of 4-hydroxypiperidine (25g), 1-bromcpentane (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 3 0.6 mmHg.) (viii) 4-(2-Hydroxyethyl) -1-propylpiperidine

A mixture of 4-(2-hydrcxyethyl)piperidine (5g), 1bromopropane (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.

qADOFUG'NAL

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- 22 (ix) 4-(2-Hydroxyethyl)-1-(3-phenyl)cropylpiperidine

A mixture of 4-(2-hydroxyethyl)piperidine (lOg), 1-bromo3-(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), 1bromoheptane (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. 110°C 0 O.lmmHg) (xi) 4- (2-Hydrcxyethyl)-1-(2-ethyl)butylpiperidine

A mixture of 4-(2-hydroxyethyl)piperidine (20g), 1-brcmc2-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. 1O2°C @ 0.3mmHg)

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- 23 (xii) l-Cyclchexyimethyl-4- (2-hydroxyethyl) piperidine

A mixture of 4-(2-hydroxyethyl)piperidine (20g), cyclohexylmethyl bromide (27.41g), potassium carbonate (26g) and ethanol (40Cml) 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-methyIfcutyl) piperidine

A mixture of 4-(2-hydroxyethyl)piperidine (20g), 1-bromo3-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. S8°C @ O.lmmHg) (xiv) l-3enzy1-4-(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 @ O.lmmHg)

BAD ORIGINAL a

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22040

- 24 (xv) 4-[2-(4-;luorophenyl)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. 4Fluorobenzyl 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-Flucrophenyl)ethyl]-1-pentylpyridinium bromide

A mixture of 4-[2-(4-fluorophenyl)ethyl)pyridine (5g), 1bromopentane (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 ccmpound (7.32g), m.p. 130 - 131°C.

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

A mixture of l-benzyl-4-[2-(4fluorophenoxy)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

AP 0 0 0 2 7 9

22040

- 25 mixture was filtered and the residue washed with ethane!. The filtrates were combined, the solvent removed and the residue was treated with hydrogen chloride in ether to give a solid. Recrystallisaticn 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% ^(C13^H18^FNO-^HC1) requires: C, 60.11; H, 7.37; N, 5.39; Ci, 13.65%

Example 1

4-[2-(4-Fluorophenoxy)ethyl]-1-pentyIpiperidine hydrochloride

A solution of 4-(2-hydroxyethyl)-1-pentylpiperidine (2.0g), 4-fluorcphenol (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 rocm temperature for 18 hours, the solvent was removed and the residue was chromatographed cn silica gel eluted with methanol/dichloromethane. The resulting oil was dissolved in ethyl acetate (5Cml) 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, 65.45; H, 8.90; N, 4.16; Cl, 10.75; F 5.76%. (C13H28FNO.HCI) requires: C, 65.54; H, 8.86; N, 4.25;

Cl, 10.75; F, 5.77%.

BAD oRIG‘^NAL

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22040

- 26 Example 2

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

A solution of 4-(2-hydroxyethyl)-l-pentylpiperidine (2.3g), 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.HC1) requires: C, 64.12; H, 8.50; N, 3.93;

Cl, 9.96%.

Fxamcle 3

4-(2-?hencxyethyl)-1-pentylpiperidlne hydrochloride

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

BAD ORIGINAL

22040

- 27 recrystal1ised from methanol,'ethyl acetate (0.88g), m.p. 158 - 159°C.

Found; C, 69.10; H, 9.80; N, 4.61; Cl, 11.34% ^(C18^H29^NO-^HC1) requires: C, 69.32; H, 9.69; N, 4.49;

Cl, 11.37%

Example 4

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

The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-l-pentylpiperidine (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% ^(C19^H28^F3^NO-^HC1) requires; C, 60.07; H, 7.69; N, 3.69;

Cl, 9.33%

Example 5

4-[2- (4-Phenylphenoxy)ethyl]-l-pentylpiperidine hydrochloride

The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-l-pentylpiperidine (2.0g), 4-phenylphenol (0.1.70g), triphenylphosphine

22040

ΑΡ π Π Π 2 7 9

- 28 (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.HCl) requires: C, 74.2; H, 8.8; N, 3.6;

Cl, 9.27%

Example 6

4-[2-(4-Benzyloxyphenoxy)ethyl]-l-pentylpiperidine hydrochloride

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 (1.3lg) 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 - 169°C.

