PT98574A - PREPARATION PROCESS OF 4-SUBSTITUTED PIPERIDINE DERIVATIVES - Google Patents

Description

-4-. 4 '

sfSSSWSR 72 953 BB / JF / rnrp / 22040

The present invention relates to the process for the preparation of 4-substituted piperidine derivatives and pharmaceutical compositions containing them and their use in therapy. The present invention therefore provides, in a first aspect, compounds of structure (I) : J (I)

I

(Phenyl) p, C2-6 alkenyl, g (phenyl) p, C2-6 alkynyl, (phenyl) p, C1-6 cycloalkyl or C1-6 alkylC1-6 alkylC1-6 alkyl, .g; p is 0 to 25; n is 0 to 6; A is a bond, oxygen, sulfur or NR 1; R 'is hydrogen, C1-4 alkyl, or phenyl (C1-4 alkyl); m is 0 to 3; and

Ar is aryl or heteroaryl, each of which may be optionally substituted; and its salts.

Suitably R is C1-4 alkyl (phenyl) p, C2-6 alkenyl (phenyl) p (C1 -C6) alkenyl (phenyl) p, C3 -C8 cycloalkyl or C1-6 alkylC3 -C12 alkyloxy-

It should be noted that the alkylcycloalkyl, alkylphenyl, alkenylphenyl and alkynylphenyl groups are attached to the piperidine nitrogen atom via the alkyl, alkenyl and alkynyl moieties, respectively. 3e.

Preferably, R is C1-8 alkyl (phenyl) p, where p is 0 or 1, C1-6 alkyl, such as n-pentyl or phenyl (C1 -C4 alkyl), such as 5 72 953 BB / Wherein R² is phenylpropyl or R² is C₂ al al alkenyl (phenyl) p where p is 1, such as cinnamyl.

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

Suitably, rn is 0 to 3; preferably m is 0 or 1; Preferably m is 0.

Suitably, A is a bond, oxygen, sulfur or NR 1, preferably A is oxygen or sulfur; 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 and partially saturated bicyclic unsaturated and cyclic ring systems having up to 10 carbon atoms, such as, for example, phenyl, riftyl and tetrahydronaphthyl. Optionally substituted phenyl rings are preferred.

Suitable substituted phenyl rings include, for example, phenyl rings substituted with a C1-4 alkylene group such as a 3,4-methylenedioxy group or with 1 to 3 substituents selected from halogen, C1-4 alkoxy, nitro, (Wherein each of the groups R 2 may be H or C 1-4 alkyl), OCF 3, C 1-6 alkyl, trifluoromethyl, CN, optionally substituted phenyl, optionally substituted phenyl (C 1-4) alkyl and phenyl (C 1-4 alkoxy) optionally substituted. Preferred phenyl rings substituted with one or two substituents, in particular with a single halogen, trifluoromethyl, unsubstituted phenyl or unsubstituted phenyl (C1-4 alkoxy) group; or with two chlorine atoms, in particular at positions 3 and 4 of the ring.

The optionally substituted phenylC1-4 alkyl groups,

Examples of such compounds include, for example, benzyl. Suitable optionally substituted phenyl (C1-4 alkoxy) groups include, for example, benzyloxy "

Suitable substituents for said optionally substituted phenyl, phenyl, (C1-4 alkyl) and phenyl (alkoxy) groups include, for example, halogen, C1-4 alkyl, C1-4 alkoxy, nitro and trifluoromethyl groups.

Suitable heteroaryl rings include, for example, unsaturated or partially saturated bicyclic unsaturated and partially saturated bicyclic ring systems having up to 10 carbon atoms containing at least one heteroatom, such as pyridyl, thienyl, quinolinyl, tetrahydroquinolinyl and imidazolyl rings. The heteroaryl ring may be attached to the rest of structure (I) through a carbon atom or through a heteroatom, e.g. a nitrogen atom.

Suitable substituents for said heteroaryl rings include, for example, 1 to 3 substituents selected from halogen, C1-4 alkyl and C1-4 alkoxy,

The alkyl groups present in the compounds of structure (I), alone or as part of another group, may be linear or branched.

It is to be understood 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, sulfate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate or addition salts of pharmaceutically inorganic or organic acids acceptable. Other non-pharmacochemically acceptable salts may be used for example as intermediates and are within the scope of this invention.

Particular compounds of the invention include: 4- [2- (4-trifluoromethylphenoxy) ethyl] -1-pentylpiperidine, 4- [2- (3-trifluoromethylphenoxy) ethyl] -1-pentylpiperidin- [4- (2- (4-fluorophenoxy) ethyl] -1-pentylpiperidine hydrochloride, 4- [2- (3-4-methylenedioxyphenoxy) ethyl] -1- 4- (2-phenyloxy) ethyl] -1-pentylpiperidine hydrochloride, 4- [2- (4-Phenylphenoxy) ethyl] -1-pen-3-per-per-dihydro-isoindole of 4- [2 (4-benzyloxyphenoxy) et. (4-fluorobenzyloxy) -1-pentylpiperidine oxalate, 4- [2- (4-fluorophenoxy) ethyl] -1-cinnamylpiperidine oxalate, 4- (4-benzylphenoxy) ethyl] -1-pentylpiperidine oxalate, 4- [2- (3,4-dichlorophenoxy) ethyl] -1-pentylpiperidine oxalate, 4- [2- (3,4-dichlorophenoxy) ethyl] -1-cinnamylpiperidine hydrochloride, 4- [2- (4-fluorophenoxy) ethyl] -1- (3-phenylpropylpiperidine hydrochloride, 4- [2- (4- fluorophenoxy) ethyl] -1-heptylpiperidine oxalate, 1- (3,3-diphenylpropyl) -4- [2- (4-fluorophenoxy) ethyl] piperidine oxalate, 4- [2- (3,4- dichlorothiophenoxy) ethyl] -1-pentylpiperidine hydrochloride, 4- [2- (4-tert-butylphenoxy) ethyl] -1-pentylpiperidine hydrochloride, 4- [2- (4-isopropylphenoxy) ethyl] ] -l-pentylpiperidine hydrochloride, 4- [2- (3,4-dichloroferhoxy) ethyl) -1- (3-phenylpropyl) piperidine hydrochloride and] -cyclopropylmethyl 4- [2- (4-fluorophenyl) enoxy) ethyl] piperidine.

It is to be understood that the compounds of structure (I) may contain one or more asymmetric centers. These compounds will exist as optical isomers (enantiomers). Both the pure enantiomers and the racemic mixtures (50% of each enantiomer) and the unequal mixtures of the two are included within the scope of the invention. In addition, all possible diastereomeric forms (pure enantiomers and mixtures thereof) are within the scope of the invention. The present invention therefore provides a process for the preparation of a compound of structure (I), which comprises: 72953 BB / JF / mrp / 22040 sfi

(a) for compounds of structure. (I) in which A is O, the reaction of a compound of structure (II):

WnAH

(I) and A is 0, 3 or NR 2 ', with a compound of structure L (CH 2) m Ar where Ar are as described for structure (I) el ~ is a group that says goodbye; (b) for compounds of structure (I) > in which A is O, S or NR 1, the reaction of a compound of structure (III):

Wn1 · 1 I J (ui) ^ ir

I

(I) and L 1 is a group displaceable by a nucleophile, with a compound of structure HA 1 (CH 2) m Ar wherein m and Ar are as described for structure (I) and R 1 is as described for structure as for structure (II) > or

H (c) for compounds of structure (I) in which A is NR, reduction of a compound of structure (IV)

(IV) n wherein R4 is the same as (CH2) n N (R1) n (R1) C (CH2) m Ar, and - (CH2) nCN (R1) (CH2) mAr, and n, m, R and

Au are described as for structure (I); (d) for compounds of structure (I), wherein A is a

The reaction of a compound of structure (V): 2'n + m (CH3) (V)

N

I

(Wherein R 1 and R 2 are as defined above) with a compound of the formula wherein Ar is as defined for structure X 1 is an alkali metal; the introduction of the group R into a compound of formula (VI):

(VI) by reaction with a compound RL2, where L2 is a leaving group; (f) reducing a compound of formula (VII);

(VII) in which R5 is C1-4 alkyl (phenyl) p9 (C2-7) alkenyl (phenyl) p1-alkynyl-C2- (phenyl) p or C1-3 alkylC1 -C3 cycloalkyl; (g) reducing a compound of structure (VIII): (A)

Uf]) &

I

H e

in which R 1, A 2, Ar, m and n are as defined above and X 1 -10 -BB / JF / mrp / 22040 is a counterion; and then, optionally, the formation of a salt.

