WO2002100861A1 - 1-(3-phenyloxypropyl)piperidine derivatives - Google Patents

Abstract

The present invention relates to 1(3-phenyloxypropyl)-piperidine derivative having general Formula (I), wherein R1 is (C1-6)alkyl or (C4-8)cycloalkyl or phenyl, optionally substituted with (C1-6)alkyl, (C1-6)alkyloxy or halogen; R2 is H or (C1-6)alkyl; or R1 and R2 form together with the carbon atom to which they are bound (C4-8)cycloalkyl, optionally substitutes with (C1-6)alkyloxy or halogen; R3 is H, OH, (C1-6)alkyloxy or (C1-6)alkylcarbonyloxy; R4 represents 1-5 substituents independently selected from H, (C1-6)alkyl, (C1-6)alkyloxy and halogen; Y represents (a), (b) and Z is H; or Y and Z together with the carbon atom to which they are bound represent the spiro atom in the spiro atom in the spiro system formed with (c) *represents the spiro carbon atom; R6 is H, (C1-6)alkyl or (CO)n-(CH2)m-R12; n is 0 or 1; m is 1-4; R8 and R10 are independently H or(C1-6)alkyl; R7, R9 and R11 are independently H, (C1-6)alkyl, (C1-6)alkyloxy or halogen; R12 is hydroxy, (C1-4)alkyloxy, (C1-4)alkylthio, (C1-4)alkyloxycarbonyl, (C1-4)alkylcarbonyloxy, 2-tetrahydrofuranyl, 4-morpholinyl or di(C1-4)alkylamino; or a pharmaceutically acceptable salt thereof. The present invention also relates to pharmaceutical compositions comprising said derivatives, as well as to the use of these 1-(3-phenyloxypropyl)-piperidine derivatives in therapy.

Description

1-(3-PHENYLOXYPROPYL)PIPERIDINE DERIVATIVES

The present invention relates to 1-(3-phenyloxypropyl)-piperidine derivatives, to pharmaceutical compositions comprising the same, as well as to the use of these 1-(3-phenyloxypropyl)-piperidine derivatives in therapy.

Pharmacological studies have firmly established that there are 3 well-defined "classical" types of opioid receptors μ, δ and K. More recently, an "orphan" receptor has been identified with a high degree of homology to the "classical" receptors. Based on sequence homology, this receptor is an opioid receptor and has been named ORL-1 (opioid-receptor-like 1 : Mollereau et al., FEBS Letters, 1994, 341, 33- 38). Notwithstanding the structural homology between these G-protein coupled receptors ORL-1 does not bind opiates and opioid receptor antagonists with high affinity. The subsequent discovery (independently by two groups) of the endogenous ligand nociceptin (so named to indicate its hyperalgesic effect as determined in the hot-plate test after icv administration in mice: Meunier et al. Nature, 1995, S77, 532- 535), also named orphanin FQ (Reinscheid et al., Science, 1995, 270, 792-794), has initiated intensive study of the potential functions of the receptor. Nociceptin is a 17- amino acid peptide bearing structural resemblance to known opioid peptides like dynorphin A, the endogenous ligand of the κ-opioid receptor. The ORL-1 receptor mRNA is present in almost all the regions of the brain (excluding the cudate-putamen and cerebellum) and in the spinal cord, and has further been found in intestine, vas deferens, liver and kidney. The wide distribution of the ORL-1 receptor suggests a broad pharmacological profile for nociceptin and of a number of potential therapeutic applications, such as those associated with the treatment of pain, learning and memory disorders, stress and anxiety, eating disorders, cognitive deficiency, drug addiction, locomotory disfunction, hypertension, neuroendocrine dysfunction and water retention. The use of "classical" opioids, such as morphine and codeine, as analgesic agent in the clinic can be accompanied by severe side effects such as respiratory depression, constipation as a result of decrease in gastrointestinal motility, nausea and emesis, pruritis, tolerance and physical dependance. The development of ORL-1 selective ligands may potentially lead to analgesics with improved side effect profile.

A number of non-peptide ORL-1 ligands, mimetics of nociceptin, have recently been reported. 2-Substituted-1-piperidinyl benzimidazole derivatives are disclosed in WO 00/08013 (Pfizer Inc.) and in EP 1069124 (Pfizer Inc.), while 4-(2-keto-1-benzimid- azolinyl)piperidine compounds are disclosed in WO 99/36421 (Pfizer Inc.) as ORL-1 receptor agonists, useful as analgesics and other ORL-1 receptor mediated activities. Nociceptin receptor antagonists useful in the treatment of pain, anxiety, cough, asthma, depression and alcohol abuse have been disclosed in WO 00/06545 (Schering Corporation), while the use of ORL-1 agonists for the specific treatment of cough is disclosed in WO 01/07050 (Schering Corporation). Recent approaches in the discovery of selective, non-peptide ORL-1 agonists and antagonists have been reviewed by Ronzoni , S. et al. (Exp. Opin. Ther. Patents, 2001, H, 525-546).

There remains a need for additional compounds useful for the selective modulation of the effects of nociceptin, especially for the management of pain and anxiety states and to produce sedation.

To that aim the present invention provides 1-(3-phenyloxypropyl)-piperidine derivatives having general formula I

wherein Formula I

R1 is (C_1-6)alkyl or (C .₈)cycloalkyl or phenyl, optionally substituted with(Cι.₆)alkyl, (Cι_-6)alkyloxy or halogen; R2 is H or (C_1-6)alkyl; or R1 and R2 form together with the carbon atom to which they are bound (C_4-8)cycloalkyl, optionally substituted with (C_1-6)alkyl, (C_1-6)alkyloxy or halogen; R3 is H, OH, (C_1-6)alkyloxy or (C_1-6)alkylcarbonyloxy; R4 represents 1-5 substituents independently selected from H, (Chalky!, (Cι_-6)alkyloxy and halogen; Y represents

and Z is H; or Y and Z together with the carbon atom to which they are bound represent the spiro atom in the spiro system formed with

(C) * represents the spiro carbon atom;

R6 is H, (C_1-6)alkyl or (CO)n-(CH₂)m-R12; n is 0 or 1; m is 1-4;

R8 and R10 are independently H or (C_1-6)alkyl; R7, R9 and R11 are independently H, (Cι_-6)alkyl, (C_1-6)alkyloxy or halogen;

R12 is hydroxy, (Cι^)alkyloxy, (C_1- )alkylthio, (C^alkyloxycarbonyl, (C_1-4)alkyl- carbonyloxy, 2-tetrahydrofuranyl, 4-morpholinyl or di(C₁^)alkylamino; or a pharmaceutically acceptable salt thereof, which are high affinity binding ligands of the ORL-1 -receptor, and which selectively bind to this receptor with respect to the other opioid receptors μ, δ and K.

1-(3-Phenyloxypropyl)-piperidine derivatives, wherein the 4-position of the piperidine ring is substituted with a 4-(2-oxo-1-benzimidazolinyl)-group [compounds according to formula I wherein R1 , R2 and R3 are hydrogen; Y represents the 4-(2-oxo-1- benzimidazolinyl)-group (A)] are known for a long time (US 3,225,052: Janssen Pharmaceutica N.V.) as compounds having central nervous system depressant activity, and particularly as neuroleptic (antipsychotic) agents. 1-(3-Phenyloxypropyl)- piperidine derivatives according to formula I wherein R1 , R2 and R3 are hydrogen and Y represents the spiro-atom in the 4-oxo-1 ,3,8-triazaspiro[4,5]decane ring system (C) (US 3,238,216: Janssen Pharmaceutica N.V.)) are also long known for their anti-psychotonic, analgesic, anti-inflammatory and anti-hypertensive activities. Compounds according to formula I wherein both R1 and R2 are hydrogen, R3 is OH and Y represents the 4-(2-oxo-1-benzimidazolinyl)-group (A) or the spiro-atom in the 4-oxo-1 , 3, 8-triazaspiro[4,5]decane ring system (C), are known (BE 786155: Sumitomo Chemical Co. Ltd.) as pharmacologically active substance, and particularly for having anti-inflammatory, analgesic, sedative, anti-convulsive or anti-hypertensive acivities.

When compared with said prior art compounds, the 1-(3-phenyloxypropyl)-piperidine derivatives of the present invention differ by the structural feature of being further substituted (R1 and R2) at the 3-position. Surprisingly, this structural modification leads to compounds having selective affinity for the ORL-1 opioid receptor.

The 1-(3-phenyloxypropyl)-piperidine derivatives of the invention can be used as . analgesic, anaesthetic, sedative, anti-inflammatory, diuretic, neuroprotective, vasodilator, and anti-anxiety agent or can be used to treat memory disorders or eating disorders. Preferably, compounds of the invention are useful as analgesic, anaesthetic or sedative agent.

The term (C_1-6)alkyl, as used in the definition of formula I, means a branched or unbranched alkyl group having 1-6 carbon atoms, like hexyl, pentyl, neopentyl, butyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl and methyl.

The term (C_1-4)alkyl means a branched or unbranched alkyl group having 1-4 carbon atoms, like butyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl and methyl.

The term (C_4-8)cycloalkyl means a cyclic alkyl group having 4-8 carbon atoms, like cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

In the terms (C_1-6)alkyloxy and (C_1-6)alkylcarbonyloxy, (Cι-s)alkyl has the meaning as defined above. Preferred are ethyloxy end methyloxy.

In the terms (Cι^)alkyloxy, (C_1-4)alkylthio, (C_1- )alkyloxycarbonyl and (C_1-4)alkyl- carbonyloxy, (C^)alkyl has the meaning as defined above. The term halogen means F, Cl, Br, or I.

Preferred are the 1-(3-phenyloxypropyl)-piperidine derivatives of formula I wherein R1 is (C_1-6)alkyl or phenyl, and R2 is H; or R1 and R2 form together with the carbon atom to which they are bound (C_4-8)cycloalkyl; R3 is H or OH.

Especially preferred are the compounds of formula I wherein the R4 substitutent at the phenyl ring represents substituents at both the 2 and the 5-position.

More preferred are the 1-(3-phenyloxypropyl)-piperidine derivatives of formula I wherein Y represents

and Z is H, and wherein R6 and R7 have the meaning as previously defined.

Particularly preferred compounds of the invention are 1-{1-[3-(2,5-dimethylphenoxy)-4-methylpentyl]-4-piperidinyl}-1 ,3-dihydro-2H- benzimidazole-2-one;

1-{1-[3-(5-methoxy-2-methylphenoxy)-4-methylpentyl]-4-piperidinyl}-1 ,3-dihydro-

2H-benzimidazole-2-one;

(S)-1-{1-[3-(5-methoxy-2-methylphenoxy-4-methylpentyl]-4-piperidinyl}-3- (methoxymethyl)-l ,3-dihydro-2H-benzimidazole-2-one;

(S)-1-{1-[3-(5-methoxy-2-methylphenoxy)-4-methylpentyl]-4-piperidinyl}-3-(2- methoxyethyl)-1 ,3-dihydro-2H-benzimidazole-2-one;

1-{1-[3-(5-methoxy-2-methylphenoxy)-4-methylpentyl]-4-piperidinyl}-3-[2-

(methylthio)ethyl]-1 ,3-dihydro-2/-/-benzimidazole-2-one; and 1 -{1 -[3-(5-methoxy-2-methylphenoxy)-4-methylpentyl]-4-piperidinyl}-3-

(acetoxymethyl)-1 ,3-dihydro-2H-benzimidazole-2-one; and pharmaceutically acceptable salts thereof.