Found: C, 70.42; H, 8.59; N, 3.50; Cl, 8.29% ^<C25^H35^NO2-^HC1-°'^5H2^O) requires: C, 70.31; H, 8.73;

N, 3.28; Cl, 8.20%

Example 7

4-[2-(3-Dimethylaminophenoxy) ethyl]-l-pentylpiperidine dioxalate

BAD ORIGINAL dfy

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22043

- 29 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% ^(C20^H34^N2°*^2C2^K2°4⁾ requires: C, 57.83; H, 7.63; N, 5.62%

Example 8

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

The title compound was prepared in a similar manner to example 1 from 4-(2-hydrcxyethyl)-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% ^(C19^H31^NO2•^c2^H2°4⁾ requires: C, 63.79; H, 8.35; N, 3.54%

Example 9

4-[2-(3,4-Dichlorophenoxy)ethylj-1-pentylpiperidine hydrochloride _BADOW^QlNAt &

22040

AP 0 0 0 2 7 9

- 30 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, 3.35; Cl, 27.93% ^(C18^H27^C12^NO’^HC1) retires: C, 56.78; H, 7.41; N, 3.68;

Cl, 27.93%

Example 10

4-[2-(4-Cyanophenoxy)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-cyancphencI (I.19gj, 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, 8.29; Cl, 10.85% ^^C19^H28^N2°*^KC1^ requires: C, 67.74; H, 8.68; N, 8.31; Cl, 10.52%

BAD ORIGINAL &

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22C40

- 31 Example 11

4-[2-(4-Chlorophenoxy)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-chlorophenol (1.30g), triphenyIphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from methanoi/ethyl acetate (0.75g), m.p. 185 -186°C.

Found: C, 62.14; H, 8.48; N, 4.44; Cl, 20.63% (C₁₈H₂₃C1NO.HC1) requires: C, 62.42; H, 8.44; N, 4.04;

Cl, 20.47%

Example 12

4-[2-(5,6,7,8-Tetrahvdro-2-napthcxy)ethyl'-1oentylpiperidine 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-napthcl (1.48g), triphenyIphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with oxalic acid gave a white solid which was recrystallised from methanoi/ethyl acetate (0.81g), m.p. 147°C.

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

AP 0 0 0 2 7 9

Example 13

4-[2- (5,6,7,8-Tetrahydrc-l-napthoxy)ethyl]-1pentyIpiperidine oxalate

The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (2.3g), 5,6,7,8-tetrahydro-l-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/ethyi acetate (1.14g), m.p. 162°C.

Found: C, 68.03; H, 8.73; N, 3.40% ^(C22^H35^NO-^C2^H2°4-°-^25H2^C) -e^ires: C, 67.97; H, 8.84;

N, 3.30%

Example 14

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

The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (1.5g), 3-nitro-4-triflucromethylphencl (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/ethyi acetate (0.61g), m.p. 139 - 141°C.

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

AP 0 ο Ο 2 7 9

22C40

Cl, 8.34%

Example 15

4-[2-(3-Fluorophenoxy)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-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% ^(C18^H28^FNC,HC1) retires: C, 65.54; H, 8.86; N, 4.25;

Cl, 10.75%

Example 16

4-[2-(4-Methylphenoxy)ethyl]-1-pentyipiperidine hydrochloride

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

AP ο 0 0 2 7 9

22040

- 34 Found: C, 70.00; H, 9.69; N, 4.15; Cl, 10.82% (^cl₉ ^H3lN°.HCl) requires: C, 70.02; H, 9.90; N, 4.30; Cl, 10.88%

Example 17

4- [2 - (4-Benzylphencxy) ethyl] -1-per.ty Ipiperidir.e 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 methancl/ethyl acetate (0.377g), m.p. 166 - 168°C.