In the process (a), the reaction between a compound of structure (II) and a compound L. (CH 2) m Ar may occur under conditions depending on the nature of the L group. For example when L is halogen or a sulfonic acid residue such as such as tosylate or mesylate, the reaction is carried out under standard conditions in a solvent, optionally in the presence of a base. When a fluorine-substituted aryl F-Ar is employed in a process (a), the reaction is carried out in the presence of a strong base such as sodium hydride and in an inert organic solvent such as dimethylformamide. Preferably, the aryl group is substituted with an activating group such as CF3 or NC2. Reaction between a compound of structure (III) and a compound of structure HA · 1 · CCH2) mAr may occur under conditions depending on the nature of the A and A. For example, when IA is hydroxy, m is 0 and A1 is oxygen or sulfur, the reaction is carried out in the presence of diethyl azodicarboxylate and triphenylphosphine. This reaction is known as the Mitsunobu reaction (described in Synthesis 1981, 1). Alternatively, the leaving group of 1A may for example be a halogen atom or a sulfonyloxy group, e.g. methanesulfonyloxy or p-toluenesulfonyloxy. In this case, the reaction may be carried out in the presence or absence of solvent at a temperature in the range of 0 to 200 ° C. Reduction of a compound of structure (IV) may be effected by methods known in the art, for example, using a reducing agent such as lithium hydride-aluminate. Conveniently, a compound of structure (IV) may be prepared (for example as described below) and reduced in a " reaction in a vessel " (" one-pot "), without isolation of the compound (IV) itself. The reaction between a compound of structure (V) and a compound of structure X 1 -Ar may occur under standard conditions known to the person skilled in the art for the formation of carbon-carbon bonds.

The reaction of a compound of structure (VI) with RL 2 according to process (e) may be carried out in a conventional manner, for example in an organic solvent such as dimethylformamide, the group L 2 may be for example a halide such as bro-met or chloride, an acyloxy group such as acetoxy or chloroacetoxy or a sulphonyloxy group such as methanesulfonyloxy or p-toluenesulfonyloxy. When L 2 is a halide, the reaction is preferably carried out in the presence of a weak base such as potassium kaolinate and when L 2 and sulfonyloxy a strong base such as sodium hydride or potassium t-butoxide can be employed. Reduction of a compound of formula (VII) may be effected using standard reducing agents such as lithium hydride-aluminate. 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 e.g. ethanol '

The compounds of structure (II) may be prepared from the corresponding compounds wherein R 2 is hydrogen, by alkylation under standard conditions. For example, compounds of structure (II) in which R 2 is n-pentyl may be prepared from the corresponding precursor wherein R3 is hydrogen, by reaction with an n-pentyl halide such as n-pentyl bromide in a suitable solvent, such as methyl ethyl ketone or a C1-4 alkanol such as ethanol, in the presence of a base, such as potassium or dimethylformamide in the presence of an iodoalkane.

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

Alternatively, the compounds of structure (II), in which...................

Oxygen may be prepared by reduction of a compound of structure (IX) π

in the dual R and n are described as for structure (I) and is a counterion "

Compounds of structure (III) wherein L 1 is OH may be prepared as described for the compounds of structure (II) and compounds of structure (III) wherein L 1 is a halogen atom or a mesyloxy or tosyloxy group may be prepared from the corresponding alcohol in a conventional manner.

Compounds of structure (IV) in which R 1 is a group may be prepared by reacting a compound of structure (II) wherein A 1 represents NR 1 with a acylation corresponding to the - (CH 2) m Ar group, for example a C 10 -C (F 2) 2 m-

Compounds of structure (IV) in which R 4 is a group O- (CH 2) n-1 CN (R 1) (CH 2) m Ar may be prepared for example by reaction of a corresponding compound in which R 4 represents " or an activated eu derivative such as an acid halide, ester or anhydride, with an amine of formula MN (R 2) (CH 2) m Ar. It should be noted that when the acid itself is used, the reaction with the amine should be carried out in the presence of a coupling agent. The carboxylic acid may itself be prepared, for example, by oxidation of the corresponding alcohol, ie a compound of structure (II) wherein A 1 is oxygen.

72 953 BB / JF / mrp / 22040 -13-

The compounds of structure (V) may be prepared analogously to compounds of structure (III); when necessary the chain length may be increased using methods well known in the art.

The compounds of structure (VI) may be prepared for example according to any one of (a) to (d) above using intermediates analogous to structures (II) to (IV) wherein R is substituted 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 triferylmethyl and acyl groups such as acetyl, trifluoroacetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl or benzyloxycarbonyl. An aralkyl group such as benzyl can be cleaved by hydrogenation and an acyl group as benzoyl can be cleaved by hydrolysis. It should be noted that when the N-protecting group is aralkyl the compound has structure (I) and this reaction sequence thus provides a means of converting a compound of formula (I) into a compound of formula (I ), different.

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

A compound of structure (VIII) may be prepared using the general methods described above in (a) and (e). In addition, the compounds of structure (VIII) in which A represents a bond can be prepared from 4-methylpyridine (pigein) by reaction with a compound of formula L. wherein L and Ar are as previously defined eq is (m + n-1), in the presence of a strong base such as sodium amide in liquid ammonia or an alkyl lithium.

The compounds of the invention have been found to exhibit high calcium influx blocking activity and as such are expected to be useful in therapy in the treatment of conditions and diseases related to calcium accumulation in the brain cells of mammals in particular of human beings. For example,

72 953 BB / JF / mrp / 22040

It is believed that the compounds are useful in the treatment of anoxia, ischemia including, for example, stroke, migraine, epilepsy, traumatic head injury, AIDS related dementia, neurodegenerative diseases such as Alzheimer's disease and memory disorders related to age and abstinence in to-addiction, such as ethanol-dependent withdrawal.

In another aspect of the invention there is provided a method of treating conditions or diseases caused or exacerbated by accumulation of calcium in mammalian brain cells which comprises administering to a subject in need an effective amount of a compound of structure (I In addition, the present invention also provides a method of treating anoxia, ischemia including for example attack, migraine, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory disorders and withdrawal from addiction, such as ethanol withdrawal, which comprises administering to a subject in need an effective amount of a compound of structure (I) or of the pharmaceutically acceptable salt thereof. The invention also provides the use of a compound of structure (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of the conditions or diseases mentioned above.

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 the process for the preparation of 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 administered orally may be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and tablets. /. (I.e.

72 953 BB / JF / mrp / 22040 -15-

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

A composition in the form of a tablet may be prepared using any suitable pharmaceutical carrier (s) routinely used in the preparation of solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.

A composition in the form of a capsule may be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled with a hard gelatin capsule; alternatively, a dispersion or suspension may be prepared using any suitable pharmaceutical carrier (s), for example aqueous gums, celluloses, syrups or oils and a gelatin capsule mole with the dispersion or suspension.

The compounds of the invention may also be administered pauperally, by bolus injection or by continuous infusion. Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous or parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution may be lyophilized and then reconstituted with a suitable solvent immediately prior to administration.

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

Each dosage unit for oral administration preferably contains 1 to 250 mg (and for pareriteric administration contains

(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 0.1 mg to 100 mg, 1 mg and 60 mg -w. exp. 1 to 40 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times daily. Alternatively, the compounds of the invention may be administered by continuous intravenous infusion, preferably a dose of up to 100 mg per day. Suitably, the compounds of the invention may be administered during a period of continuous therapy, for example for a week or more,

DAPOS M. introduction of the current of Ca2 +

Preparations ..... cell phones

Sensory neurons were dissociated from the dorsal root ganglia of rat pups at 1 day of age (Forda et al, Deveiopmental Brain Research, 22 (1985), 55-65). Cells were coated on glass slides and used within 3 days to allow effective voltage fixation of the Ca 2+ currents.