The invention provides in a further aspect pharmaceutical compositions comprising a 1-(3-phenyloxypropyl)-piperidine derivative derivative having general formula I, or a pharmaceutically acceptable salt thereof, in admixture with pharmaceutically acceptable auxiliaries.

The 1-(3-phenyloxypropyl)-piperidine derivatives of the invention can be prepared from an alkylation of a compound of formula II, wherein R1-R4 have the meanings as previously defined, and wherein L represents a leaving group such as for example

Formula II Formula III a halogen, i.e. chloro, bromo or iodo, or an activated sulfonate group, such as methylsulphonate, tosylate of tresylate (2,2,2-trifluoroethanesulphonate), with a cyclic amine of formula III, wherein Y and Z have the meanings as previously defined. It will be appreciated by the skilled person that certain functional groups, for instance the hydroxy group in case R3 represents OH, may require temporarily protection during this alkylation reaction. Suitable protecting groups for such functional groups are well known in the art, for example from Wuts, P.G.M. and Greene, T.W.: Protective Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999.

An alternative route for the synthesis of compounds of formula I wherein R3

Formula IV Formula III is OH, is presented by the alkylation of a cyclic amine of Formula III, wherein Y and

Z have the previously defined meanings, by an epoxide derivative of formula IV, wherein R1 , R2 and R4 have the meanings as previously defined.

Compounds of formula II can be prepared from the Mitsunobu condensation (Mitsunobu, O. et al. Bull. Chem. Soc. Japan, 1967, 40, 935 and 2380) of an alcohol derivative of Formula V, wherein R1-R3 have the meanings as previously defined, provided that when R3 is OH it is to be protected by an appropriate protecting group, with a phenol derivative of Formula VI using triphenylphosphine and diethylazodicarboxylate.

Formula V Formula VI Formula II Compounds of formula wherein Y represents the 4-(2-oxo-1-benzimidazolinyl)- group (A) and Z is H, can be prepared as described in the art, for instance as disclosed in US 3,225,052 (Janssen Pharmaceutica N.V.) and in WO 99/36421 (Pfizer Inc.).

Compounds of formula III wherein Y represents the benzimidazol-1-yl group (B) and Z is H, can be prepared as described in the art, for example using methods disclosed in WO 00/08013 (Pfizer Inc.).

Compounds of formula III wherein Y and Z together with the carbon atom to which they are bound represent the spiro atom in the spiro system formed with (C),

(C) i.e. 4-oxo-1 ,3,8-triazaspiro[4,5]decane derivatives, can be prepared as described in the literature, for instance using methods exemplified in DE 4405178 (Hoechst AG). Compounds of formula IV can be prepared by condensation of a phenol derivative of Formula VI with an 1-bromo-1-carboxaldehyde compound according to Formula VIII to give the intermediate compound of Formula VII, the aldehyde group of which can be converted into the epoxide group, for instance by reaction with dimethylsulfonium- methylide. Starting materials such as the compounds of Formula V, Formula VI and Formula VIII are commercially available or are known or can be prepared using procedures known to the person skilled in the art.

Formula VIII Formula VI Formula VII Formula IV

The compounds of this invention may possess chiral carbon atoms, and can therefore be obtained as pure stereoisomers, or as a mixture of stereoisomers. Of the 1-(3-phenyloxypropyl)-piperidine derivatives of the invention which have a single asymmetric center at the carbon atom to which R1 and R2 are bound, the dextrorotary (+) enantiomers are preferred.

Methods for asymmetric synthesis whereby the pure stereoisomers are obtained are well known in the art, e.g. synthesis with chiral induction, enantioselective enzymatic ester hydrolysis, crystallization of salts which are obtained from optically active acids and the racemic mixture, separation of stereoisomers or enantiomers using chromatography on chiral media, or on straight phase or reversed phase chromat- ography media. Such methods are for example described in Chirality in Industry (edited by A. N. Collins, G. N. Sheldrake and J. Crosby, 1992; John Wiley).

Pharmaceutically acceptable salts of the compounds of formula I may be obtained by treating the free base of the compounds according to formula I with a mineral acid such as hydrochloric acid, phosphoric acid, sulphuric acid, preferably hydrochloric acid, or with an organic acid such as for example ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulphonic acid and the like.

The compounds of the invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent with the unsolvated forms for the purpose of the invention.

The pharmaceutical compositions for use according to the invention comprise a 1-(3- phenyloxypropyl)-piperidine derivative having formula I or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable auxiliaries, and optionally other therapeutic agents. The term "acceptable" means being compatible with the other ingredients of the composition and not deleterious to the recipients thereof. The compositions can be prepared in accordance with standard techniques such as for example are described in the standard reference: Gennaro, A.R. et al., Remington: The Science and Practice of Pharmacy (20th Edition, Lippin- cott Williams & Wilkins, 2000, see especially Part 5: Pharmaceutical Manufacturing). Compositions include e.g. those suitable for oral, sublingual, intranasal, subcutaneous, intravenous, intramuscular, local, or rectal administration, and the like, all in unit dosage forms for administration. For oral administration, the active ingredient may be presented as discrete units, such as tablets, capsules, powders, granulates, solutions, and suspensions. For parenteral administration, the pharmaceutical composition of the invention may be presented in unit-dose or multi-dose containers, e.g. injection liquids in predetermined amounts, for example in sealed vials and ampoules, and may also be stored in a freeze dried (lyophilized) condition requiring only the addition of sterile liquid carrier, e.g. water, prior to use.

The invention further includes a pharmaceutical composition, as hereinbefore described, in combination with packaging material suitable for said composition, said packaging material including instructions for the use of the composition for the use as hereinbefore described.

In a general aspect the invention relates to the use of a 1-(3-phenyloxypropyl)- piperidine derivative according to formula I of claim 1 , or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disorder or condition which is responsive to modulation of the ORL-1 receptor. In a preferred embodiment such medicaments can be used as analgesic, anaesthetic, sedative, anti-inflammatory, diuretic, neuroprotective, vasodilator or as an anti- anxiety agent or used to treat memory disorders (e.g. Alzheimer's disease) or eating disorders.

This invention also related to a method of treating a disorder or a condition, or anaesthetizing a mammal including a human, the treatment of which is responsive to modulation of the ORL-1 receptor, which comprises administering to a mammal, including a human, an effective amount of a 1-(3-phenyloxypropyl)-piperidine derivative according to formula I. The compounds of the invention may be administered for humans in a dosage of 0.001-50 mg per kg body weight, preferably in a dosage of 0.01-20 mg per kg body weight:

The invention is illustrated by the following examples.

General: All mass spectrometry was carried out on either a PE SCI EX API 150EX or a PE SCIEX API 365 machine. Optical rotations were determined on a Shimadzu Graphicord UV-Visible recording spectrophotometer.

Example 1.

1-(1-r3-(2-chloro-5-methylphenoxy)-3-phenylpropyn-4-piperidinyl}-1 ,3-dihvdro-2 - - benzimidazole-2-one.

A: 3-chloro-1-phenyl-1-propanol.

A magnetically stirred mixture of 3-chloropropiophenone (1.69 g, 10 mmol) and sodium bicarbonate (1.0 g) in ethanol (8 mL) and water (4 mL) was cooled in an ice bath. Sodium borohydride (0.19 g, 5 mmol) was added over 10 minutes, the cooling bath was removed and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and the remainder was acidified by the addition of 1M hydrochloric acid (50 mL) and extracted with diethyl ether. The organic layer was washed with saturated brine, dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (CH₂CI₂ as eluant) to give 3-chloro-1-phenyl-1-propanol (1.05 g, 62%).

B: 3-(2-chloro-5-methylphenoxy)-3-phenylpropyl chloride.

Diethyl azodicarboxylate (1.10 mL, 7.0 mmol) was added to a stirred solution of 2-chloro-5-methyl phenol (1.00 g, 7.0 mmol), 3-chloro-1-phenyl-1-propanol (1.00 g, 5.87 mmol) and triphenylphosphine (1.84 g, 7.0 mmol) in tetrahydrofuran (30 mL). The mixture was stirred for 3h at room temperature and the resulting solution was concentrated under reduced pressure. Flash chromatography on silica gel using petroleum ether - ethyl acetate (95:5, v/v) as eluant gave 3-(2-chloro-5- methylphenoxy)-3-phenylpropyl chloride as a colourless oil (1.34 g, 77%) C: Title compound using method I: A mixture of 4-(2-oxo-1-benzimidazolinyl)-piperidine (0.109 g, 0.5 mmol), 3-

(2-chloro-5-methylphenoxy)-3-phenylpropyl chloride (0.148 g, 0.5 mmol; described under B), potassium carbonate (0.069 g, 0.5 mmol) and sodium iodide (0.025 g, 0.16 mmol) in Λ/,Λ/-dimethylformamide (3 mL) was heated at 50 °C for 72 h with magnetic stirring. The mixture was then poured onto water, which was extracted (2x) with ethyl acetate. The combined organic layers were washed with water (3x), dried (Na₂SO ) and concentrated under reduced pressure to give an oil. Purification by flash chromatography on silica gel [CH₂CI₂ elution followed by CH₂CI₂ /CH₃OH (98:2)] gave 1-{1-[3-(2-chloro-5-methylphenoxy)-3-phenylpropyl]-4-piperidinyl}-1 ,3-dihydro-2H- benzimidazole-2-one as a colourless oil (0.117 g, 49%). MS (ES): 476.1 (MH⁺ )

D: Title compound using method II.

A mixture of 4-(2-oxo-1-benzimidazolinyl)-piperidine (0.063 g, 0.29 mmol), 3- (2-chloro-5-methylphenoxy)-3-phenylpropyl chloride (0.086 g, 0.29 mmol), and triethylamine (0.049 mL, 0.35 mmol) in acetonitrile (5 mL) was heated at 80 °C for 72 h with magnetic stirring. The solution was concentrated under reduced pressure and the residue dissolved in CH₂CI₂. The solution was washed with 10% aq. Na₂CO₃, dried (Na₂SO ) and concentrated under reduced pressure to give an oil. Purification by flash chromatography on silica gel [CH₂CI₂ elution followed by CH₂CI₂ /CH₃OH (98:2)] gave 1-{1-[3-(2-chloro-5-methylphenoxy)-3-phenylpropyl]-4-piperidinyl}-1 ,3- dihydro-2/-/-benzimidazole-2-one as a colourless oil (0.039 g, 29%), identical by MS and 1 H-NMR to the material obtained via Method I.

Example 2.

1-(1-r3-(2.5-dimethylphenoxy)-4-methylpentvN-4-piperidinyl)-1 ,3-dihydro-2/-/- benzimidazole-2-one

A: 4-methyl-pentane-1 ,3-diol A round-bottomed flask was charged with a solution of lithium aluminium hydride in tetrahydrofuran (30.2 mL of a 1M solution, 30.2 mmol) under a nitrogen atmosphere and the solution was cooled to -20 °C. Ethyl isobutyrylacetate (2.44 mL, 15.1 mmol) was added slowly with magnetic stirring, such that the temperature of the solution was kept below -20 °C. After the addition was complete, the reaction was allowed to warm to room temperature and stirred for 72h. The reaction was then cooled in an ice bath and quenched by the addition of water (1.15 mL), 4M NaOH (1.15 mL) then water (3.45 mL). The mixture was filtered through a pad of Celite, which was washed with tetrahydrofuran and the resulting solution was concentrated under reduced pressure to give 4-methyl-pentane-1 ,3-diol as a colourless oil (1.60 g, 90%). B: 4-methyl-1 ,3-pentanediol-1 -methanesulfonate.