Found: C, 70.86; H, 8.02; N, 3.07% ^(C25^K35^NO’^C2^h2°4⁾ -«^ires: C, 71.18; H, 8.19; N, 3.0^-7%

Example 18

4-£2-(3-chlorgphencxy) ethyl 1 -Ι-pentylpioeridlne hydrochloride

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. 151 - 153°C.

bad OR'O'^NAL

AP Ο Ο Ο 2 7 9

C 4 Ο

- 35 Found: C, 62.13; Η, 8.30; Ν, 4.05; C1, 10.20% (C₁₈H28C1NO.HC1) requires: C, 62.42; Η, 8.44; Ν, 4.04; Cl, 10.23%

Example 19

4-3enzyl-l-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 @ 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 - 19G°C.

Found: C, 70.00; H, 9.69; N, 4.15; Cl, 10.82% ^<C19^H31^NO'^HC1) requires: C, 70.02; H, 9.90; N, 4.30;

Cl, 10.88%

Example 20 — Γ2—(4-Fluorcohenoxy) ethyl]-1-cinnamylpioeridlne oxalate

A solution of 4-(2-hydroxyethyl)-1-cinnamyipiperidine (2.94g), 4-fluorophenol (1.31g) and triphenylphosphine 30 (3.15g) in tetrahydrofuran (5Cml) was treated with diethyl azodicarboxylate (2.09g). The resulting solution was stirred at room temperature for 18 hours, the solvent

BAD ORIGINAL A

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22040

- 36 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) tc give the title compound (1.10g), m.p. 180 °C.

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

^(C22^H26^FNO-^C2^H2°4^> requires: C, 67.11; H, 6.57; N, 3.26%

Example 21

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

A solution of 4-(2-hydrcxyethyl)-1-cinnamylpiperidine (2.02g), 3,4-dichlcrophenol (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 - 130°C.

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

BAD ORIGINAL

22040

AH υ υ 0 2 7 9 (C₂₂ ^H25^C12^NC-^C2^H2°4⁾ requires: C, 60.01; H, 5.67;

N, 2.92; Cl, 14.76%

Example 22

4-[3-(4-Fluorophenoxy;procyl]-1-pentylpiperidine hydrochloride

The title compound was prepared in a similar manner to example 1 from l-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% ^<C19^H30^FNO,HC1) retires: C, 66.36; H, 9.09; N, 4.07;

Cl, 10.31%

Example 23

4-[3-(4-3enzyloxyphenoxy)propyl1-1-pentylpiperidine hydrochloride

The title compound was prepared in a similar manner to example 1 from l-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.

AP 0 0 0 2 7 9

22040

Found: C, 72.43; H, 8.91; N, 3.31; Cl, 8.06% ^(C26^H37^NO2*^HC1) requires: C, 72.28; H, 8.86; N, 3.24;

Cl, 8.21%

Example 24

4-(4-Flucrocher.cxy)methyl-l-pentylpiperidine hydrochloride

The title compound was prepared in a similar manner to example 1 from l-pentyl-4-hydroxymethylpiperidine (l.lg), 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. Ill -112^cC.

Found: C, 60.25; H, 7.56; N, 3.88% ^<C17^H26^FNO’^C2^H2°4·0·^5H2^O) requires: C, 60.3; H, 7.72;

N, 3.70%

Example 25

4-(4-Fluorofcenzyloxy)-l-pentvloioeridine cxalate

A solution of 4-hydroxy-l-pentylpiperidine (2.0g) in dimethylformamide (25 mi) was treated with sodium hydride (0.012 mole) and then stirred for 1 hour when 4fluorobenzyl chloride (1.43 ml) was added and the mixture was stirred for 3 days. Water (100 ml) and dichlorcmethane (100 ml) were added and the organic layer was separated, washed with water (2 x 100 ml), and dried

AP 0 0 0 2 7 9

22040 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 recrystal Used (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%.