Solutions The pipette (internal solution) contained in mM: CsCl, 130; HEPES, 10; EQTA, 10; MgCl2, 4; ATP, 2; buffered at pH 7.2 with CsOH-

Cells were plated in a normal Tyrodes solution prior to establishment of whole cell registration when the bath solution was changed to another allowing isolation of the 0a2 + currents. The external solution for recording the currents of the Ca 2+ channels contained in mM: HCl, 10; TEA-C1, 130; glucose, 10; HEPES, 10; MgCl2, 1; buffered to pH 7.3 with TEA-OH. The barium was used. 72 953 BB / JF / rnrp / 22040 as a carrier of charge as this assists the insulation of the current and calcium inactivation of the current is avoided.

The compounds were dissolved in DMSO to make a " concentrated " (" stock ") 20 mM. At the concentration of drug used, the vehicle (0.1¾) had no significant effect on the Ca 2+ streams.

All experiments were performed at a temperature between 21 and 24 ° C. The cell currents were recorded using List EPC-7 amplifiers and stored, digitized for further analysis using PC programs and compatible similar to those already described (Benharn & Tsien, Journal of Physiology (1988), 404, 767-784).

Current Results ...... of Ca2 " 1 "

Currents of Ca2 + channels provided with peak voltage port of up to 10 nA of dorsal root ganglion neurons were recorded using 10 mM Ba2 + as the charge carrier. The currents were evoked from a conservation potential of -80 mV to a test potential of 0 or +10 mV every 15 seconds. This test potential was at a peak current voltage ratio and the evaluation of the block at this point reduces any errors due to the conservation potential deviation. Some cells showed a slow

Hi as is commonly observed when recording Ca 2+ currents. The rate of weakening was measured under control conditions and extrapolated over the drug application time to derive a control value to relate the drug affected current to it. Blocking by 20 μ droga drug was evaluated 3 minutes after drug application.

The compounds of the invention showed a percent inhibition of Ca2 + current of the plateau in the range of 30 to 100 °. -18- / -72 953 BB / JF / mrp / 22040

The compound of Example 9 did not exhibit any toxicologically adverse effects when administered to rats at a dose of 10 mg / kg, i.e., E.

Intermediate (i) 4- (2-Hydroxyethyl) -1-pentylPyperidone

A mixture of 4- (2-hydroxyethyl) piperidine (20 g), 1-bromopentane (19.2 g), potassium carbonate (21.42 g) and ethanol (400 ml) 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 removed to give the title compound as an oil (30.2 g) which was used without further purification. (ii) 4- (2-Hydroxyethyl) -1-cinnamylpiperidine

A mixture of 4- (2-hydroxyethyl) piperidine (16.4 g), cinnamyl bromide (25.0 g), potassium carbonate (17.55 g) and ethanol (350 ml) was heated at reflux for 3 days. ) The solution was filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel, eluted with methanol / dichloromethane affording the title compound (12.0 g) as an impure solid which was used without further purification. (Iii) 4- ( 3-hydroxypropyl) -1-pentylpyridinium bromide A solution of 4- (3-hydroxypropyl) pyridine (27.43 g), 1-bromopentane (37.67 g) and acetone (50 ml ), cooled and poured into diethyl ether (200 ml), the oil which precipitated was collected by decantation and then washed with deketyl ether (5 x 100 ml) and dried at 50øC / 0.1 mmHg to give the title compound which was used without further purification - (iv) 4- (3-Hydroxypropyl) -1-pentylpiperidine

A mixture of 4- (3-hydroxypropyl) -1-pentylpyridinium bromide (8.65 g), platinum oxide (0.5 g) and ethanol (120 ml) was stirred under an atmosphere of hydrogen for 3 hours. hours.

The residue was dissolved in dilute sodium hydroxide (70 ml) and extracted with dichloromethane (3 x 75 ml). The extracts were combined, dried over sodium sulfate, and evaporated to dryness. sulfate and the solvent was removed giving the title compound as an oil (4.68 g). (v) 4-Hydroxymethyl-1-pentylpyridinium bromide .....

A solution of 4-hydroxymethyl-pyridine (25 g), 1-bromopentane (43.2 g) and acetone (50 ml) was refluxed for 24 hours, cooled and poured into diethyl ether (200 ml). The oil which precipitated was collected by settling and then washed by decantation with pentane (5 x 100 ml) and dried at 50 ° C / 0.1 mmHg to give the title compound which was used without further purification. (vi) 4-Hydroxymethyl-1-pentylpiperidine

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

A mixture of 4-hydroxypiperidine (25 g), 1-bromopentane (37.33 g), potassium carbonate (34.13 g) and ethanol (400 ml) 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 was removed and the resulting oil was distilled under reduced pressure to give the title compound as an oil. (18.00 g, bp 100 ° C 0.6 mmHg) - (viii) 4- (2-hydroxyethyl) -1-propylpiperidine

A mixture of 4- (2-hydroxyethyl) piperidine (5 g), 1-bromopropane (4.87 g), potassium carbonate (5.5 g) and ethanol (100 g) was heated at reflux for 1 day. ml). The solution was filtered and the solution washed with water.

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 (5.1 g) which was used without further purification. A mixture of 4- (2-hydroxymethyl) piperidine (10 g), 1- (2-hydroxyethyl) piperidin-1-yl) (15.8 g), potassium carbonate (10.69 g) and ethanol (200 ml). 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 (14.52 g) (bp 141øC, 0.2 mmHg). (x) -4- (2-Hydroxyethyl) -1-heptylpiperidine

A mixture of 4- (2-hydroxyethyl) piperidine (20 g), N-bromoheptane (27.73 g), potassium carbonate (21.39 g) and potassium carbonate were refluxed for 24 hours and ethanol (400 ml). 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, yielding the title compound as an oil (10.01 g) (bp 110 ° C 0.1 mm Hg). (xi) 4- (2-Hydroxyethyl) -1- (2-ethyl) butylpiperidine

A mixture of 4- (2-hydroxyethyl) piperidine (20 g), 1-bromo-2-ethylbutane (17.9 g), potassium carbonate (26 g) and ethanol were heated at reflux for 4 days. (400 ml). The solution was filtered and the solvent removed under reduced pressure. The residue was distilled to give the title compound as an oil (29.61 g) (bp 102 ° C 0.3 mm Hg). (xii) 1-Cyclohexylmethyl-4- (2-hydroxyethyl) piperidine A mixture of 4- (2-hydroxyethyl) piperidine (20 g), cyclohexylmethyl- hexylmethyl "(27.41 g), potassium carbonate (26 g) and ethanol (400 ml). The solution was filtered and the solvent removed under reduced pressure. The residue was distilled to give the title compound as an oil (27 g) (bp 165 ° C 0.5 mmHg). -21, ν 72 953 / Τ BB / JF / mrp / 22040 (xiii) 4- (2 " hydroxyethyl) -1- (5-methylbutyl) piperidine

A mixture of 4- (2-hydroxyethyl) piperidine (20 g), 1-bromo-3-methylbutyl (25.57 g), potassium carbonate (26 g) and ethanol (400 ml). The solution was filtered and the solvent was removed under reduced pressure. The residue was distilled to give the title compound as an oil (23.21 g) (bp 98.0- 0.1 mmHg). (xiv) 1-Benzyl-4- (2-hydroxyethylpiperidine

A mixture of 4- (2-hydroxyethyl) piperidine (5 g), benzyl bromide (6.15 g), potassium carbonate (5.35 g) and ethanol (50 ml) was heated at reflux for 24 hours. The organic phase was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was distilled to give the title compound as a white solid. oil (5.13 g) (bp 120-130 ° C 0.1 mm Hg) (xv) 4- [2- (4-Fluorophenyl) pyridine