A magnetically stirred solution of 4-methyl-pentane-1 ,3-diol (7.05 g, 59.7 mmol) and triethylamine (9.15 mL, 65.6 mmol) in CH₂CI₂ (60 mL) was cooled to 0 °C under a nitrogen atmosphere. Methanesulfonyl chloride (5.08 mL, 65.6 mmol) was added dropwise over 20 min and the solution was stirred 18h at 0 °C. The reaction mixture was diluted with additional CH₂CI₂ (40 mL), washed with saturated aqueous sodium hydrogen carbonate, water, dried (Na₂SO ) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (CH₂CI₂/CH₃OH, 100:0 to 98:2, gradient elution) to give 4-methyl-1 ,3-pentanediol-1- methanesulfonate as an oil (5.01 g, 42%). C: Title compound.

Diethyl azodicarboxylate (1.76 mL, 11.0 mmol) was added to a stirred solution of 2,5-dimethyl phenol (1.34 g, 11.0 mmol), 4-methyl-1 ,3-pentanediol-1-methane- sulfonate (1.82 g, 9.16 mmol; described under B) and triphenylphosphine (2.86 g, 11.0 mmol) in tetrahydrofuran (60 mL). The mixture was stirred for 18h at room temperature and the resulting solution was concentrated under reduced pressure. Flash chromatography on silica gel using petroleum ether-ethyl acetate (1 :1) as eluant gave 3-(2,5-dimethylphenoxy)-4-methyl-pentan-1-ol-methanesulfonate as an impure colourless oil, which was directly used in the next step. The impure product, 4-(2-oxo-1-benzimidazolinyi)-piperidine (1.98 g) and triethylamine (2.53 mL) in aceto- nitrile (100 mL) were heated at reflux with magnetic stirring for 48 h. The mixture was concentrated under reduced pressure and the residue was subjected to flash chromatography on silica-gel (eluting with CH₂CI₂ / CH₃OH, 99:1 to 95:5, gradient elution) to give 1-{1-[3-(2,5-dimethylphenoxy)-4-methylpentyl]-4-piperidinyl}-1 ,3-dihydro-2H- benzimidazole-2-one as a pale yellow foam (0.63 g, 16% overall yield from 4-methyl-

1 ,3-pentanediol-1-methanesulfonate). MS (ES): 421.8 (MH⁺ )

D: Chiral separation of enantiomers of 1-|1-r3-(2,5-dimethylphenoxy)-4-methylpentvπ-

4-piperidinyl)-1 ,3-dihvdro-2 -/-benzimidazole-2-one : The product obtained as described under C (200 mg) was dissolved in ethanol (10 ml) and diethylamine (1 ml) and injected (1 ml) onto a Chirapak^® AD preparative column (2cm x 25cm) eluting with isohexane/isopropanol (95:5; v/v) at a flow rate of 12 ml/min. and the detector at 254nm. Enantiomers collected separately.

This was repeated (x 9) and separated fractions evaporated to dryness under vacuum to give enantiomer 1 (70mg) and enantiomer 2 (70mg).

Maleic acid was dissolved in diethyl ether/dichloromethane (10ml) and was added to a solution of enantiomer 1 (70mg) in diethyl ether. The resulting precipitate was filtered and dried to leave an off white solid (75mg). Enantiomeric ratio 100 : 0.

[α]_D = +18.1° (c=1.7; methanol.) Maleic acid was dissolved in diethyl ether/dichloromethane (10ml) and was added to a solution of enantiomer 2 (70mg) in diethyl ether. The resulting precipitate was filtered and dried to leave an off white solid (61 mg). Enantiomeric ratio 99.7:0.3.

[α]_D = -16.6° (c=1.6; methanol).

Example 3.

1 -(1 -f3-(5-methoxy-2-methylphenoxy)-4-methylpentyl1-4-piperidinyl)-1 ,3-dihydro-2H- benzimidazole-2-one.

A: 1 -chloro-4-methyl-pentan-3-one

A solution of isobutyryl chloride (5.24 mL, 0.05 mol) in dichloromethane (150 mL) was cooled to 0 °C and aluminium trichloride (8.00 g, 0.06 mol) was added portion-wise under a nitrogen atmosphere with magnetic stirring. When addition was complete, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature. Ethylene was bubbled through the stirred reaction mixture for 8 h. The reaction mixture was then cooled to -10 °C and slowly quenched by the addition of ice / water (150 mL). The organic layer was collected and the aqueous layer was extracted further (2 x CH₂CI₂). The combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure to give 1-chloro-4-methyl- pentan-3-one (4.20 g, 62 %). B: 1 -chloro-4-methyl-pentan-3-ol

1-Chloro-4-methyl-pentan-3-ol was prepared following the procedure described in Example 1A, using 1-chloro-4-methyl-pentan-3-one in place of 3-chloropropio- phenone. The product was obtained in 43 % yield following purification by flash chromatography on silica-gel [CH₂CI₂/CH₃OH, (100:0 to 95:5, gradient elution) as eluant].

C: 3-(5-methoxy-2-methylphenoxy)-4-methylpentyl chloride

Diethyl azodicarboxylate (0.475 mL, 3.00 mmol) was added to a magnetically stirred solution of 5-methoxy-2-methylphenol (0.413 g, 3.00 mmol; prepared according to the procedure of S. Ram and L.D. Spicer, Tetrahedron Letts., 1988, 29, 3741), 3-hydroxy-4-methylpentyl chloride (0.342 g, 2.50 mmol) and triphenylphosphine (0.785 g, 3.00 mmol) in tetrahydrofuran (20 mL). After 18 h the solution was concentrated under reduced pressure and the residue was subjected to flash chromatography on silica-gel (CH₂CI₂ -Et₂O; 100:0 to 80:20; gradient elution) to give 3-(5-methoxy-2-methylphenoxy)-4-methylpentyl chloride (0.172 g, 27 %) as a colour- less oil.

D: Title compound

1 -{1 -[3-(5-methoxy-2-methylphenoxy)-4-methylpentyl]-4-piperidinyl}-1 ,3- dihydro-2H-benzimidazole-2-one was prepared according to the procedure described in Example I D using 3-(5-methoxy-2-methylphenoxy)-4-methylpentyl chloride in place of 3-(2-chloro-5-methylphenoxy)-3-phenylpropyl chloride. The product was obtained in 53% yield. MS (ES): 438.2 (MH⁺ )

E: Chiral separation of 1-f1-r3-(5-methoxy-2-methylphenoxy)-4-methylpentvπ-4- piperidinyl)-1 ,3-dihvdro-2 -/-benzimidazole-2-one.

The product obtained as described under D (100mg) was dissolved in ethanol (5 ml) and injected (1 ml) onto a Chiracel^® OD preparative column (2 cm x 25 cm) eluting with isohexane/isopropanol/diethylamine (90:10:0.1 ; v/v) at a flow rate of 12 ml/min. and the detector at 230nm. Enantiomers collected separately.This was repeated (x4) and separated fractions evaporated to dryness in vacuo to give enantiomer 1 (40 mg) and enantiomer 2 (40 mg). Enantiomer 1 (40 mg) was dissolved in ethanol (1 ml) and 2M HCl in diethyl ether added with stirring. Solution reduced in volume under vacuum and precipitated with diethyl ether. The resulting solid was filtered and dried to leave 31 mg of off white solid. Enantiomeric ratio 95.6:4.4. [α]_D = -23.5° (c=1.7; methanol).

Enantiomer 2 (40 mg) was dissolved in ethanol (1 ml) and 2M HCl in diethyl ether added with stirring. Solution reduced in volume under vacuum and precipitated with diethyl ether. The resulting solid was filtered and dried to leave 26mg of off white solid. Enantiomeric ratio 99.5:0.5. [α] = +25.7 ° (c=1.8; methanol). F: (R) and (S)-enantiomers of the citrate salt of the title compound.

The product obtained as described in Example D was subjected to chiral chromatography on a Chiracel^®OD column (2 cm x 25 cm), eluting with isohexane/isopropanol 90/10 (v/v) at 15 ml/min. A total of 2.0 g were separated by repeated injections of 500μl (100mg) to give 910 mg of enantiomer 1 (R) and 1050 mg of enantiomer 2 (S). However, both components were found to be contaminated with the N-oxide derivative, and thus were further chromatographed on 40 g silica gel eluting with dichloromethane-ethanol (97:3). Recovered enantiomer 1 (420mg) and enantiomer 2 (390mg) were then converted to the citrate salts with 1 equivalent of citric acid in dichloromethane/ethanol and then precipitated twice from acetone by flooding with diethyl ether to give 510mg and 480mg respectively. Enantiomer 1 (R); HPLC purity 99.3%, enantiomeric ratio 98.6 : 1.4%, [α]_D = -17.0° (c=4.4; methanol); MS 438.2 (MH⁺) Enantiomer 2 (S); HPLC purity 99.5%, enantiomeric ratio 4.5 : 95.5%, [α]_D = +13.0° (c=5.1 ; methanol); MS 438.2 (MH⁺)

Example 4.

1 -(1 -f3-(5-methoxy-2-methylphenoxy)-4-methylpentyll-4-piperidinyl>-3-methyl-1 ,3- dihvdro-2H-benzimidazole-2-one

A magnetically stirred solution of 3-(5-methoxy-2-methylphenoxy)-4- ethylpentyl chloride (0.200 g, 0.78 mmol), 3-methyl-1-(4-piperidinyl)-1 ,3-dihydro- 2/-/-benzimidazole-2-one (0.180 g, 0.78 mmol) and triethylamine (0.40 mL, 2.87 mmol) in acetonitrile (10 mL) was heated at 80 °C for 4 days. The reaction mixture was then concentrated under reduced pressure and the residue was partitioned between ethyl acetate and 5% aqueous sodium carbonate. The organic layer was collected and the aqueous layer was again extracted with ethyl acetate. The combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel (CH₂CI₂ - CH₃OH; 100:0 to 95:5; gradient elution) to give 1-{1-[3-(5-methoxy-2-methyl- phenoxy)-4-methylpentyl]-4-piperidinyl}-3-methyl-1 ,3-dihydro-2H-benzimidazole-2- one as a colourless oil (0.140 g, 40%). MS (ES): 452.2 (MH⁺ )

Example 5

8-f3-(5-methoxy-2-methylphenoxy)-4-methylpentvn-1-phenyl-1.3.8- triazaspirof4.51decan-4-one

The title compound was prepared according to the procedure described in Example 4, substituting 1-phenyl-1 ,3,8-triazaspiro[4,5]decan-4-one for 3-methyl-1-(4- piperidinyl)-1 ,3-dihydro-2H-benzimidazole-2-one. The product was obtained in 44% yield. MS (ES): 452.2 (MH⁺ )

Example 6.