^(C17^H26^FNO-^C2^H2°4⁾ requires: C, 61.77; H, 7.64; N, 3.79%

Example 26

4-3enzyloxy-1-pentylplperidine 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% (Cl₇H₂₇NO.^c2---2⁰4⁾ 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-l-pentylpiperidir.e (2.0g), 4fluorophenol (1.31g), triphenylphosphine (3.15g) and diethyl azodicarboxylate (2.09g). Treating the product

22040 _Ap 0 0 0 2 7 9

- 40 with oxalic acid gave a white solid which was recrystallised from methanol/ethyl acetate (0.65g), m.p. 16 4 °C.

Found: C, 60.91/ H, 7.56/ N, 4.06% (C;gH24cNO.C₂H₂C₄) requires: C, 60.53/ 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-l-pentylpiperidine (2.0g), sesamol (1.6og), triphenylphosphine (3.15g) and diethyl azodicarboxylate (2.09g). Treating the product with oxalic acid gave a white solid which was recrystallised frcm methanol/ethyl acetate (0.65g), m.p. 164°C.

Found: 0, 59.76/ H, 7.22/ N, 3.72% (C27H25NO2.C2H2O4) r equ i res: u, 59.83/ H, 7.14/ N, 3.6/%

Example 29

4-[2- (4-Fluorophencxy)ethyl]-l-propylpioeridine oxalate

The title compound was prepared in a similar manner to example 1 frcm 4-(2-hydroxyethyl)-1-prcpylpiperidine (1.85c), 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 frcm methanol/ethyl acetate (0.3g), m.p. 1O9-112°C.

AP Ο Ο Ο 2 7 9

3.33% es : C,

ORIGINAL A

AP 0 0 0 2 7 9

22040

- 42 which was recrystaliised from methanol/ethyl acetate (i.lg), m.p. 139-141°C.

Found: C, 66.71; H, 9.32; N, 4.05; Cl, 10.08% (^c2qH₃₂FNO.HC1) 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; Ci, 9.26% ^<C21^H33^NO3-^HC-⁾ -e^ires: C, 65.69; H, 8.93; N, 3.65;

Ci, 9.23%

Example 33

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

The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-(2ethyl)butylpiperidine (2.97g), 4-fluorophenol (1.08g),

AP Ο Ο Ο 2 7 9 (,-

AP 0 0 0 2 Ί9

- 44 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.HC1) requires: C, 66.04; H, 8.44; N, 3.67;

Cl, 9.28%

Example 36

4-[2-(4-Flucrophenoxy)ethyl]-1-cyclohexylmethylpiceridine hydrochloride

The title compound was prepared in a similar manner to example 1 from l-cycIohexylmethyl-4-(2hydroxyethyl)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, 67.63; H, 8.35; N, 4.12; Cl, 9.37% ^(C20^H3C^FNO-^KC1) retires: C, 67.68; H, 8.78; N, 3.94;

Cl, 9.96%

Example 37

1-(3-Methylbuty1)-4-[2-(3,4-methylenedioxyphenoxy)ethyl]piperidine hydrochicride

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- 45 The title compound was prepared in a similar manner to example 1 from 1-(3-methylbutyl)-4-(2-hydrcxyethyl)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. 163-169°C.

Found: C, 63.95; H, 8.50; N, 4.05; Cl, 10.17% ^(C19^H29^NO3‘^HC1) retires: C, 64.12; H, 8.50; N, 3.94;

Cl, 9.96%

Example 33 l-Senzyl-4-[2-(4-fluoroohenoxy)ethyli-1-piperidine hydrochloride

The title compound was prepared in a similar manner to example 1 from l-benzyl-4-(2-hydroxyethyl)piperidine (3.83g), 4-fluorcphenol (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% ^(C20^H25^FNO,HC1) requires: C, 68.66; H, 7.20; N, 4.00;

Cl, 10.13%

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- 4 6Zxample 39

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

A mixture of 4-[2-(4-flucrophencxy)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-?henylethyi bromide (0.3mi) was added and the mixture stirred for 43 hours. The mixture was poured into water (50mi) 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 (0.223g) m.p. 21O-2I2°C

Found: C, 69.61; H, 7.48; N, 3.96; Cl, 9.77% ^iC21^H26^FNC,HC1) requires: C, 69.12; H, 7.73; N, 3.84; CI, 9.72%

Example 40

4-[2-(4-Flucrophencxy)ethyl )-1-(4-phenylbutyI)-piperidine hydrochloride

The title compound was prepared in a similar manner to example 39 starting from 4-(2-(4-fluorophencxy)ethyl]piperidine hydrochloride (l.Og), sodium hydride (80% in oil) (0.3g) and 4-phenyibutyl chloride (0.649g) in dimethylformamide (20ml) and recrystallising the product from ethyl acetate/metha.ool, yield (0.39g), m.p. 166168°C.