4-Picoline (30 g) was added over 30 minutes to a suspension of sodium amide (12.56 g) in liquid ammonia (150 ml) and the resulting mixture was stirred for 1.5 hours. Then 4-fluorobenzyl chloride (40 ml) was added over 15 minutes and the mixture was stirred for 3 hours. Ammonium chloride (50 g) was added and the solvent was allowed to evaporate. The residue was dissolved in chloroform (300 ml) and dilute sodium hydroxide (300 ml) and the organic phase was separated, dried over magnesium sulfate and the solvent removed. The residue was recrystallised from petroleum ether to give the title compound as white needles (25.3 g), m.p. 69-70.5 ° C. (xvi) 4- [2- (4-Fluorophenyl) ethyn-1-pentylpyridinium bromide

A mixture of 4- [2- (4-fluorophenyl) ethyl] pyridine (5 g), 1-bromopentane (7.0 g) and acetone (10 ml) was heated at reflux for 18 hours. The solvent was removed under reduced pressure and the residue was recrystallized from ethyl acetate / methanol to give the title compound (7.32 g), m.p. 130-131 ° C. (Xvii) 4-t-Butyl-4-fluorophenoxyethylpiperidine hydrochloride

A mixture of 1-benzyl-4- [2- (4-fluorophenoxy) ethyl] piperidine (1.50 g), 10% palladium on carbon (0.6 g) and ethanol (120 ml) was stirred under an atmosphere of hydrogen at 50 psi (345 kPa) for 24 hours. The mixture was filtered and the residue washed with ethanol. The filtrates were combined, the solvent was removed and the residue was treated with hydrogen chloride in ether to give a solid. Recrystallization from ethyl acetate afforded the title compound (0.45 g), m.p. 122-123Â ° C.

Found: C 59.58; H, 7.37; N, 5.35; Cl, 13.33% (C 13 H 18 FNO · HCl) required; C, 60.11; H, 7.37; N, 5.39; Cl, 13.65% [M + H] + [1 H]; 1-pentylpiperidine.

A solution of 4- (2-hydroxyethyl) -1-pentylpiperidine (2.0 g), 4-fluorophenol (1.12 g) and triphenylphosphine (2.62 g) in tetrahydrofuran (40 ml was treated with azodicarboxylate (1.74 g) in tetrahydrofuran (10 ml) The resulting solution was stirred at ambient temperature for 18 hours, the solvent was removed and the residue was chromatographed on silica gel and eluted with methanol / The resulting oil was dissolved in ethyl acetate (50 ml) and treated with ethereal hydrogen chloride, the precipitate was collected by filtration and recrystallised (methanol / ethyl acetate) affording the title compound (1.1 g ), mp 167-169 ° C.

Found; C, 65.45; H, 8.90; N, 4.16; Cl, 10.75; F 5.76%. (C18 H28 FNO · HCl) required; C, 65.54; H, 8.86; N, 4.25; Cl, 10.75; F, 5.77%.

Example 2 2-Hydrochloride ... ... of ......... 4,7, 2,7, 3, 4, 5, .Delta.i.fen.bs.ri.di.na

A solution of 4- (2-hydroxyethyl) -1-pentylpiperidine (2.0 g), sesamol (1.39 g) and triphenylphosphine (2.62 g) in tetrahydrofuran (40 ml) was treated with diethyl azodicarboxylate (1.74 g) in tetrahydrofuran (10 ml). The resulting solution was stirred at r

After stirring 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 (50 ml) and treated with ethereal hydrogen chloride. The precipitate was collected by filtration and recrystallized (methanol / ethyl acetate) affording the title compound (0.45 g). mp 134-136 ° C.

Found: C, 64.12; H, 8.52; N, 4.03; Cl, 10.00%. (C 19 H 29 NO 3 .HCl) required; C, 64.12; H, 8.50; N, 3.93; Cl, 9.96%.

Example ..... 3β-Hydrochloride of ..... 4- (2-phenoxyethyl) -1-pentylpiperidine

The title compound was prepared in a manner similar to that of Example 1 from 4- (2-hydroxyethyl) -1-pentylpiperidine (2.0 g), phenol (0.94 g), triphenylphosphine 62 g) and diethyl azodicarboxylate (1.74 g). Treatment of the product with hydrogen chloride gave a white solid which was recrystallized from methanol / ethyl acetate (0.88 g), mp 158-159 ° W.

Found: C, 69.10; H, 9.80; N, 4.61; Cl, 11.34% (C 18 H 29 NO 2 -HCl) required; C, 69.32; H, 9.69; N, 4.49; Cl, 11.37%

Example 4

Hydrochloride .......... of 4-4- (2- (3-trifluoromethylphenoxy) ethyn-1-pentylpiperidine

The title compound was prepared in a manner similar to Example 1 from 4- (2-hydroxyethyl) -1-pentylpiperidine (2.0 g), α, α, α-trifluoro-m-cresol (1, 62 g), triphenylphosphine (2.62 g) and diethyl azodicarboxylate (1.74 g). Treatment of the product with hydrogen chloride gave a white solid which was recrystallised from methanol / ethyl acetate (0.44 g) mp 154 ° C.

Found: C, 59.51; H, 7.62; N, 3.80; Cl, 9.49% (C 19 H 28 F 3 NO-HCl) required: C, 60.07; H, 7.69; N, 3.69; Cl, 9.33% -24- / ..., .......... 72 953 BB / JF / mrp / 22040

Example ..... 5

4-C2- (4-phenylphenoxy) ethyl] -1-pentylpiperidine hydrochloride

The title compound was prepared in a similar manner to Example 1 from 4- (2-hydroxyethyl) -1-pentylpiperidine (2.0 g), 4-phenylphenol. (1.70 g), triphenylphosphine (2.62 g) and diethyl azodicarboxylate (1.74 g). Treatment of the product with hydrogen chloride afforded a white solid which was recrystallized from methanol / ethyl acetate (0.4 g), m.p. 205-206 ° C.

Found: C, 73.77; H, 8.88; N, 3.66; Cl, 9.14% (Q24H33NO.HCl) required: C, 74.2; H, 8.8; N, 3.6; Cl, 9.27%

Example ..... 6

 € ƒâ € ƒâ € ƒ ..... 4- [2- (4-Benzyloxyphenoxy) ethyl] -1-penti] piperidine hydrochloride

The title compound was prepared in a manner similar to Example 1 from 4- (2-hydroxyethyl) -1-pentylpiperidine (1.0 g), 4-benzyloxyphenol (1.00 g), triphenylphosphine (1, 31 g) and diethyl azodi-carboxylate (0.87 g). Treatment of the product with hydrogen chloride afforded a white solid which was recrystallized from methanol / ethyl acetate (0.1 g), m.p. 168-169 ° C.

Found: C, 70.42; H, 8.59; N, 3.50; Cl, 8.29%. C 25 H 35 N 2 O • HCl • 0.5H 2 O) required: C, 70.31; H, 8.73; N, 3.28; Cl, 8.20%

Example ..... 7

The title compound was prepared in a similar manner to Example 1, m.p. 128-130Â ° C. Anal. Calc'd for C 20 H 20 N 3 O 3.

Found: C, 57.82; H, 7.63; N, 5.62% (C 20 H 34 N 2 O 2 requires: C, 57.83; H, 7.63; N, 5.62%

Example ..... 8.

Oxalate The title compound was prepared in a similar manner to that of Example 1, mp 119-121 ° C (decomp.). . Μ 25 72 953 88 / JF / mrp / 22040

Found: C, 63.54; H, 8.47; N, 3.69% C 19 H 31 N 2 O • C 2 H 12 O 4 required: C, 63.79; H, 8.35; N, 3.54%

Example ..... 9

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

The title compound was prepared in a manner similar to Example 1 from 4- (2-hydroxyethyl) -1-pentylpiperidine (2.0 g), 3,4-dichlorophenol (1.63 g.), (2.62 g) and diethyl acodicarboxylate (1.76 g). Treatment of the product with hydrogen chloride afforded the title compound as white prisms from methanol / acetic acid ethyl acetate (1.02 g), mp 177-178 ° C,

Found: C, 57.05; H, 7.43; N, 3.85; Cl, 27.93% (C 18 H 27 Cl 2 N 2 • HCl) required: C, 56.78; H, 7.41; N, 3.68; Cl, 27.93%

The following compounds were prepared in a manner similar to Example 1.