1-(1-r3-(2-chloro-5-methoxyphenoxy)-4-methylpentvn-4-piperidinyl)-1.3-dihvdro-2 -/- benzimidazole-2-one

A: 2-chloro-5-methoxyphenol

A magnetically stirred solution of 3-methoxyphenol (10.97 mL, 0.10 mol) in chloroform (35 mL) contained in a round-bottomed flask was cooled in an ice-bath. A solution of sulfuryl chloride (8.84 mL, 0.11 mol) in chloroform (15 mL) was added dropwise over 15 min. The reaction was then heated to 65 °C for 2 h. The solution was allowed to cool to room temperature, washed with saturated brine (2 x 100 mL), dried (Na₂SO₄) and concentrated under reduced pressure. Flash chromatography on silica-gel using CH₂CI₂ as eluent gave 2-chloro-5-methoxyphenol (8.90 g, 56%) as a colourless oil. B: 3-(2-chloro-5-methoxyphenoxy)-4-methyl-pentan-1-ol-methanesulfonate

Diethyl azodicarboxylate (0.95 mL, 6.0 mmol) was added to a stirred solution of 2-chloro-5-methoxyphenol (0.95 g, 6.0 mmol) 4-methyl-1 ,3-pentanediol-1-meth- anesulfonate (0.98 g, 5.0 mmol) and triphenylphosphine (1.57 g, 6.0 mmol) in tetrahydrofuran (30 mL). The solution was stirred for 18h at room temperature and then concentrated under reduced pressure. Flash chromatography on silica gel using dichloromethane as eluant gave 3-(2-chloro-5-methoxyphenoxy)-4-methyl-pentan-1-ol- methanesulfonate (0.61 g, 36%) as a colourless oil. C: Title compound.

A solution of 3-(2-chloro-5-methoxyphenoxy)-4-methyl-pentan-1-ol-methane- sulfonate (0.202 g, 0.6 mmol), 4-(2-oxo-1-benzimidazolinyl)-piperidine (0.13 g, 0.6 mmol) and triethylamine (0.25 mL, 1.8 mmol) in acetonitrile (5 mL) was heated at 80 °C with magnetic stirring for 96 h. The mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane (10 mL) and 5% aqueous potassium carbonate (10 mL). The organic layer was collected, washed with saturated brine, dried (Na₂SO ) and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica-gel (eluting with CH₂CI₂/ CH₃OH, 98:2 to 95:5, gradient elution; then CH₂CI₂ / CH₃OH / cone. NH₄OH, 90:10:0.5) to give 1-{1-[3-(2-chloro-5-methoxyphenoxy)-4-methylpentyl]-4-piperidin- yl}-1 ,3-dihydro-2H-benzimidazole-2-one as an oil (0.25 g, 90%).MS(ES):458.5 (MH⁺ )

Example 7.

1 -(1 -f3-(2-chloro-5-methoxyphenoxy)-4-methylpentyl1-4-piperidinyl}-3-methyl-1.3- dihvdro-2H-benzimidazole-2-one.

The title compound was prepared in 85% yield according to the procedures described in Example 6 using 3-methyl-1-(4-piperidinyl)-1 ,3-dihydro-2H-benzimida- zole-2-one in place of 4-(2-oxo-1-benzimidazolinyl)-piperidine. MS (ES): 472.3 (MH⁺ ) Example 8.

8-[3-(2-chloro-5-methoxyphenoxy)-4-methylpentyll-1-phenyl-1 ,3.8- triazaspirof4.51decan-4-one

The title compound was prepared according to the procedures described in Example

6, substituting 1-phenyl-1 ,3,8-triazaspiro[4,5]decan-4-one for 4-(2-oxo-1-benzimid- azolinyl)-piperidine. The product was obtained in 77% yield. MS (ES): 472.3 (MH⁺ )

Example 9.

1 -(1 -f3-(2-chloro-5-methylphenoxy)-3-phenylpropyn-4-piperidinyl)- 2-methyl-1 H-benz- imidazole

A: 1-benzyl-4-(2-nitroanilino)-piperidine 4-Amino-Λ/-benzylpiperidine (2.87 mL, 14.08 mmol) was added to a magnetically stirred solution of 1-fluoro-2-nitrobenzene (1.35 g, 12.80 mmol) and diisopropylethylamine (4.48 mL, 32.00 mmol) in acetonitrile (100 mL) at room temperature under a N₂ atmosphere. The mixture was warmed to reflux for 72 h, then allowed to cool to room temperature. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (150 mL) and saturated aqueous sodium hydrogen carbonate (100 mL). The organic layer was collected, washed with water (2 x 75 mL), dried (Na₂SO ) and concentrated under reduced pressure to give 1-benzyl-4-(2-nitroanilino)-piperidine (3.05 g, 77%) as an orange solid.

B: N-\ 1 -(phenylmethyl)-4-piperidinvN-1 ,2-benzenediamine

A mixture of 1-benzyl-4-(2-nitroanilino)-piperidine (0.204 g, 0.66 mmol) and tin chloride dihydrate (0.739 g, 3.28 mmol) in ethanol (2 mL) was heated to 70 °C for 30 minutes with magnetic stirring. The mixture was poured onto iced water (15 mL), which was extracted with ethyl acetate (15 mL). The organic layer was washed with saturated brine (10 mL), dried (Na₂SO₄) and concentrated to give Λ/-[1- (phenylmethyl)-4-piperidinyl]-1 ,2-benzenediamine as a brown solid (0.179 g, 97%). C: 2-methyl-1-ri-(phenylmethyl)-4-piperidinyl1-1H-benzimidazole

A solution of /-[1-(phenylmethyl)-4-piperidinyl]-1 ,2-benzenediamine (0.090 g, 0.32 mmol) in acetic acid (1 mL) was heated at 80 °C with magnetic stirring for 18 h. The acetic acid was removed under reduced pressure and the residue was partitioned between dichloromethane (2 mL) and saturated aqueous sodium hydrogen carbonate solution (1 mL). The organic layer was collected and concentrated under reduced pressure. The residue was dissolved in ethanol (2 mL) and water (0.75 mL) and concentrated hydrochloric acid (0.25 mL) were added. The mixture was heated to reflux for 1 h with magnetic stirring. The volatiles were removed under reduced pressure and the residue was partitioned between dichloromethane (15 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL). The organic layer was collected, washed with water (10 mL), dried (Na₂SO ) and con- centrated under reduced pressure to give 2-methyl-1-[1-(phenylmethyl)-4-piperidinyl]- 1H-benzimidazole as a red gum (0.066 g, 68%). D: 2-methyl-1 -(4-piperidinvπ-1 /7-benzimidazole

A magnetically stirred solution of 2-methyl-1-[1-(phenylmethyl)-4-piperidinyl]- 1 /-/-benzimidazole (0.065 g, 0.213 mmol) in dichloromethane (1.5 mL) was cooled to 0 °C. α-Chloroethylchloroformate (0.048 mL, 0.447 mmol) was added and the mixture was allowed to warm to room temperature and stirred 18 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in methanol (2 mL) and heated to reflux with magnetic stirring for 18 h. The solvent was removed under reduced pressure and the residue was triturated with diethyl ether. The solid obtained was collected by filtration, rinsed with diethyl ether and dried in vacuo to give 2-methyl-1-(4-piperidinyl)-1H-benzimidazole as a red solid (0.073 g, quantitative yield). E: Title compound

2-Methyl-1-(4-piperidinyl)-1H-benzimidazole (0.028 g, 0.11 mmol), 3-(2- chloro-5-methylphenoxy)-3-phenylpropyl chloride (0.036 g,, 0.12 mmol) and triethylamine (0.032 mL, 0.23 mmol) in acetonitrile (1 mL) were heated at reflux with magnetic stirring for 72 h. The solvent was removed under reduced pressure and the residue was subjected to reverse-phase semi-preparative HPLC to give 1-{1-[3-(2- chloro-5-methylphenoxy)-3-phenylpropyl]-4-piperidinyl}- 2-methyl-1H-benzimidazole as a brown solid (1.7 mgs, 3%). MS (ES): 474.0 (MH⁺ )

Example 10.

1-f1-(2-f1-(2-chloro-5-methylphenoxy)-cvclohexyn-2-hydroxyethyl>-4-piperidinyl}-1.3- dihvdro-2H-benzimidazole-2-one

A: 1 -bromo-cvclohexane-1 -carboxaldehyde Bromine (2.30 mL, 44.6 mmol) was added dropwise over 30 min to a magnetically stirred solution of cyclohexanecarboxaldehyde (5.40 mL, 44.6 mmol) in chloroform (30 mL), such that the temperature of the reaction was maintained below 35 °C. Stirring was then continued at room temperature for 1 h after the addition was complete. The solution was washed with saturated aqueous sodium thiosulfate (2 x 30 mL), water (2 x 30 mL), saturated brine (2 x 30 mL), dried (Na₂SO ) and concentrated under reduced pressure to give 1-bromo-cyclohexane-1 -carboxaldehyde (8.5 g, 100%) as a liquid. B: 1 -(2-chloro-5-methylphenoxy)-cvclohexane-1 -carboxaldehyde

Sodium hydride (2.14 g, 50% dispersion in oil, 44.5 mmol) was placed in a 500 mL 3-necked flask, washed with heptane (2x) and suspended in toluene (60 mL) under an atmosphere of nitrogen. A solution of 2-chloro-5-methylphenol (6.35 g, 44.5 mmol) in toluene (60 mL) was added to the magnetically stirred suspension dropwise such that the reaction temperature remained below 35 °C. The resulting suspension was stirred for 1 h at room temperature. A solution of 1-bromo- cyclohexane-1 -carboxaldehyde (8.50 g, 44.5 mmol) in toluene (60 mL) was added over 10 min and the reaction mixture was warmed to reflux for 48 h. The reaction mixture was then allowed to cool to room temperature and washed with water, he organic layer was retained and the aqueous was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with saturated brine, dried (Na₂SO₄) and concentrated under reduced pressure. The residue was subjected to chromatography on silica (heptane/diethyl ether, 95:5 as eluant) to give 1-(2-chloro- 5-methylphenoxy)-cyclohexane-1 -carboxaldehyde as a colourless oil (6.26 g, 56%). C: 1 -(2-chloro-5-methylphenoxy)-cvclohexyl-1 -oxirane

Sodium hydride (1.20 g, 50% dispersion in oil, 25.08 mmol) was washed with heptane (2x) then dimethyl sulfoxide (25 mL) was added under a nitrogen atmosphere. Trimethylsulfoxonium iodide (5.77 g, 26.2 mmol) was added in portions to the magnetically stirred reaction mixture, stirring was continued until the evolution of hydrogen gas ceased. A solution of 1-(2-chloro-5-methylphenoxy)-cyclohexane-1- carboxaldehyde (5.76 g, 22.8 mmol) in dimethyl sulfoxide (25 mL) was added rapidly from a dropping funnel and the reaction was then stirred at room temperature for 30 min, then warmed to 50 °C for 30 min. The solution was allowed to cool to room temperature and carefully diluted with water (600 mL). The mixture was extracted with diethyl ether (3 x 200 mL) and the combined organic layers were washed with saturated brine, dried (Na₂SO₄) and concentrated under reduced pressure. The residue was subjected to FC on silica (heptane / diethyl ether, 99:1 to 98:2, gradient elution) to give 1-(2-chloro-5-methylphenoxy)-cyclohexyl-1 -oxirane as a colourless oil (4.06 g, 67%). D: Title compound

A solution of 4-(2-oxo-1-benzimidazolinyl)-piperidine (6.53 g, 33.5 mmol) and 1-(2-chloro-5-methylphenoxy)-cyclohexyl-1 -oxirane (8.93 g, 33.5 mmol) in ethanol (70 mL) was heated at reflux with magnetic stirring for 11 h. An additional quantity of 1-(2-chloro-5-methylphenoxy)-cyclohexyl-1 -oxirane (1.1 g, 4.1 mmol) was added and reflux was continued for 3 h. The resulting solution was concentrated under reduced pressure and the solid was recrystallised from acetone to give 1-{1-{2-[1-(2-chloro-5- methylphenoxy)-cyclohexyl]-2-hydroxyethyl}-4-piperidinyl}-1 ,3-dihydro-2 - -benz imidazole-2-one (7.60 g , 52 %) as a white solid. MS (ES): 484.2 (MH⁺ )

Example 11.