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Found: C, 70.23; H, 8.00; N, 3.87; Cl, 3.91% ^(C23^H30^FNO-^HC1) 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-diphenylprcpane-l-ylmethanesulphonate (2.23g) and sodium hydride (80% in oil) (0.58g) in dimethylformamide (40ml) was stirred at 60°C under nitrogen for 43 hours. The mixture was poured into water (20Cml) 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 ccmpcund crystallised. Yield (0.963g), m.p. i60-ioi°c

Found: C, 70.96; H, 6.75; N, 2.33% ^<C28^H32^FNO,C2^H2°4^{) rec}TJ^ire^{s: c}> 70.98; H, 6.90; N, 2.66%

Example 42

4- [2- (4-Fluorothiophenoxy) ethyl] -1-per.tylpiper idine hydrochloride

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- 43 The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentyipiperidine (2.00g), 4-fluorothiop'nenol (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% (^C1S^H2SFNS.HCl) requires: C, 62.49; H, 8.45; N, 4.05; Cl, 10.25%

Example 43

4-[2- (3,4-C ichlorothlochenoxy)ethyl]-l-pentylpiperidine hydrochloride

The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-l-pentylpiperidine (2.C0g), 3,4-dichlorothicphencl (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%

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- 49 Example 44 l-Pentyl-4- (3-phenylpropyl)piperidine hydrochloride A mixture of 4-(3-phenylpropyl)piperidine (5g) , 1bromopentane (7.42g), potassium carbonate (lOg) 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 dichlorcmethane and the dichlorcmethane 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, xecrystallisation 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% ^(C19^H31^N-^HC1-°-^25H2⁰⁾ requires: C, 72.56; H, 10.36; N, 4.45; Cl, 11.27%

Example 45

4-i2-(4-Fluoroohenyl)ethyl]-l-pentylpiperidine hydrobromide

A mixture of 4-[2-(4-fluorophenyi)ethyl]-1pentylpyridinium 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.

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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 dimethyl formamide (20ml) was heated at 50°C for 1.5 hours. l-rlucro-4nitrcbenzene (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.174-176°C.

Found: C, 60.35; H, 8.15; N, 7.85; Cl', 9.^0% ^(C18^h28^NO3’^HC1) C, 60.58; H, 3.19; N, 7.85; C

9.93%

Example 47

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

The title compound was prepared in a similar manner to example 1 from 4-(2-hydrcxyethyl)-1-pentylpiperidine (1.5g), 2-fluorophenol (0.84g), triphenylphosphir.e (1.96g) and diethyl azodicarboxylate (1.19ml). Treating the product with hydrogen chloride gave a white solid which

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- 51 was recrystallised from ethyl acetate/methancl 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% ^(C18^H28^FNO-^HC1) requires: C, 65.54<H, 8.86; N, 4.25; Cl, 10.75%

Example 48

4-[2- (4-tert-Eutylphencxy)ethyl]-1-centylpiperldine hydrochloride

The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (1.5g), 4-tert-butyIphenol (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.139-191°C.

Found: C, 71.67; H, 10.50; N, 3.88; Cl', 9.63% ^<C22^H37^NO-^HC1) requires: C, 71.8; H, 10.41; N, 3.31; Cl, 9.63%

Example 49 l-Pentyl-4- [ 2- (4-tri fluoromethoxypher.oxy) ethyl I piperidine hydrochloride

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

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22C40

- 52 (1.5g), 4-trifluoromethcxyphenol (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% <^C1S^H28^F3^NO2^{lHC1) re}^^ires: C, 57.64; H, 7.38; N, 3.54;