Exemolo 10

4- [2- (4-Cyanophenoxy) ethyl] -1-pentylpiperidine hydrochloride m.p. 173-174Â ° C m

Found: C, 67.69; H, 8.84; N, 8.28; Cl, 10.85% (C 19 H 28 N 2 O, HCl) required: C, 67.74; H, 8.68; N, 8.31; Cl, 10.52%

Example 11

4- [2- (4-Chlorophenoxyethyl] -1-pentyl] piperidine hydrochloride m.p. 185-186

Found: C, 62.14; H, 8.48; N, 4.44; Cl, 20.63% (C 15 H 12 ClNO.HCl) required: C, 62.42; H, 8.44; N, 4.04; Cl, 20.47% ... · η Λ! * 72 953 * * * BB / JF / mrp / 22040 -26-

Example 12

_______ 4-T 2 - (5,6,7,8-tetrahydro-2-hydroxyphenoxy) ethyl] -1-pentylpiperidine hydrochloride m.p. 147 ° C.

Found: C, 68.88; H, 9.07; N, 3.40 (C22 H35 N2 O2: 2H2 O4): C, 68.71; H, 8.89; N, 3.34.

Example 13

 € ƒâ € ƒâ € ƒ4-β2- (5,6,7,8-Tetrahydro-1-naphthoxylethyl) -1-pentylploridine oxalate m.p. 162 ° C.

Found: C, 68.03; H, 8.73; N, 3.40 (C22 H35 N0 -C2 H2 O4 • 0.25H2 O) required: C, 67.97; H, 8.84; N, 3.30%

EXAMPLE 14

4-12- (4-Fluoro-3-trifluoromethylphenyl) chloride and 113.1 -1-p-nitropiperidine hydrochloride m.p. 139-141 ° C.

Found: C, 53.80; H, 6.50; N, 6.45; Cl, 8.30 (d, J = 9 Hz, 27 F 3 N 2 O 3 .HCl) required: C, 53.71; H, 6.64; N, 6.59; Cl, 8.34%

Example 15

4- [2- [5-Fluorophenoxy] ethyl] -1-pentylpiperidine hydrochloride, m.p. 157-159 ° C.

Found: C, 65.27; H, 8.67; N, 4.61; Cl, 10.75 (C 18 H 28 FNO " HCI) required: C, 65.54; H, 8.86; N, 4.25; Cl, 10.75%

Example 16

4- [2- (4-Methylphenoxyethyl] -1-pentylpiperidine hydrochloride, m.p. 164-166 ° C.

Found: C, 70.00; H, 9.69; N, 4.15; Cl, 10.82% (c) 9H31NG (HCl) required: C, 70.02; H, 9.90; N, 4.30; Cl, 10.88 ± 72.953 BB / JF / mrp / 22040 /

-27

Example ..... 17

The title compound was prepared in a similar manner to that of Example 1 (mp: 166-168 ° C). 1H NMR (DMSO-d6):? W-

Found: C, 70.86; H, 8.02; N, 3.07% C 25 H 35 N 2 O • C 2 H 2 O 4 • Requires: C, 71.18; H, 8.19; N, 3.07%

Example ..... 18

The title compound was prepared in a similar manner to that of Example 1. The title compound was prepared in a similar manner to that of Example 1. p-

Found: C, 62.13; H, 8.30; N, 4.05; Cl, 10.20% (C 18 H 28 ClNO-HCl) required: C, 62.42; H, 8.44; N, 4.04; Cl ", 10.23%

Example ..... 19

Hl.drpc challenge ... of ..... 4-benzyl-1-pentylpiperidine

A mixture of 4-benzylpiperidine (3.0 g), pentyl bromide (2.84 g), potassium carbonate (4.72 g) and ethanol (40 ml) 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 apparatus to give an oil (bp 150øC 0.1 mm Hg) which was treated with hydrogen chloride to give the title compound , as a white solid, from methanol / ethyl acetate (2.06 g), mp 188-190 ° C.

Found: C, 70.00; H, 9.69; N, 4.15; Cl, 10.82 (C 19 H 13 NNO-HCD required: C, 70.02; H, 9.90; N, 4.30; Cl, 10.88%

Example 20

A solution of 4- (2- (4-fluorophenoxy) ethyl) -1-cinnamoylpiperidine

A solution of 4- (2-hydroxyethyl) -1-cinnamylpiperidine (2.94 g), 4-fluorophenol (1.31 g) and triphenylphosphine (3.15 g) in tetrahydrofuran (50 ml) was treated with azodicarboxylate (2.09 g). The resulting solution was stirred at room temperature for 18 hours, the solvent was removed and the residue was chromatographed

The residue was chromatographed on silica gel and eluted with methanol / dichloromethane. The resulting oil was dissolved in ethyl acetate (50 ml) and treated with oxalic acid (1.1 molar equivalents). The precipitate was collected by filtration and recrystallized (methanol / ethyl acetate) to give the title compound (1, 10 g), mp 180 ° C.

Found: C, 67.14; H, 6.60; N, 3.56%. (C22h26FN0 "C2h204) required; C, 67.11; H, 6.57; N, 3.26.

Example ..... 21

Oxalate ....., 4- [2- (5,4-dichlorophenyl) ethyl] -1-cinnamoylpiperidine

A solution of 4- (2-hydroxyethyl) -1-cinnamylpiperidine (2.02 g), 3,4-dichlorophenol (1.34 g) and triphenylphosphine (2.16 g) in tetrahydrofuran (50 ml) was treated with diethyl azodicarboxylate (1.44 g). The resulting solution was stirred at ambient temperature for 18 hours. The solvent was removed and the residue was dissolved in ethyl acetate and extracted with dilute hydrochloric acid. The aqueous extract was basic and extracted with ethyl acetate. The resulting organic layer was dried over magnesium sulfate, filtered and the solvent was removed. The residue was dissolved in ethyl acetate (50 ml) and treated with oxalic acid (1.1 molar equivalents). The precipitate was collected by filtration and recrystallized (methanol / ethyl acetate) to give the title compound (0.3 g), m.p. 179-180 ° C.

Found; C, 60.07; H, 5.67; N, 2.92; Cl, 14.79%. (C 22 H 25 Cl 2 N 3 O requires C 20 H 20 N 4 O 2 requires: C, 60.01; H, 5.67; N, 2.92; Cl, 14.76%

The following compounds were prepared in a similar manner to Example 1:

Example 22

..... 4- [3- (4-fluorophenoxy) propyl] -1-pentylpyridine hydrochloride m.p. 148-150 ° C.

Found: C, 65.94; H, 9.29; N, 4.15; Cl, 10.32% (C 19 H 30 FNO-HCl) required: C, 66.36; H, 9.09; N, 4.07; Cl, 10.31%

T " 72 953 BB / JF / mrp / 22040 -29 "

Example ..... 23

4- [3- (4-Benzyloxyphenoxy) propyl] -1-pentylpyrimidine hydrochloride β- 163-164 ° C.

Found: C, 72.43; H, 8.91; N, 3.31; Cl, 8.06% (C 26 H 37 NO 2 .HCl) required: C, 72.28; H, 8.86; N, 3.24; Cl, 8.21%

Example ..... 2.4

4- (4-Fluorophenoxy) methyl-1-periylpiperidine hydrochloride p-F- 111-112 ° C-

Found: C, 60.25; H, 7.56; N, 3.88% C 17 H 26 FNO 4: C 2 úH 4 O: Requires: C, 60.3; H, 7.72; N, 3.70%

Example 25 ..... of 4-C4-fluorobenzyloxy) -1-pentylpyridine

A solution of 4-hydroxy-1-pentylpiperidine (2.0 g) in dimethylformamide (25 ml) was treated with sodium hydride (0.012 mol) and then stirred for 1 hour when 4-fluorobenzyl chloride (1 , And the mixture was stirred for 3 days. Water (100 ml) and dichloromethane (100 ml) were added and the organic phase was separated, washed with water (2 x 100 ml) and dried, The solvent was removed and the residue was chromatographed on silica gel and eluted with methanol / dichloromethane. The resulting oil was dissolved in ethyl acetate and treated with oxalic acid (1.1 molar equivalents). The precipitate was collected by filtration and recrystallized (methanol / ethyl acetate) to afford the title compound (0.2 g), mp 124-125 ° C.