1 -(1 -^~2- ^ -(2-chloro-5-methylphenoxy)-cvclohexyn-2-hvdroxyethyl)-4-piperidinyl}-3- methyl-1 ,3-dihvdro-2H-benzimidazole-2-one

A: 1 -f 1 -(terf-butoxycarbonyl)-4-piperidinvN-1 ,3-dihvdro-2H-benzimidazole-2-one

A mixture of 4-(2-oxo-1-benzimidazolinyl)-piperidine (8.32 g, 38.3 mmol), di- tert-butyldicarbonate (8.36 g, 38.3 mmol) and sodium bicarbonate (9.65 g, 0.115 mol) in methanol was sonicated for 1 hour. The insoluble material was removed by filtration and the filtrate was evaporated under reduced pressure. The residue was subjected to flash chromatography on silica gel [CH₂CI₂ / CH₃OH (98:2) as eluant] to give 1-[1-(te/τ-butoxycarbonyl)-4-piperidinyl]-1 ,3-dihydro-2H-benzimidazole-2-one as a colourless solid (13.14 g, quantitative yield). B: 1 -f 1 -(ten^*-butoxycarbonyl)-4-piperidinyπ-3-methyl-1 ,3-dihydro-2/-/-benzimidazole-2- one

Sodium hydride (1.20 g, 0.03 mol, 60% dispersion in oil) was added to a magnetically stirred solution of 1-[1-(terf-butoxycarbonyl)-4-piperidinyl]-1 ,3-dihydro-2H- benzimidazole-2-one (6.34 g, 0.02 mol) in tetrahydrofuran (200 mL). The reaction mixture was warmed to 50 °C for 3 h, then allowed to cool to room temperature. lodomethane (3.73 mL, 0.06 mol) was added and the reaction mixture was warmed to 50 °C for 3 h. The reaction mixture was then cooled (ice-bath) and quenched by the careful addition of water. The volatiles were removed under reduced pressure and the residue was partitioned between water and diethyl ether. The organic layer was collected and the aqueous was extracted further (2 x) with diethyl ether. The combined organic layers were washed with saturated brine, dried (Na2SO4) and concentrated under reduced pressure to give 1-[1-(tert-butoxycarbonyl)-4-piperidinyl]- 3-methyl-1 ,3-dihydro-2H-benzimidazole-2-one as a colourless solid (5.87 g, 89%). C: 3-methyl-1 -(4-piperidinyl)-1 ,3-dihvdro-2H-benzimidazole-2-one

Trifluoroacetic acid (50 mL) was added to a magnetically stirred solution of 1- [1-(tert-butoxycarbonyl)-4-piperidinyl]-3-methyl-1 ,3-dihydro-2H-benzimidazole-2-one (5.87 g, 17.73 mmol) in dichloromethane (200 mL). After 3 h, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between water (200 mL) and diethyl ether (200 mL). The organic layer was discarded and the aqueous layer was washed further (2 x 100 mL) with diethyl ether. The aqueous layer was then made basic by the addition of saturated aqueous sodium carbonate and extracted with diethyl ether (3 x 100 mL). The combined organic layers were washed with saturated brine, dried (Na₂SO ) and concentrated under reduced pressure to give 3-methyl-1-(4-piperidinyl)-1 ,3-dihydro-2H-benzimidazole-2-one (3.90 g, 95%) as a white solid. D: Title compound A magnetically stirred solution of 3-methyl-1-(4-piperidinyl)-1 ,3-dihydro-2/- - benzimidazole-2-one (0.157 g, 0.68 mmol) and 1-(2-chloro-5-methylphenoxy)-cyclo- hexyl-1 -oxirane (0.219 g, 0.82 mmol) in ethanol (10 mL) was heated under reflux for 18 h. The reaction mixture was concentrated under reduced pressure and the residue was subjected to FC on silica (CH₂CI₂ / CH₃OH, 100:0 to 96:4, gradient elution) to give 1-{1-{2-[1-(2-chloro-5-methylphenoxy)-cyclohexyl]-2-hydroxyethyl}-4- piperidinyl}-3-methyl-1 ,3-dihydro-2H-benzimidazole-2-one (0.144 g, 43%) as a white solid. MS (ES): 498.4 (MH⁺ )

Example 12. 8-(2-f1-(2-chloro-5-methylphenoxy)-cvclohexyn-2-hvdroxyethyl)-1-phenyl-1.3.8- triazaspiror4,51decan-4-one

The title compound was prepared according to the procedure described in Example 11 D. substituting 1-phenyl-1 ,3,8-triazaspiro[4,5]decan-4-one for 3-methyl-1- (4-piperidinyl)-1 ,3-dihydro-2H-benzimidazole-2-one.The product was obtained in 47% yield. MS (ES): 498.4 (MH⁺ )

Example 13.

1-(1-r3-(5-methoxy-2-methylphenoxy)-4-methylpentvn-4-piperidinyl)-3-f2- (dimethylamino)ethyl1-1 ,3-dihvdro-2H-benzimidazole-2-one

A:1-f1-(tet -butoxycarbonyl)-4-piperidinvn-3-(2-chloroethyl)-1 ,3-dihydro-2/-/- benzimidazole-2-one

A magnetically stirred suspension of 1-[1-(tert-butoxycarbonyl)-4-piperidinyl]- 1 ,3-dihydro-2/-/-benzimidazole-2-one (prepared according to the procedure described in Example 11A. 9.51 g, 30.0 mmol), 1-bromo-2-chloroethane (17.21 g, 120.0 mmol) and anhydrous potassium carbonate (18.22 g, 130.0 mmol) in anhydrous N,N- dimethylformamide (80 mL) was warmed under nitrogen at 50 °C for 72 h. The reaction mixture was allowed to cool to room temperature, then partitioned between ethyl acetate and water. The organic layer was collected, washed with water, dried (Na₂SO ) and evaporated to give 1-[1-(terf-butoxycarbonyl)-4-piperidinyl]-3-(2-chloro- ethyl)-1 ,3-dihydro-2H-benzimidazole-2-one as a colourless solid (10.61 g, 93 %). B: 3-r2-(dimethylamino)ethvn-1 -(4-piperidinyl)-1 ,3-dihydro-2/-/-benzimidazole-2-one

A solution of 1-[1-(fert-butoxycarbonyl)-4-piperidinyl]-3-(2-chloroethyl)-1 ,3- dihydro-2H-benzimidazole-2-one (7.38 g, 19.4 mmol) in ethanol (50 mL) was treated in one portion with dimethylamine (50.0 mL, 33 % solution in ethanol) and the resultant solution heated at 85 °C for 12 h. The volatiles were removed under reduced pressure, and the oily residue partitioned between ethyl acetate and water. The organic layer was collected and extracted with 2N hydrochloric acid solution. The acid extracts were collected, washed with ethyl acetate, and allowed to stand at room temperature overnight. The acid extracts were adjusted to pH 14 by addition of 10N potassium hydroxide solution, and extracted with ethyl acetate. The organic extracts were washed with water, dried (Na₂SO₄) and evaporated to give 3-[2- (dimethylamino)ethyl]-1-(4-piperidinyl)-1 ,3-dihydro-2/-/-benzimidazole-2-one as a yellow oil (3.74 g , 67 %). C: Title compound

1-{1-[3-(5-Methoxy-2-methylphenoxy)-4-methylpentyl]-4-piperidinyl}-3-[2- (dimethylamino)ethyl]-1,3-dihydro-2/- -benzimidazole-2-one was prepared according to the procedure described in Example 1C, using 3-[2-(dimethylamino)ethyl]-1-(4- piperidinyl)-1 ,3-dihydro-2H-benzimidazole-2-one in place of 4-(2-oxo-1 ,3-dihydro-2H- benzimidazolinyl)-piperidine and 3-(5-methoxy-2-methylphenoxy)-4-methylpentyl chloride (prepared according to the procedure described in Example 3C) in place of 3-(2-chloro-5-methylphenoxy)-3-phenylpropyl chloride. The product was obtained in 62% yield. MS (ES): 509.4 (MH⁺).

Example 14.

1-(1-f3-(2-Chloro-5-methylphenoxy)-4-methylpentvn-4-piperidinyl)-3-f2- (dimethylamino)ethyll-1.3-dihvdro-2/-/-benzimidazole-2-one

A: 3-(2-Chloro-5-methylphenoxy)-4-methylpentyl chloride

Diisopropyl azodicarboxylate (9.45 g, 47.0 mmol) was added dropwise to a stirred solution of 2-chloro-5-methyl-phenol (6.70 g, 47.0 mmol), 1-chloro-4- methylpentan-3-ol (prepared according to the procedure described in Example 3B, 5.70 g, 42.0 mmol) and triphenylphosphine (12.30 g, 47.0 mmol) in dichloromethane (200 mL) with cooling to maintain reaction temperature below 10 °C. The resultant solution was stirred at room temperature for 12 h, then concentrated under reduced pressure. The residue was dissolved in diethyl ether (50 mL) and treated with heptane (300 mL). The solution was decanted from the oily precipitate, and washed with dilute aqueous sodium hydroxide solution, water, dried (Na₂SO₄) and evaporated to give a yellow oil. Purification by flash chromatography on silica gel using heptane as eluent gave 3-(2-chloro-5-methylphenoxy)-4-methylpentyl chloride (4.45 g, 41%) as a colourless oil. B: Title compound 1 -{1 -[3-(2-Chloro-5-methylphenoxy)-4-methylpentyl]-4-piperidinyl}-3-[2-

(dimethylamino)ethyl]-1 ,3-dihydro-2H-benzimidazole-2-one was prepared according to the procedure described in Example 1C using 3-(2-chloro-5-methylphenoxy)-4- methylpentyl chloride in place of 3-(2-chloro-5-methylphenoxy)-3-phenylpropyl chloride and 3-[2-(dimethylamino)ethyl]-1-(4-piperidinyl)-1 ,3-dihydro-2H-benzimidaz- ole-2-one (prepared according to the procedure described in Example 13B) in place of 4-(2-oxo-1 ,3-dihydro-2H-benzimidazolinyl)-piperidine. The product was obtained in 57% yield. MS (ES): 513.4 (MH⁺).

The following compounds (15-19) were prepared using similar process steps as described in Example 13 and 14:

Example 15: 1 -{1 -[3-(2-chloro-5-methoxyphenoxy)-4-methylpentyl]-4-piperidinyl}-3-

[2-(dimethylamino)ethyl]-1 ,3-dihydro-2H-benzimidazole-2-one;

MS (ES): 529.0 (MH⁺).

Example 16: 1-(1-[3-(5-methoxy-2-methylphenoxy)-4-methylpentyll-4-piperidinyl^'r-3- f2-(diethylamino)ethvn-1.3-dihydro-2 - -benzimidazole-2-one;

MS (ES): 537.4 (MH⁺).

Example 17: 1-(1-r3-(2-chloro-5-methylphenoxy)-4-methylpentyl1-4-piperidinyl)-3-f2-

(diethylamino)ethvπ-1.3-dihvdro-2H-benzimidazole-2-one;

MS (ES): 541.4 (MH⁺). Example 18: 1-(1-r3-(2,5-dimethylphenoxy)-4-methylpentyll-4-piperidinyl}-3-r2-

(diethylamino)ethvn-1 ,3-dihydro-2H-benzimidazole-2-one;

MS (ES): 521.2 (MH⁺).