Cl, 3.96%

Example 50

4-[2- (4-iso-Prooylphenoxy)ethyl]-1-pentyIpiperldine hydrochloride

The title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (1.5g), 4-isopropylpnenol (1.02g), triphenylphosphine (1.96g) and diethyl azodicarboxylate (1.19ml). Treating the product with hydrogen chloride gave a white solid which was recrystal Used 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, 10.03% (C₂₁H₃₅NO.^HC1) requires: C, 71.26; H, 10.25; N, 3.96; Cl, 10.02%

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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-hydrcxyeohyl)-1-pentylpiperidine (1.5g), 3-isoprcpylphenol (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% ^(C21^H35^NO-^HC1) requires: C, 71.26; H, 10.25; N, 3.96; Cl, 10.023

Example 52

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

The title compound was prepared in a similar manner to example 1 from 4-(2-hydrcxyethyl)-1-pentylpiperidine (1.5g), 3-tert-butyiphenol (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%

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- 54 ^(C22^H37^NC,HC1) requires: C, 71.8; H, 10.41; N, 3.81; Cl, 9.63%

Example 53

4-[2- (2-phenylphencxy)ethyl]-1-pentyloiperldine hydrochloride

The title compound was prepared ir. a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentyIpiperidine (1.5g), 2-pkenyiphenol (i.28g), triphenylphosphine (1.96g) and diethyl azodicarboxylate (l.i9g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from ethyl acetate/methanol to give the title ccmpound as a white crystalline solid (1.05g), m.p.1^_5-177°C.

Example 54 l-?entyl-4-[2-(4-triflucromethylchencxy)ethyl]-piperidine oxalate

A mixture of 4-(2-hydroxyethyl)-1-pentyIpiperidine <2.0g), sodium hydride {60% in oil) (0.4c) and dimethylformamide (20ml) was refluxed 1.5 hours. 4-Fiuorotrifluoromethylbenzene (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.

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22040 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%

3.2%

Example 55

4-(2-(3,5 Dichlorophenoxy)ethyl]-l-pentylpioeridine 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.l68-170°C.

Found: C, 56.80; H, 7.40; N, 3.64; Cl, 9.33; Cl, 27.92% ^(C18^h27^C12^NO'^HC1) requires: C, 56.73; K, 7.41; N, 3.68;

Cl, 9.30; Cl, 27.93%

Example 56

4-[2- (3,4-Dichlorochencxy)ethyl)-1-heptylpiperldine 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

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22043

- 5 6 (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% ^(C20^H21^C12^NO-^HC1) requires: C, 58.76; H, 7.89; N, 3.43; Cl, 8.63; Ci, 26,01%

Fxamole 57

4-(2-(3,4-Dichlorophenoxy)ethyl]-l-(3phenylPropyl)piperidine hydrochloride

The tide compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-(3-phenylpropyl) piperidine (2.47g), 3,4-dichlorophenoi (1.63g), triphenylphosphine (2.62g) ar.d 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, 3.7% ^(C22^H27^C12^NO-^HC1’°·^{1 H}2^C) requires: C, 61.56; H, 6.34; N, 3.27; Cl, 8.30% bad

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- 57 Example 58

1-CyclopropyImethy1-4-[2-(4-fluorophenoxy) ethyl 1 piperidine oxalate

The title compound was prepared in a’ similar manner to example 41 from 4-[2-(4-fluorophencxy)ethyl]-piperidine hydrochloride (2.0g), bromcmethylcyclopropane (2.0ml) and sodium hydride (80% in oil) (0.58g) in dimethyl formamide (4Cml). 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% ^(C17^H24^FNO-^C2^H2°4⁾ requires: C, 62.11; H, 7.13; N, 3.81%

Example 59

1-(3,3-Dichenylprop-2-enyl)-4-[2-(4-fluorophenoxy)ethyl Ιο ioe rid ine 1-(3, 3-Diphenyl prop-2-er.yl) - 4- [2 - (4fluoroohenoxv)ethyl]-piperidine oxalate

Methanesulphonyl chloride ((0.46ml) was added to a solution of 1,l-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 ’•curs then heated at reflux for 8 hours. The mixture was poured into water (200ml) and extracted with ether. The ether phase was dried ever

BAD'ORIGINAL £

Claims (14)

1-cyclopropylmethyl-4-(2-(4-fluorophenoxy)ethyl]30 piperidine;

or a pharmaceutically acceptable salt thereof.