Found: C, 61.71; H, 7.69; N, 3.94%. (C 17 H 26 N 2 O · C 2 H 20 4) required: C, 61.77; H, 7.64; N, 3.79%

Example 26

4-Benzyloxy-1-pentylpiperidine oxalate. Substitution of 4-fluorobenzyl chloride with benzyl bromide (2.0 g) in the procedure described in Example 25 afforded the title compound as a white solid for -30 Recrystallization from methanol / ethyl acetate, yield (0.2 g), mp 119 DEG-121 DEG C..

Found: C, 64.63; H, 8.11; N, 4.14% (C 17 H 27 NO 6 Cl 2 H 2 O 4) required: C, 64.98; H, 8.32; N, 3.99%

The following compounds were prepared in a similar manner to Example 1:

Example ..... 27

Oxalate ..... of 4- (4-fluorophenoxy) -1-pentylpiperidine m.p. 164 ° C.

Found: C: 60.91; H, 7.56; N, 4.06% (C 16 H 24 FNO-C 2 H 20 O 4) required: C, 60.83; H, 7.37; N, 3.94%

Exemp.l.P ..... 28

Oxalate ..... of 4- (3,4-methylenedioxyphenoxy) -1-pentylpiperidine. 164 * C.

Found: C, 59.76; H, 7.22; N, 3.72% C 17 H 25 NO 3 - C 2 H 2 O 4: required: C, 59.83; H, 7.14; N, 3.67%

Example ...... 2.9

Oxalate ..... of 4- [2- (4-fluorophenoxy) ethyl] -1-propylpiperidine, mp 109 DEG-

Found: C, 59.66; H, 7.46; N, 3.80% (C 16 H 24 FNO " C 2 H 20 4 "O, 5H 2 O) required: C, 59.50; H, 7.43; N, 3.86%

Example 30

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

The title compound was prepared in a manner similar to Example 1 from 4- (2-hydroxyethyl) -1- (3-phenylpropyl) piperidine (2.47 g), 4-fluorophenol (1.12 g), triphenylphosphine (2.62 g) and diethyl azodicarboxylate (1.74 g). Treatment of the product with hydrogen chloride afforded a white solid which was recrystallized from ethyl acetate. 72 953 BB / JF / m / z / 22040 in methanol / ethyl acetate (0.65 g), m.p. 111-113 * 0,

Found: C, 68.04; H, 7.72; N, 3.83; C, 9.11% (C22 H28 FNOâ € ¢ HC1: 1 â € ¢ H2 O) Requires: C, 68.23; H, 7.75; N, 3.60; Cl, 9.04% H NMR (DMSO-d6):? 3.1

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

The title compound was prepared in a manner similar to Example 1 from 4- (2-hydroxyethyl) -1-heptylpiperidine (2.27 g), 4-fluorophenol (1.12 g), triphenylphosphine 62 g) and diethyl azodicarboxylate (1.74 g) Treatment of the product with hydrogen chloride afforded a white solid which was recrystallized from methanol / ethyl acetate (1.1 g), mp 139 DEG- 141 * C,

Found: C, 66.71; H, 9.32; N, 4.05; Cl, 10.08% (C 20 H 32 FNO "HCl) required: C, 67.10; H, 9.29; N, 3.91; Cl, 9.90% The following compounds were prepared in a similar manner to Example 1:

Example 32

4-C2- (3,4-methylenedioxyphenoxy) ethyn-1-heptylpiperidine hydrochloride, m.p. 129-131 ° C,

Found: C, 65.61; H, 8.85; N, 3.71; Cl, 9.26% (C 21 H 33 N 3 .3HCl) required: C, 65.69; H, 8.93; N, 3.65; Cl, 9.23%

Example ..... 33

4- [2- (4-fluorophenoxy) ethyl] -1H-1,2-ethyldiimidazo [biphenyl] p-f, 137-138Â ° C,

Found: C, 63.24; H, 8.26; N, 3.58% (c19 H 3 FNO · C 2 H 20 O 4) required: C, 63.46; H, 8.11; N, 3.52%

72 953 BB / JF / mrp / 22040

Example 34

4- [2- (3,4-methylenedioxyphenoxy) ethyl] -1- (2-ethyl) butylpiperidine oxalate, m.p. 133-134 ° C.

Found: C, 62.05; H, 7.88; N, 3.39 (C 20 H 31 N 3 O 3 · C 2 H 2 O 4) required: C, 62.39; H, 7.85; N, 3.31

Example ..... 35

1 H -cyclohexylmethyl-4- (2-C3,4-methylenedioxyphenoxy) ethyl] piperidine hydrochloride m.p. 177-178 ° C.

Found: C, 66.01; H, 8.44; N, 3.85; Cl, 9.39 (C 21 H 31 NO 3 -HCl): C, 66.04; H, 8.44; N, 3.67; Cl, 9.28%

Example ...... 36

4-F2-f4-fluorophenoxyethyl-1-cyclohexylmethylpiperidine hydrochloride m.p. 178-180 ° C.

Found: C, 67.68; H, 8.85; N, 4.12; Cl, 9.87% (C 20 H 30 FNO-HCl) required: C, 67.68; H, 8.78; N, 3.94; Cl, 9.96%

Example 37

1- [3-Methylbutyl] -4- [2- [3,4-triethylenedioxyphenoxy] ethylpiperidine hydrochloride m.p. 168-169 ° C.

Found: C, 63.95; H, 8.50; N, 4.05; Cl, 10.17% (C 19 H 29 NO 3 • HCl) required: C, 64.12; H, 8.50; N, 3.94; Cl, 9.96%

Example 38

1-Benzyl-4- [2- (4-fluorophenoxyethyl) -1-piperidine hydrochloride, m.p. 175-176 ° C.

Found: C, 68.48; H, 7.22; N, 3.92; Cl, 10.07% (c 20 H 25 FNO 3 CH 2) required: C, 68.66; H, 7.20; N, 4.00; Cl, 10.13 723 BB / JF / rnrp / 22040

33

Example 39

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

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

Found: C, 69.61; H, 7.48; N, 3.96; Cl, 9.77% (c 21 H 26 FNO-HCl) required: C, 69.12; H, 7.73; N, 3.84; Cl, 9.72%

Example 40

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

The title compound was prepared in a similar manner to Example 39 from 4- [2- (4-fluorophenoxy) ethyl] piperidine hydrochloride (1.0 g), sodium hydride (80% in oil) ( 0.3 g) and 4-phenylbutyl chloride (0.649 g) in dimethylformamide (20 ml) and recrystallizing the product from ethyl acetate / methanol, yield (0.39 g), mp 166-168 ° C.

Found: C, 70.20; H, 8.00; N, 3.87; Cl, 8.91 (c 23 H 30 FN 3 OCH 3) requires: C, 70.48; H, 7.97; N, 3.57; Cl, 9.05

Example 41

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

A mixture of 4- [2- (4-fluorophenoxy) ethyl) piperidinium hydrochloride (2.0 g), 3,3-diphenylpropane-1-ylmethanesulfonate (2.23 g) and sodium hydride (80% in oil) (0.58 g) in dimethylformamide (40 ml) was stirred at 60 ° C under nitrogen for 48 hours. The mixture was poured into water (200 ml) and extracted with ether. The ether phase was treated with dilute hydrochloric acid and a BB / JF / mrp / 22040 oil precipitated. The oil was separated and dissolved in dichloromethane. The dichloromethane solution was washed with dilute sodium hydroxide solution, dried over sodium sulfate and the solvent removed. The residue was dissolved in ethyl acetate and treated with oxalic acid when the title compound crystallized. Yield (0.963 g), m.p. 160-161 ° C.