Example 19: 1-f1-f3-(2-chloro-5-methoxyphenoxy)-4-methylpentvπ-4-piperidinyl>-3- r2-(diethylamino)ethvn-1.3-dihydro-2 - -benzimidazole-2-one; MS (ES): 557.2 (MH⁺).

Example 20.

1-(1-[3-(5-methoxy-2-methylphenoxy)-4-methylpentyll-4-piperidinyl>-3-r2- (methylthio)ethvn-1.3-dihydro-2H-benzimidazole-2-one

A: 1 -π -(te/t-butoxycarbonyl)-4-piperidinyll-3-r2-(methylthio)ethyll-1 ,3-dihvdro-2H- benzimidazole-2-one

A suspension of 1-[1-(te/τ-butoxycarbonyl)-4-piperidinyl]-3-(2-chloroethyl)-1 ,3- dihydro-2H-benzimidazole-2-one (prepared according to the procedure described in Example 13A, 3.54 g, 9.3 mmol) and sodium thiomethoxide (2.00 g, 28.6 mmol) in methanol (50 mL) was heated under reflux for 12 h, then allowed to cool to room temperature. The reaction mixture was poured onto dilute aqueous sodium carbonate solution, and extracted with dichloromethane. The combined extracts were washed with water, dried (Na₂SO ) and evaporated to give 1-[1-(te/τ-butoxycarbonyl)-4- piperidinyl]-3-[2-(methylthio)ethyl]-1 ,3-dihydro-2H-benzimidazole-2-one as a colourless solid in a yield of 73%. B: 3-r2-(methylthio)ethvn-1 -(4-piperidinyl)-1 ,3-dihvdro-2H-benzimidazole-2-one

3-[2-(Methylthio)ethyl]-1-(4-piperidinyl)-1 ,3-dihydro-2H-benzimidazole-2-one was prepared in quantitative yield according to the procedure described in Example 11 C, using 1 -[1 -(terf-butoxycarbonyl)-4-piperidinyl]-3-[2-(methylthio)ethyl]-1 ,3- dihydro-2/-/-benzimidazole-2-one in place of 1-[1-(terf-butoxycarbonyl)-4-piperidinyl]- 3-methyl-1 ,3-dihydro-2/- -benzimidazole-2-one. C: Title compound. 1-{1-[3-(5-methoxy-2-methylphenoxy)-4-methylpentyl]-4-piperidinyl}-3-[2-

(methylthio)ethyl]-1 ,3-dihydro-2H-benzimidazole-2-one was prepared according to the procedure described in Example 1 D, using 3-[2-(methylthio)ethyl]-1-(4- piperidinyl)-1 ,3-dihydro-2H-benzimidazole-2-one in place of 4-(2-oxo-1-benz- imidazolinyl)-piperidine and 3-(5-methoxy-2-methylphenoxy)-4-methylpentyl chloride (prepared according to the procedure described in Example 3C) in place of 3-(2- chloro-5-methylphenoxy)-3-phenylpropyl chloride. The product was obtained in 58% yield. MS (ES): 512.4 (MH⁺).

The following compounds (21-22) were prepared using similar process steps as described in Example 20:

Example 21 : 1-f1-r3-(2-chloro-5-methylphenoxy)-4-methylpentyl1-4-piperidinyl)-3-^r2-

(methylthio)ethyl1-1 ,3-dihydro-2H-benzimidazole-2-one;

MS (ES): 516.2 (MH⁺).

Example 22: 1-f1-f3-(2.5-dimethylphenoxy)-4-methylpentvn-4-piperidinylV3-f2- (methylthio)ethyl1-1 ,3-dihvdro-2H-benzimidazole-2-one;

MS (ES): 496.2 (MH⁺).

Example 23: 1-(1-[3-(2-chloro-5-methylphenoxy)-4-methylpentvn-4-piperidinyl-1.3- dihydro-2/-/-benzimidazole-2-one This compound was prepared according to the procedure described in

Example 1C using 3-(2-chloro-5-methylphenoxy)-4-methylpentyl chloride (prepared according to the procedure described in Example 14A) in place of 3-(2-chloro-5- methylphenoxy)-3-phenylpropyl chloride. The product was obtained in 15 % yield. MS (ES): 442.0 (MH⁺).

Example 24:

(R) and (S)-enantiomers of 1-(1-r3-(5-methoxy-2-methylphenoxy-4-methylpentvn-4- piperidinyl)-3-(methoxymethyl)-1 ,3-dihvdro-2H-benzimidazole-2-one methanesulfonate

A: 1 -H -(tett-άutoxycarbonyl)-4-piperidinvπ-3-methoxymethyl-1 ,3-dihydro-2H- benzimidazole-2-one

A magnetically stirred solution of 1-[1-(tetf-butoxycarbonyl)-4-piperidinyl]-1 ,3- dihydro-2H-benzimidazole-2-one (prepared according to the procedure described in Example 11 A, 5.0 g, 15.75 mmol), in anhydrous Λ/,Λ/-dimethylformamide (50 mL) was treated with sodium hydride (60% dispersion in mineral oil, 0.64 g, 16.0 mmol), portion-wise under a nitrogen atmosphere. The reaction mixture was stirred for 30 min then chloromethylmethyl ether (1.2 mL, 15.8 mmol) added dropwise and the resultant mixture stirred overnight. The reaction mixture was concentrated to low volume under reduced pressure, quenched with water and extracted with ethyl acetate. The organic extracts were washed with water, brine and concentrated under reduced pressure to give 1-[1-(terf-butoxycarbonyl)-4-piperidinyl]-3-methoxymethyl- 1 ,3-dihydro-2/- -benzimidazole-2-one (5.7 g, 100 %). B: 3-methoxymethyl-1-(4-piperidinyl)-1 ,3-dihvdro-2H-benzimidazole-2-one

3-Methoxymethyl-1 -(4-piperidinyl)-1 ,3-dihydro-2H-benzimidazole-2-one was prepared following the procedure described in Example 11C, using ^-[^-(tert- butoxycarbonyl)-4-piperidinyl]-3-methoxymethyl-1 ,3-dihydro-2H-benzimidazole-2-one in place of 1-[1-(te/τ-butoxycarbonyl)-4-piperidinyl]-3-methyl-1 ,3-dihydro-2/-/-benz- imidazole-2-one. The product was obtained in 37 % yield.

C: 1-f3-(5-methoxy-2-methylphenoxy)-4-methylpentvn-4-piperidinyl)-3-methoxymethyl -1 ,3-dihydro-2/-/-benzimidazole-2-one 1-{1-[3-(5-Methoxy-2-methylphenoxy)-4-methylpentyl]-4-piperidinyl}-3- (methoxymethyl)-1 ,3-dihydro-2H-benzimidazole-2-one was prepared following the procedure described in Example 1C, using 3-[(methoxymethyl)-1-(4-piperidinyl)]-1,3- dihydro-2H-benzimidazole-2-one in place of 4-(2-oxo-1 ,3-dihydro-2H- benzimidazolinyl)piperidine, and 3-(5-methoxy-2-methylphenoxy)-4-methylpentyl chloride (prepared according to the procedure described in Example 3C) in place of 3-(2-chloro-5-methylphenoxy)-3-phenylpropyl chloride, to give 1-{1-[3-(5-methoxy-2- methylphenoxy)-4-methylpentyl]-4-piperidinyl}-3-(methoxymethyl)-1 ,3-dihydro-2/- - benzimidazole-2-one as yellow oil in 21% yield. MS (ES): 482 (MH⁺). D: Title compounds

1-{1-[3-(5-Methoxy-2-methylphenoxy)-4-methylpentyl]-4-piperidinyl}-3- (methoxymethyl)-1 ,3-dihydro-2/-/-benzimidazole-2-one was subjected to chiral chromatography on a Chiralpak^®AD column (2 cm x 25 cm), eluting with isohexane/isopropanol 90/10 (v/v) at 15 ml/min. 2.7 g were separated by repeated injections of 1000μl (200mg) to give 1030mg of enantiomer 1 (S) and 1150mg of enantiomer 2 (R). The purified enantiomers were converted to the methanesulfonate salts with 1 equivalent of methanesulfonic acid in dichloromethane and then precipitated twice from a concentrated acetone solution by flooding with diethyl ether to give 1020 mg enantiomer 1 (S) and 920 mg enantiomer 2 (R).

Enantiomer 1 (S): HPLC purity 99.2%, enantiomeric ratio 99.6 : 0.4%, [α]_D = +29.5° (c=1.3; methanol); MS 482.4 (MH)⁺

Enantiomer 2 (R): HPLC purity 99.4%, enantiomeric ratio 0.6 : 99.4%, [α]_D = -25.8° (c=1.3; methanol); MS 482.4 (MH)⁺

The following compounds (25-33 and 38-44) were prepared using similar process steps as described in Example 24:

Example 25: 1 -{1 -[3-(2-chloro-5-methoxyphenoxy)-4-methylpentyl]-4-piperidinyl}-3-

(ethoxymethyl)-1 ,3-dihydro-2H-benzimidazole-2-one; MS (ES): 516.2 (MH⁺).

Example 26: 1 -{1 -[3-(2-chloro-5-methoxyphenoxy)-4-methylpentyl]-4-piperidinyl}-3-

(2-methoxyethyl)-1 ,3-dihydro-2H-benzimidazole-2-one; MS (ES): 516.2 (MH⁺).

Example 27: (R) and (S) enantiomer of 1-{1-[3-(5-methoxy-2-methylphenoxy)-4- methylpentyl]-4-piperidinyl}-3-(2-methoxyethyl)-1 ,3-dihydro-2H-benzimidazole-2-one methane sulfonate: Enantiomer 1 (S); HPLC purity 99.0%, enantiomeric ratio 100 : 0.0%, [α]_D = +6.4°

(c=4.4; methanol); MS 496.2 (MH⁺)

Enantiomer 2 (R); HPLC purity 98.1%, enantiomeric ratio 0.3 : 99.7%, [α]_D = -4.8°

(c=2.6; methanol); MS 496.2 (MH⁺) The chiral assignment was confirmed by single crystal X-Ray of the HCl salt of enantiomer 1.

Example 28: 1 -{1 -[3-(5-methoxy-2-methylphenoxy)-4-methylpentyl]-4-piperidinyl}-3-

(ethoxymethyl)-1 ,3-dihydro-2H-benzimidazole-2-one; MS (ES): 496.5 (MH⁺).

Example 29: 1-{1-[3-(5-methoxy-2-methylphenoxy)-4-methylpentyl]-4-piperidinyl}-3- [(2-tetrahydrofuranyl)methyl]-1 ,3-dihydro-2H-benzimidazole-2-one;

MS (ES): 522.5 (MH⁺).

Example 30: 1-{1-[3-(2,5-dimethylphenoxy)-4-methylpentyl]-4-piperidinyl}-3-(ethoxy- methyl)]-1 ,3-dihydro-2H-benzimidazole-2-one; MS (ES): 480.0 (MH⁺).

Example 31: 1 -{1 -[3-(2-chloro-5-methylphenoxy)-4-methylpentyl]-4-piperidinyl}-3- (methoxyethyl)]-1 ,3-dihydro-2tf-benzimidazole-2-one; MS (ES): 500.0 (MH⁺).