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

1. A compound of structure (I):

(CHJ^CH^Ar (I) in which

R is Cj_gaIky1(phenyl)p, C₂_₈alkenyl(phenyl)p,

C₂_₈alkenyl(phenyl)p,

C₃.₈cycloalkyl ^or Cj^.galkylCj.gcycloalkyl; p is 0 to 2; n is 0 to 6;

A is a bond, oxygen, sulphur or NR¹;

R¹ is hydrogen, Cy_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'n

1C (II)

R in which R and n are as described for structure (l)ar.d A¹ is C, £ or NR-, with a compound cf structure L(CH->)..-Ar in which m and Ar are as described for structure (Σ) , and L is a leaving group;

(b) for compounds cf structure (I) in which A is C, S cr XR-, reaction of a compound of structure (III):

(CH_n)

R in which n and R are as described for structure (Σ' and L* is a group displaceable by a nucleophile, with a compound cf structure EA^CH?' Ar where m and Ar are as described for smruccure (1) and A^x is as described for structure (II); or

35 (c) for compounds of structure (Σ) in which A is NR-,

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- 62 Λ ί

R group

- (CK-,) „ _ - CN ί R~ (CH-,) _Ar

2. A compound according to claim 1 wherein R is ^cl-8 aifcyl, phenyl(Cj.g)alkyl or phenyl(C₂_₈)-alkenyl.

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

4-(2-(4-iso-propylphenoxy) ethyl]-1-pentylpiperidine, 4-(2-(3,4-dichlorophenoxy)ethyl]-1-(3-phenylpropyl)piperidine, or

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

25 4-(2-(4-tert-butylphencxy)ethyl]-1-pentylpiperidine,

4-(2-(4-fluorophenoxy)ethyl]-1-heptyIpiperidine,

4-(2-(3,4-dichlorophencxy)ethy1]-1-cinnamyIpiperidine,

20 4-(2-(4-fluorophenoxy)ethyl]-1-(3-phenylpropylpiperidine,

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

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

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

4-(2-(4-benzyloxyphencxy)ethyl]-1-pentylpiperidine,

15 4-(2-(4-fluorophenoxy)ethy1]-1-cinnamyIpiperidine,

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

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

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

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

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

5 which Ar is optionally substituted phenyl.

6. A compound according to any of claims 1 to 5 in

7. A compound according to claim 1 which is:

8. A process for preparing a compound of structure

35 (I) which comprises:

SAD

AP Ο Ο Ο 2 7 9

- 61 (a) ccmpcur.ds cf structure (Σ) in which A is 0, S :tion cf a compound of structure (ΣΙ):

'C- i -~H

9. A pharmaceutical composition comprising a compound of structure (I) as claimed in any of claims 1 to 7 or a pharmaceutic C·’ 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.

10 in which λ⁴ represents the

O

- (CH₂)(R¹)C(CH₂)_m_ _xAr cr and n, m, R and Ar are as described fcr structure (I);

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

L¹ i

(V;

R (wherein R, L¹, n and m are as hereinbefore defined) with a compound cf structure χ-Ar in which Ar is as described fcr structure (I;, and X* is an alkali metal;

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

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

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

(VII)

COR'

20 wherein R⁵ is C₁_₇alkyl(phenyl)p, C₂_₇alkenyl(phenyl)p, C₂_₇alkynyl(phenyl)p or C^-yalkylC^gcycloalkyl;

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

(VIII) wherein R, A, Ar π and n are as hereinbefore defined and X“ is a counter ion;

and optionally thereafter forming a salt.

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10 4-[2-(4-fluorophenoxy)ethyl]-1-pentylpiperidine,

11. Use of a compound of structure (I) as defined in any of claims l 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 tc a subject in need thereof an effective amount of a compound

20 of structure (I) as defined in any of claims 1 to 7 or a pharraceutically 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.