Found: C, 70.96; H, 6.75; N, 2.83 (C 28 H 32 FNO " C 2 H 2 O 4) required: C, 70.98; H, 6.90; N, 2.66%

Example 42

4- [2- (4-Fluorothiophenoxy) ethyl] -1-pentylpiperidine hydrochloride The title compound was prepared in a similar manner to Example 1, m.p. 164-165 ° C.

Found: C, 62.41; H, 8.47; N, 4.09; Cl, 10.17% (C 18 H 28 FNS "HCl) required: C, 62.49; H, 8.45; N, 4.05; Cl, 10.25

Example 43

4- [2- (5,4-dichlorothiophenoxy) ethyl] -1-pentylpiperidine hydrochloride

The title compound was prepared in a manner similar to Example 1 from 4- (2-hydroxyethyl) -1-pentylpiperidine (2.00 g), 3,4-dichlorothiophenol (1.79 g), triphenylphosphine ( 2.62 g) and diethyl azo dicarboxylate (1.74 g). Treatment of the product with hydrogen chloride afforded a white solid which was recrystallized from ethyl acetate to give the title compound as a white crystalline solid (0.77 g), m.p. 158-159 ° C.

Found: C, 54.41; H, 7.11; N, 3.48; Clq., 8.89 ° (C 18 H 27 Cl 2 NH 4 HCl) required: C, 54.48; H, 7.11; N, 3.53; Cl ", 8.93 "

Example 44

1-Pentyl-4- (5-phenylpropyl) piperidine hydrochloride

A mixture of 4- (3-phenylpropyl) piperidine (5 g), 1-bromopentane (7.42 g), potassium carbonate (10 g) and ethanol (125 ml) was heated at reflux for 18 hours. The solution was filtered and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and the solution of dichloromethane was washed with dilute sodium hydroxide solution, dried over sodium sulfate and the solvent was removed. The residue was treated with hydrogen chloride in ether to give a solid. Recrystallization from ethyl acetate afforded the title compound (4.19 g), m.p. 188-189 ° C.

Found: C, 72.56; H, 10.29; N, 4.58; Cl, 11.44% (C 19 H 31 N 3 · HCl): 25H 2 O) required: C, 72.56; H, 10.36; N, 4.45; Cl, 11.27%

Example 45

4- [2- (4-Fluorophenylethyl) -1-pentylpiperidine hydrobromide

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

Example 46

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

A mixture of 4- (2-hydroxyethyl) -1-pentylpiperidine (2.5 g), sodium hydride (60% in oil) (0.42 g) was heated at 50 ° C for 1.5 hours, and dimethylformamide (20 ml). 1-Fluoro-4-nitrobenzene (2.14 ml) was added and the mixture was stirred at 50 ° C for 5 hours. The mixture was cooled, poured into water and extracted with dichloromethane. The extracts of dichloromethane were dried over magnesium sulfate and the solvent was 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 recrystallized from ethyl acetate to give the title compound as a solid crystalline yellow (0.937 g), mp 174-176 ° C.

Found: C, 60.35; H, 8.15; N, 7.85; Cl, 9.70% (C 18 H 28 N 3 O 4) required: C, 60.58; H, 8.19; N, 7.85; Cl, 9.93%. 72 953 BB / JF / mrp / 22040

Example ..... 4.7

4- [2- (2-fluorophenoxy) ethyl] -1-pentylpiperazine hydrochloride

The title compound was prepared in a similar manner to Example 1. m.p. 150-152 ° C.

Found: C, 65.14; H, 8.87; N, 4.30; Cl, 10.82% (C 18 H 28 FNO " HCl) required: C, 65.54; H, 8.86; N, 4.25; Cl, 10.75%

Example 48

..... 4- [2- (4-tert-butylphenoxy) ethyl] -1-pentylpyridine hydrochloride

The title compound was prepared in a manner similar to Example 1 from 4- (2-hydroxyethyl) -1-pentylpiperidine (1.5 g), 4-tert-butylphenol (1.127 g), triphenylphosphine (1.96 g) and diethyl azo dicarboxylate (1.19 g). Treatment of the product with hydrogen chloride afforded a white solid which was recrystallized from ethyl acetate / methanol to give the title compound as a white crystalline solid (1.23 g), m.p. 189-191 ° C.

Found: C, 71.67; H, 10.50; N, 3.88; Cl ", 9.68% C 22 H 37 NO 2 --HCl) required: C, 71.8; H, 10.41; N, 3.81; Cl, 9.63%

Example ..... 4.9

??? ..... 1-pentyl-4- [2- (4-trifluoromethoxyphenoxy) ethyl] piperidine dihydrochloride

The title compound was prepared in a similar manner to Example 1. m.p. 154-156 ° C.

Found: C, 57.29; H, 7.31; N, 3.52; Cl, 8.59% (C 19 H 28 F 3 NO 2 · HCl) required: C, 57.64; H, 7.38; N, 3.54; Cl, 8.96%

Example ..... 5.0.

..... 4- [2- (4-iso-propylphenoxy) ethyn-1-pentylpiperidine hydrochloride

The title compound was prepared in a manner similar to Example 1 from 4- (2-hydroxyethyl) -1-pentylpiperidine (1.5 g), 4-isopropylphenol (1.02 g), triphenylphosphine (1, 96 g) and diethyl azodi-carboxylate (1.19 ml). Treatment of the product with hydrogen chloride gave a white solid which was recrystallized from ethyl acetate / methanol to give the title compound as a white crystalline solid ( 1.21 g), m.p. 185-187Â ° C.

Found: C, 71.35; H, 10.23; N, 4.05; Cl ", 10.08% (C 21 H 35 N 5 .HCl) required; C, 71.26; H, 10.25; N, 3.96; Cl, 10.02%

The following compounds were prepared in a similar manner to Example 1:

Example ..... 51

4- [2- (3-Isopropylphenoxy) ethyn-1-Dentloxyperidinyl] p -F- 166-168Â ° C.

Found: C, 71.40; H, 10.30; N, 3.97; Cl ", 10.00% (C 21 H 35 N0 -HCl) required: C, 71.26; H, 10.25; N, 3.96; Cl, 10.02%

Example ..... 52

4- [2- (3-tert-butylphenoxy) ethyl] -1-pentylpiperidine hydrochloride mp 171-173 ° C

Found: C, 71.80; H, 10.57; N, 3.88; Cl ", 9.67% (C 22 H 37 NO 4 .HCl) required: C, 71.8; H, 10.41; N, 3.81; Cl, 9.63%

Example ..... 53

(2-phenylphenoxy) ethyl] -1-pentylpiperidine hydrochloride. 175-177 ° C. l. > < tb >

Oxalate ..... 1-pentyl-4- [2- (4-trifluoromethylphenoxy) ethyl] piperidine

A mixture of 4- (2-hydroxyethyl) -1-pentylpiperidine (2.0 g), sodium hydride (60% in oil) (0.4 g) and dimethylformamide (20 ml). 4-Fluoro-trifluoromethylbenzene (1.64 ml) 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 sulfate and the solvent was removed. The residue was chromatographed

Si: 38-72 953 BB / JF / mrp / 22040 on silica gel, with methanol / dichloromethane as eluent, and the product was treated with oxalic acid to give a solid. This was recrystallized from ethyl acetate / methanol to give the title compound (0.5 g), m.p. 101-103 ° C.

Found: C, 57.76; H, 7.00; N, 3.27% (C 19 H 28 F 3 N 2): C 2 H 204 O 4: Requires: C, 57.9; H, 6.9; N, 3.2%

Example ..... 55

4- (2- (3,5-dichlorophenoxy) ethyl] -1-pentylpiperidine hydrochloride

The title compound was prepared in a similar manner to Example 1. m.p. 168-170Â ° C.