Example 32: 1-{1-[3-(2-chloro-5-methylphenoxy)-4-methylpentyl]-4-piperidinyl}-3-

(ethoxymethyl)]-1 ,3-dihydro-2H-benzimidazole-2-one; MS (ES): 500.0 (MH⁺).

Example 33: 1 -{1 -[3-(2-chloro-5-methoxyphenoxy)-3-phenylpropyl]-4-piperidinyl}-3-

(2-methoxyethyl)-1 ,3-dihydro-2H-benzimidazole-2-one; MS (ES): 550.5 (MH⁺). Example 38: 1-{1-[3-(2,5-dimethylphenoxy)-3-phenylpropyl]-4-piperidinyl}-3-(2- methoxyethyl)-1 ,3-dihydro-2H-benzimidazole-2-one; MS (ES): 514 (MH⁺).

Example 40: 1 -{1 -[3-(2-chloro-5-methoxyphenoxy)-3-phenylpropyl]-4-piperidinyl}-3-

(methoxymethyl)-1 ,3-dihydro-2H-benzimidazole-2-one; MS (ES): 520.5 (MH⁺).

Example 41: 1-{1-[3-(5-methoxy-2-methylphenoxy)-4-methylpentyl]-4-piperidinyl}-3- (ethoxyethyl)-l ,3-dihydro-2H-benzimidazole-2-one; MS (ES): 511 (MH⁺).

Example 42: 1 {1 -[3-(2,5-dimethylphenoxy)-4-methylpentyl]-4-piperidinyl}-3-(meth- oxymethyl)1 ,3-dihydro-2H-benzimidazole-2-one; MS (ES): 466 (MH⁺).

Example 43: 1-{1-[3-(2,5-dimethylphenoxy)-4-methylpentyl]-4-piperidinyl}-3-(ethoxy- ethyl)-1 ,3-dihydro-2H-benzimidazole-2-one; MS (ES): 494 (MH⁺). Example 44: 1-{1-[3-(2,5-dimethylphenoxy)-3-phenylpropyl]-4-piperidinyl}-3-(meth- oxycarbonylmethyl)-1 ,3-dihydro-2/- -benzimidazole-2-one;

MS (ES): 565 (MH⁺).

Example 34. 1 -(1 -r3-(2.5-methylphenoxy)-3-phenylpropyn-4-piperidinyl-1 ,3-dihvdro-2H- benzimidazole-2-one

A: 3-(2.5-dimethylphenoxy)-3-phenylpropyl chloride

3-(2,5-Dimethylphenoxy)-3-phenylpropyl chloride was prepared following the procedure described in Example 1 B, using 2,5-dimethylphenol in place of 2-chloro-5- methylphenol. The product was obtained as a colourless gum in 30 % yield. B: Title compound

1-{1-[3-(2,5-Methylphenoxy)-3-phenylpropyl]-4-piperidinyl-1 ,3-dihydro-2H- benzimidazole-2-one was prepared following the procedure described in Example 1C using 3-(2,5-dimethylphenoxy)-3-phenylpropyl chloride in place of 3-(2-chloro-5- methylphenoxy)-3-phenylpropyl chloride. The product was obtained as a colourless solid in 38% yield. MS (ES): 456 (MH⁺).

Example 35.

1-(1-f3-(5-methoxy-2-methylphenoxy)-4-methylpentvN-4-piperidinyl}-3-(2- acetoxyethyl)-1.3-dihvdro-2H-benzimidazole-2-one

A:1-f1-(fe -butoxycarbonyl)1-4-piperidinyn-3-(2-acetoxyethyl)-1.3-dihvdro-2/-/- benzimidazole-2-one

1 -[1 -(terf-Butoxycarbonyl)]-4-piperidinyl]-3-(2-acetoxyethyl)-1 ,3-dihydro-2H- benzimidazole-2-one was prepared following the procedure described in Example 24A, using 2-bromoethyl acetate instead of chloromethyl methyl ether to give 1-[(1- tert-butoxycarbonyl)-4-piperidinyl]-3-(2-acetoxyethyl)-1 ,3-dihydro-2H-benzimidazole- 2-one as a yellow gum in 38% yield. B: 3-(2-acetoxyethyl)-1 -(4-piperidinyl)-1 ,3-dihvdro-2/-/-benzimidazole-2-one

3-(2-Acetoxyethyl)-1-(4-piperidinyl)-1 ,3-dihydro-2H-benzimidazole-2-one was prepared following the procedure described in Example 11C using 1-[(1-terf- butoxycarbonyl)-4-piperidinyl]-3-(2-acetoxyethyl)-1 ,3-dihydro-2H-benzimidazole-2- one in place of 1-[1-(te/τ-butoxycarbonyl)-4-piperidinyl]-3-methyl-1 ,3-dihydro-2/-/- benzimidazole-2-one. The product was obtained as a yellow gum in 52% yield. C: Title compound

1-{1-[3-(5-methoxy-2-methylphenoxy)-4-methylpentyl]-4-piperidinyl}-3-(2- acetoxyethyl)-1 ,3-dihydro-2H-benzimidazole-2-one was prepared following the procedure described in Example 1C, using 3-(2-acetoxyethyl)-1-(4-piperidinyl)-1 ,3- dihydro-2/-/-benzimidazole-2-one in place of 4-(2-oxo-1,3-dihydro-2H- benzimidazolinyl)piperidine and 3-(5-methoxy-2-methylphenoxy)-4-methylpentyl chloride (prepared according to the procedure described in Example 3C), in place of 3-(2-chloro-5-methylphenoxy)-3-phenylpropyl chloride. The product was obtained as a colourless solid in 14 % yield. MS (ES): 524 (MH⁺).

The following compounds were prepared using similar process steps as described in

Example 35:

Example 36: 1-{1-[3-(5-methoxy-2-methylphenoxy)-4-methylpentyl]-4-piperidinyl}-3- (acetoxymethyl)-1 ,3-dihydro-2H-benzimidazole-2-one; MS (ES) 510 (MH⁺).

Example 37: 1 -{1 -[3-(5-methoxy-2-methylphenoxy)-4-methylpentyl]-4-piperidinyl}-3-

(2-hydroxyethyl)-1 ,3-dihydro-2H-benzimidazole-2-one; MS (ES): 482 (MH⁺).

Example 39: 1-{1-[3-(2,5-dimethylphenoxy)-4-methylpentyl]-4-piperidinyl}-3-(terf- butylcarbonyloxymethyl)-1 ,3-dihydro-2W-benzimidazole-2-one; MS (ES): 536 (MH⁺). Example 45: 1-{1-[3-(2,5-dimethylphenoxy)-4-methylpentyl]-4-piperidinyl}-3-(2-acet- oxyethyl)-1 ,3-dihydro-2H-benzimidazole-2-one; MS (ES): 508 (MH⁺).

Example 46: 1-{1-[3-(2,5-dimethylphenoxy)-3-phenylpropyl]-4-piperidinyl}-3-(2-acet- oxyethyl)-1 ,3-dihydro-2H-benzimidazole-2-one;MS (ES): 542 (MH⁺).

Example 49: 1-{1-[3-(2,5-methylphenoxy)-3-phenylpropyl]-4-piperidinyl}-3-(2- hydroxyethyl)-1 ,3-dihydro-2H-benzimidazole-2-one; MS (ES): 500 (MH⁺).

Example 47.

1~f1-r3-(2,5-dimethylphenoxy)-4-methylpentyl1-4-piperidinyl)-3-(methoxyacetyl)-1.3- dihydro-2 - -benzimidazole-2-one

A stirred solution of 1-{1-[3-(2,5-dimethylphenoxy)-4-methylpentyl]-4- piperidinyl}-1 ,3-dihydro-2H-benzimidazole-2-one (prepared according to the procedure described in Example 2, 810 mg, 1.9 mmol), in anhydrous N,N- dimethylformamide (10 mL), was treated with sodium hydride (60% suspension in mineral oil, 100 mg, 2.3 mmol) at ambient temperature. The mixture was heated to 50 °C for 3 h, then cooled to ambient temperature. A solution of methoxyacetyl chloride (0.2 mL, 2.3 mmol) in anhydrous Λ/,/V-dimethylformamide (2 mL) was added dropwise and the resultant mixture stirred for 3 h. The reaction was quenched with water (0.5 mL), then extracted with dichloromethane. The organic phase was washed with water, dried (Na₂SO ) and the solvent removed under reduced pressure. The residue was purified by flash chromatography on silica gel, using gradient elution (0.5-1% methanol in dichloromethane) to afford 1-{1-[3-(2,5- dimethylphenoxy)-4-methylpentyl]-4-piperidinyl}-3-(methoxyacetyl)-1 ,3-dihydro-2H- benzimidazole-2-one in 12% yield. MS (ES): 494 (MH⁺).

Example 48. 1-(1-r3-(5-methoxy-2-methylphenoxy)-4-methylpentyll-4-piperidinyl)-3- (acetoxyacetyl)-1 ,3-dihvdro-2H-benzimidazole-2-one

1-{1-[3-(5-Methoxy-2-methylphenoxy)-4-methylpentyl]-4-piperidinyl}-3-(2- acetoxyacetyl)-1 ,3-dihydro-2H-benzimidazole-2-one was prepared following the procedure described in Example 47, using 1-{1-[3-(5-methoxy-2-methylphenoxy)-4- methylpentyl]-4-piperidinyl}-1 ,3-dihydro-2H-benzimidazole-2-one (prepared according to the procedure described in Example 3), in place of 1-{1-[3-(2,5-dimethylphenoxy)- 4-methylpentyl]-4-piperidinyl}-1 ,3-dihydro-2H-benzimidazole-2-one, and acetoxyacetyl chloride in place of methoxyacetyl chloride. The product was obtained in 5% yield. MS (ES): 538 (MH⁺).

Example 50 Opioid Receptor Binding Affinity

A: ORL1 receptor binding

CHO cells stably expressing the human ORL1 (hORL1) were harvested by hand using Cell Dissociation Solution (Sigma), washed and stored as pellets at

-80°C. Membranes prepared from these cell pellets were suspended in 50mM Tris- HCI buffer (pH 7.4) containing Iμg.ml^"1 bovine serum albumin, and incubated for one hour at room temperature in 96-well microtitre plates in the absence or presence of varying concentrations of test compounds and 50pM leucyl-[³H]-nociceptin (NEN). Test compounds were dissolved in dimethyl sulphoxide (DMSO) and diluted with Tris-HCI buffer to give a final concentration of DMSO in the assay not exceeding 1 %. Non specific binding (NSB) was defined using 100nM Nociceptin (1-13). Experiments were performed in triplicate.

Incubation was terminated by filtration through Packard GF/B filterplates pre- soaked for one hour at 4°C in 0.3% polyethylenimine solution. Filters were washed with 3X1 ml Tris-HCI buffer and the radioactivity was counted using a Packard Topcount liquid scintillation counter. Specific binding was calculated by subtracting NSB from total binding. Data were analysed using a computerised logistic curve fitting programme (GraphPad Prism) from which Ki values were determined by the method of Cheng and Prussof.

B: u-Opioid receptor binding

Membranes were prepared from CHO cells stably expressing the human μ- opioid receptor (hMOR) and incubated at room temperature for 2.5 hours in buffer containing 50mm Tris-HCI, 5mM MgCI₂ and 0.5nM [³H]-diprenorphine. NSB was defined using 200μM naloxone. Harvesting of membranes and estimation of μ-opioid receptor binding in the presence of varying concentrations of test compounds was carried out as described above.

C: κ-opioid receptor binding

Binding affinity of test compounds to human κ-opioid receptors was estimated by incubating at room temperature for 3 hours with membranes expressing K- receptors in buffer containing 50mM Tris-HCI, 5mM MgCI₂ and 3nM [³H]-U-69593. NSB was defined using 100μM naloxone. Harvesting of membranes and estimation of κ-opioid receptor binding in the presence of varying concentrations of test compounds was carried out as described above.

D: δ-opioid receptor binding

Binding affinity of test compounds to human δ-opioid receptors was estimated by incubating at room temperature for 4 hours with membranes expressing δ- receptors in buffer containing 50mM Tris-HCI, 5mM MgCI₂ and 0.15nM [³H]- naltrindole. NSB was defined using 20μM naltrindole. Harvesting of membranes and estimation of δ-opioid receptor binding in the presence of varying concentrations of test compounds was carried out as described above.

Table I: Binding affinities (Ki) for ORL1 and opioid receptors.

Compound ORL1 μ δ K nM nM nM nM

1-{1-[3-(2,5-dimethylphenoxy)-4-methylpentyl]-4-piperidinyl}- 11 65 1055 86 1 ,3-dihydro-2H-benzimidazole-2-one (Example 2)

1 -{1 -[3-(2-chloro-5-methoxyphenoxy)-4-methylpentyl]-4- 5 36 966 86 piperidinyl}-1 ,3-dihydro-2H-benzimidazole-2-one (Example 6) 1 -{1 -[3-(2-chloro-5-methoxyphenoxy)-4-methylpentyl]-4- 5 19 1342 448 piperidinyl}-3-methyl-1 ,3-dihydro-2H-benzimidazole-2-one {Example 7)

8-[3-(2-Chloro-5-methoxyphenoxy)-4-methylpentyl]-1-phenyl- 4 39 771 75 1 ,3,8-triazaspiro[4,5]decan-4-one (Example 8) 1 -{1 -[3-(5-methoxy-2-methylphenoxy)-4-methylpentyl]-4- 4 59 823 106 piperidinyl}-1 ,3-dihydro-2H-beπzimidazole-2-one (Example 3)

8-[3-(5-methoxy-2-methylphenoxy)-4-methylpentyl]-1-phenyl- 5 46 1227 55

1 ,3,8-triazaspiro[4,5]decan-4-one (Example 5)

1 -{1 -[3-(5-methoxy-2-methylphenoxy)-4-methylpentyl]-4- 11 42 2486 464 piperidinyl}-3-methyl-1 ,3-dihydro-2H-beπzimidazole-2-one

(Example 4)

1 -{1 -[3-(5-methoxy-2-methylphenoxy)-4-methylpentyl]-4- 105 5350 piperidinyl}-3-[2-(dimethylamino)ethyl]-1 ,3-dihydro-2H- benzimidazole-2-one (Example 13)

1 -{1 -[3-(5-methoxy-2-methylpheπoxy)-4-methylpentyl]-4- 1.4 27 1340 piperidinyl}-3-[2-(methylthio)ethyl]-1 ,3-dihydro-2H- benzimidazole-2-one (Example 20)

(S)-1 -{1 -[3-(5-methoxy-2-methylphenoxy-4-methyl- 2.8 70 1250 94 pentyl]-4-piperidinyl}-3-(methoxymethyl)-1 ,3-dihydro-2H- benzimidazole-2-one methanesulfonate (Example 24)

(S) 1 -{1 -[3-(5-methoxy-2-methylphenoxy)-4-methylpentyl]-4- 1.7 60 2120 394 piperidinyl}-3-(2-methoxyethyl)-1 ,3-dihydro-2H-beπzimidazole-

2-one (Example 27)

1 -{1 -[3-(5-methoxy-2-methylphenoxy)-4-methylpeπtyl]-4- 1.9 83 1967 181 piperidinyl}-3-(acetoxymethyl)-1 ,3-dihydro-2 - -benzimidazole-

2-one (Example 36)

1-{1-[3-(2,5-dimethylphenoxy)-4-methylpentyl]-4-piperidinyl}-3- 17 122

(methoxyacetyl)-1 ,3-dihydro-2H-benzimidazole-2-one

(Example 47)

1 -{1 -[3-(2-chloro-5-methylphenoxy)-propyl]-4-piperidinyl}-1 ,3- 282 77 dihydro-2H-benzimidazole-2-one (reference) 1-[1-(3-phenoxypropyl)-4-piperidinyl]-1 ,3-dihydro-2 -/- 935 benzimidazole-2-one (reference) Example 51.

Formalin test for Antinociception

The antinociceptive effects of test compounds were determined in the formalin test in mice. This model assesses behavioural responses to continuous, noxious stimulation generated by injured tissue. The injection of a dilute solution of formalin into one hind paw of the mouse produces two distinct phases of nociceptive behaviour in several species (Dubuisson and Dennis, 1977). The first period begins immediately after formalin injection and lasts for 4-5 minutes. This early phase is followed by a period of 10-15 minutes of quiescent behaviour, after which a second phase of nociceptive behaviour occurs. This phase continues for a further 20-30 minutes. In mice, recording the time spent licking or biting the injected paw is the most common method of behavioural assessment.

Male ICR mice (22-30g; n=6-10 per dose) were habituated to their test environment by placing them, singly, into clear perspex observation boxes for ~ 2 hours on the day prior to the experiment and for 1 hour prior to drug administration on the day of the experiment. Formalin solution, 0.3% in sterile saline, was prepared as a fresh solution daily. Test compounds, dissolved in 10% tween 80 in saline, or vehicle, were administered intravenously (i.v.), 10ml. kg^"1, 15 minutes prior to the subplantar injection into one hind paw of 20μl of formalin solution. The time in seconds that each animal spent licking its injected paw was then measured. Licking behaviour was measured during two time periods after formalin injection; 0-5 minutes (Phase 1) and 20-30 minutes (Phase 2). ED50 values were calculated for each compound for each of the two phases of licking using a non-linear regression fit, sigmoidal dose-response curve (GraphPad Prism).

Table 2:

Antinociception (ED₅₀) after i.v. administration in the formalin test.

Compound Phase 1 Phase 2 (μmol.kg ¹) (μmol.kg^'1)

1-{1-[3-(2,5-dimethylphenoxy)-4-methylpentyl]-4-piperidinyl}-

1,3-dihydro-2H-benzimidazole-2-one (Example 2) 5 1

1 -{1 -[3-(5-methoxy-2-methylphenoxy)-4-methylpentyl]-4- piperidinyl}-1 ,3-dihydro-2/- -benzimidazole-2-one (Example 3) 3 0.1

(S)-1 -{1 -[3-(5-methoxy-2-methylphenoxy-4-methylpentyl]-4- piperidinyl}-3-(methoxymethyl)-1 ,3-dihydro-2H-benzimidazole- 1.7 0.9

2-one methanesulfonate (Example 24)

Claims

CLAIMS 1. A 1-(3-phenyloxypropyl)-piperidine derivative having general formula

wherein Formula I

R1 is (C_1-6)alkyl or (C₄.₈)cycloalkyl or phenyl, optionally substituted with(C_1-6)alkyl,

(C_1-6)alkyloxy or halogen;

R2 is H or (d_-6)alkyl; or R1 and R2 form together with the carbon atom to which they are bound

(C .₈)cycloalkyl, optionally substituted with(Cι_-6)alkyl, (C_1-6)alkyloxy or halogen;

R3 is H, OH, (C^alkyloxy or (C_1-6)alkylcarbonyloxy;

R4 represents 1-5 substituents independently selected from H, (C_1-6)alkyl,

(C_1-6)alkyloxy and halogen;

Y represents

and Z is H; or Y and Z together with the carbon atom to which they are bound represent the spiro atom in the spiro system formed with

* represents the spiro carbon atom;

R6 is H, (C_1-6)alkyl or (CO)n-(CH₂)m-R12; n is 0 or 1; m is 1-4; R8 and R10 are independently H or (C_1-6)alkyl;

R7, R9 and R11 are independently H, (C^alkyl, (C_1-6)alkyloxy or halogen; R12 is hydroxy, (Cι_-4)alkyloxy, (C_1-4)alkylthio, (C_1-4)alkyloxycarbonyl, (C_1- )alkyl- carbonyloxy, 2-tetrahydrofuranyl, 4-morpholinyl or di(C_1-4)alkylamino; or a pharmaceutically acceptable salt thereof.

2. The 1-(3-phenyloxypropyl)-piperidine derivative of claim 1 , wherein R1 is (C_1-6)- alkyl or phenyl, and R2 is H; or R1 and R2 form together with the carbon atom to which they are bound (C _-8)cycloalkyl, and R3 is H or OH.

3. The 1-(3-phenyloxypropyl)-piperidine derivative according to claim 1 or 2, wherein R4 represents substituents at the 2 and the 5-position.

4. The 1-(3-phenyloxypropyl)-piperidine derivative of any one of claims 1-3, wherein Y represents

and Z is H.

5. A 1-(3-phenyloxypropyl)-piperidine derivative according to claim 4 selected from: 1-{1-[3-(2,5-dimethylphenoxy)-4-methylpentyl]-4-piperidinyl}-1 ,3-dihydro-2H- benzimidazole-2-one;

1-{1-[3-(5-methoxy-2-methylphenoxy)-4-methylpentyl]-4-piperidinyl}-1 ,3-dihydro-

2H-benzimidazole-2-one;

(S)-1-{1-[3-(5-methoxy-2-methylphenoxy-4-methylpentyl]-4-piperidinyl}-3- (methoxymethyl)-l ,3-dihydro-2H-benzimidazole-2-one;

(S)-1-{1-[3-(5-methoxy-2-methylphenoxy)-4-methylpentyl]-4-piperidinyl}-3-(2- methoxyethyl)-1 ,3-dihydro-2 - -benzimidazole-2-one;

1-{1-[3-(5-methoxy-2-methylphenoxy)-4-methylpentyl]-4-piperidinyl}-3-[2-

(methylthio)ethyl]-1 ,3-dihydro-2 -/-benzimidazole-2-one; and 1 -{1 -[3-(5-methoxy-2-methylphenoxy)-4-methylpentyl]-4-piperidinyl}-3-

(acetoxymethyl)-1 ,3-dihydro-2H-benzimidazole-2-one; or a pharmaceutically acceptable salt thereof.

6. A 1-(3-phenyloxypropyl)-piperidine derivative according to any one of claims 1-5 for use in therapy.

7. A pharmaceutical composition comprising a 1-(3-phenyloxypropyl)-piperidine derivative according to any one of claims 1-5 together with a pharmaceutically acceptable carrier therefore.

8. Use of a 1-(3-phenyloxypropyl)-piperidine derivative according to formula I of claim 1 , or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disorder or condition which is responsive to modulation of the ORL-1 receptor

9. The use according to claim 8, wherein the medicament is an analgesic, anaesthetic, sedative, anti-inflammatory, diuretic, neuroprotective, vasodilator or an anti-anxiety agent or used to treat memory disorders (eg Alzheimer's disease) or eating disorders.

10. A method of treating a disorder or a condition, or anaesthetizing a mammal including a human, the treatment or anaesthetization of which is responsive to modulation of the ORL-1 receptor, which comprises administering to a mammal, including a human, an effective amount of a 1-(3-phenyloxypropyl)-piperidine derivative according to formula I of claim 1.