Found: C, 56.80; H, 7.40; N, 3.64; Cl ", 9.33; Cl, 27.92% (C 18 H 27 Cl 2 N 2 • HCl •): C, 56.78; H, 7.41; N, 3.68; Cl, 9.30; Cl, 27.93%

Example ..... 56

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

The title compound was prepared in a similar manner to Example 1. mp 138-139 ° C-

Found: C, 58.87; H, 7.88; N, 3.50; Cl, 8.68; Cl, 26.00% < C20 H31 Cl2 N0 -HCl): C, 58.76; H, 7.89; N, 3.43; Cl ", 8.68; Cl, 26.01%

Example 57

______ 4- (2- (3,4-Dichlorophenoxy) ethyl) -1-1- (5-phenylpropyl) piperidine hydrochloride

The title compound was prepared in a manner similar to Example 1 from 4- (2-hydroxyethyl) -1- (3-phenylpropyl) piperidine (2.47 g), 3,4-dichlorophenol (1 , 63 g), triphenylphosphine (2.62 g) and diethyl azodicarboxylate (1.74 g) Treatment of the product with hydrogen chloride afforded a white solid which was recrystallized from ethyl acetate / methanol to give the title compound as a white crystalline solid (0.75 g), mp 137-138 ° C. -39- 72 953 BB / JF / mrp / 22040

Found: C, 61.24; H, 6.45; N, 3.36; Cl, 8.7% (C 22 H 27 Cl 2 N 3 O 3 · HCl-0.11%) required: C, 61.56; H "6.34; N, 3.27; Cl, 8.30%

Example ..... 58

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

The title compound was prepared in a similar manner to Example 41 from 4-C2- (4-fluorophenoxy) ethylpiperidine hydrochloride (2.0 g), bromomethylcyclopropane (2.0 ml) and hydrazide (80% in oil) (0.58 g) in dimethylformamide (40 ml), treatment of the product with oxalic acid in ethyl acetate gave a solid which was recrystallized from ethyl acetate to give the title compound. Yield (0.963 g), m.p. 129-132 ° C.

Found: C, 61.95; H, 7.05; N, 3.91% C 17 H 24 FNO 2 · 2H 2 O 4 Requires: C, 62.11; H, 7.13; N, 3.81%

Example ..... 59

Oxalate ..... 1- (3,5-diphenylprop-2-enyl) -4- [2- (4-fluorophenoxy) ethyl] piperidine

To a solution of 1,1-diphenyl-2-hydroxymethylethylene (1.14 g) in tetrahydrofuran (20 ml) was added methanesulfonyl chloride (0.46 ml). The mixture was stirred for 1 hour when 4- (2- (4-fluorophenoxy) ethyl] piperidine (1.42 g) and triethylamine (0.8 ml) was added. The mixture was stirred under nitrogen for 48 hours, then heated to reflux The residue was chromatographed on silica gel with methanol / dichloromethane as eluent. The residue was chromatographed on silica gel with methanol / dichloromethane as eluent. The organic extracts were dried over sodium sulfate, and the product was treated with oxalic acid to yield a solid. This was recrystallized from ethyl acetate / methanol to give the title compound, (0.687 g), mp 174-176 ° C.

Found: C, 70.84; H, 6.34; N, 2.93% C 28 H 30 FNO 2 · C 2 H 2 O 4 Requires: C, 71.27; H, 6.38; N, 2.77% -40 72 953 BB / JF / mrp / 22040

Example 60

Hydrochloride ...... of 4- [2- (2-benzylphenoxy) -1-pentylpiperidine

The title compound was prepared in a similar manner to Example 1. m.p. 109-120Â ° C.

Found: C, 73.32; H, 8.94; N, 3.61; Cl, 8.70 (C25H35NOâ € ¢ HCl ° â € ƒâ € ƒâ € ƒ3H2O) Requires: C, 73.59; H, 8.89; N, 3.43; Cl, 8.69%

Claims (7)

. . A process for the preparation of a compound of structure (I): R (I) in which R is C1-4 alkyl (phenyl) p, C2-6 alkenyl (phenyl) p, C2-6 alkynyl (phenyl) p, C3-6 cycloalkyl or C1-6 alkylC3 cycloalkylC3; p is 0 to 2; n is 0 to 6; A is a bond, oxygen, sulfur or NR ···; R 2 is hydrogen, C 1-4 alkyl or phenyl (C 1-4 alkyl); f 1 is 0 to 3; and Ar is aryl or heteroaryl, each of which may optionally be substituted; or a salt thereof, which comprises: (a) for compounds of structure (I) wherein A is O, S or NR ', the reaction of a compound of structure (II): in which R 2 and R 2 are as described for structure (I) and A 2 is O, S or NR 3, with a compound of structure L (CH 2) m Ar where m and Ar are as described for structure (I) and L is leaving group: or (b) for compounds of structure (I) wherein A is O, S or NR 1 to 9 and M is a reaction of a compound of structure (III): (following formula III). .5 ^ 72 953 BB / JF / mrp / 22040 (I) and wherein R 1 and R 2 are as described for structure (I) and A 1 is a group displaceable by a nucleophile, with a compound of structure HA- · 1 is defined as for structure (II); or (c) for compounds of structure (I) wherein A is NR1, reduction of a compound of structure (IV): (IV): in which R 1 represents the group and - (CH 2) n N (R 1) C (CH 2) r R 1 Ar or - (CH 2) m CNKR 1) (CH 2) m Ar, en, m, R 2 Ar are as described for structure (I); (d) for compounds of structure (I) wherein A is a bond, reaction of a compound of structure (V): (Wherein R 1, n and m are as defined above) with a compound of structure wherein Ar is as described for structure (I) and X 1 is an alkali metal; (e) the introduction of the group R into a compound of formula (VI): (following formula): compound RL, wherein L 'is a leaving group; (f) reducing a compound of formula (VII): (VII) in which R1 is C1 -C6 alkyl (phenyl) p, C2 -C7 alkenyl (phenyl) p, C2-7 alkynyl (phenyl) p or C1-7 alkylCcycloC1-3 alkyl; (g) reducing a compound of structure (VIII): < fH2 > nA (CH2 > B, lr (WXXI) P wherein R 1, A, Ar is a counterion; and, optionally, m and n are as defined above and X is then the formation of a salt. A process according to claim 1, wherein R is C1-6 alkyl, phenyl (C1-6 alkyl) or phenyl (C2-8 alkenyl) " 3. A process as claimed in claim 1 or claim 2, wherein A is oxygen. A process according to any one of claims 1 to 23, characterized in that n is 0 to 3. -44-72 953 BB / JF / mrp / 22040 A process according to any one of claims 1 to 4, characterized in that m is 0 to 3. A process according to any one of claims 1 to 5, characterized in that A is optionally substituted phenyl. Process according to claim 1, characterized in that a compound selected from the group " is prepared. Methyl-4- [2- (4-trifluoromethylphenoxy) ethyl] -1-piperazinecarboxylate, 4- [2- (3-trifluoromethylphenoxy) ethyl] 4- [2- (4-fluorobenzoxy) ethyl] -1-pentylpiperidine, 4- [2- (3,4-methylenedioxyphenoxy) ethyl] -1-pentylpiperidine, 4- (2-phenoxyethyl) -1-pentylpiperidine , 4- [2- (4-benzyloxyphenoxy) ethyl] -1-pentylpiperidine, 4- [2- (4-fluorophenoxy) ethyl] -1- 4- [2- (3,4-dichlorophenoxy) ethyl] -1-pentylpiperidine, 4- [2- (4-benzylphenoxy) ethyl] -1-pentylpiperidine, 4- (4-fluorobenzyloxy) -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-iso-propylphenoxy) ethyl] -1-pentylpiperidine, 4- [2- (3,4-dichlorophenyl) dichlorophenoxy) ethyl] -1- (3-phenylpropyl) p iperidine, or 1-cyclopropylmethyl-4 '[2- (4-fluorophenoxy) ethyl] piperidine; or a pharmaceutically acceptable salt thereof. 8. A process for the preparation of a pharmaceutical composition comprising a compound of structure (I) as defined in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier. 72 953 BB / JF / mrp / 22040 ~ 45 > Lisbon > -5. m 1991 By SMITH KLINE & FRENCH LABORATORIES LIMITED ~ 0 OFFICIAL AGENT =