CN1316994A - Piperidine derivatives - Google Patents

Abstract

The invention relates to compounds of general formula and to their use with pharmaceutically acceptable acidsAddition salts of (2), wherein R¹Is tetrahydronaphthyl; or- (CH)₂)_n－C₆H₅－R₄Wherein n is 0-4 and R⁴Is H, lower alkyl or lower alkoxy; or C unsubstituted or substituted by lower alkyl₅－C₁₂A cycloalkyl group; r²H, OH, lower alkoxy, lower alkenyloxy or lower alkyl; r³Is unsubstituted or substituted by a substituent C₅－C₇Cycloalkyl or phenyl, said substituents being OH, halogen, lower alkoxy, lower alkenyloxy, lower alkyl or-O- (CH)₂)_n－C₆H₅Wherein n is 0 to 3. The compounds of formula are suitable for the treatment of memory and attention deficits, psychiatric, neurological and physiological disorders such as anxiety and stress disorders, depression, memory loss due to Alzheimer's disease or other dementias such as vascular dementia and AIDS dementia complex, Parkinson's disease, epilepsy and convulsions, acute and/or chronic pain disorders, withdrawal symptoms and reduction of abuse/craving of addictive drugs, control of water balance, Na⁺Voiding and arterial blood pressure diseases and metabolic diseases such as obesity.

Description

Piperidine derivatives

其中：The present invention relates to novel compound of formula I and pharmaceutically acceptable acid addition salt thereof

in:

R ¹ is tetrahydronaphthyl;

Or -(CH ₂ ) _n -C ₆ H ₅ -R ₄ , wherein n is 0-4 and R ⁴ is H, lower alkyl or lower alkoxy;

Or C ₅ -C ₁₂ cycloalkyl unsubstituted or substituted by lower alkyl;

R ² is H, OH, lower alkoxy, lower alkenyloxy or lower alkyl;

R ³ is C ₅ -C ₇ cycloalkyl or phenyl unsubstituted or substituted by a substituent, the substituent is OH, halogen, lower alkoxy, lower alkenyloxy, lower alkyl or -O -(CH ₂ ) _n -C ₆ H ₅ , wherein n is 0-3.

The compounds of formula I and their salts are characterized by their valuable therapeutic properties. It has surprisingly been found that the compounds of the present invention are agonists/antagonists of the OFQ receptor. Accordingly, they will be used in the treatment of memory and attention deficits, psychiatric, neurological and physiological disorders, including but not limited to the improvement of symptoms of disorders such as anxiety and stress disorders, depression, Alzheimer's disease or other dementias such as memory loss due to vascular dementia and AIDS dementia syndrome, Parkinson's disease, epilepsy and convulsions, acute and/or chronic pain disorders, withdrawal symptoms of addictive drugs and reduction of their abuse/craving, Control of water balance, Na ⁺ excretion and arterial blood pressure diseases and metabolic diseases such as obesity.

A 17-amino acid peptide (F-G-G-F-T-G-A-R-K-S-A-R-K-L-A-N-Q) Orphanin FQ (OFQ), which has been isolated from rat brain, is a natural ligand for G-protein-coupled receptors (OFQ-R), and it is expressed in brain tissue The content is higher.

OFQ was shown to agonize OFQ-R activity in vitro and in vivo.

Julius (Nature 377, 476, [1995]) discusses the findings of OFQ, noting that the peptide has the greatest sequence similarity to dynorphin A, an established endogenous opioid receptor ligand. OFQ inhibits adenylyl cyclase in CHO(LC132 ⁺ ) cultured cells and induces hyperalgesia when administered intracerebroventricularly to mice. The results indicated that the heptadeptide is an agonist of the endogenous LC132 receptor and that it appears to have pronociceptive properties. It has been described that OFQ slows locomotion and induces hyperalgesia when given to mice by intraventricular injection, and it has been postulated that OFQ may act as a brain neurotransmitter to modulate nociceptive and motor behavior.

Preferred compounds are compounds of the following formula I, wherein ^R is unsubstituted or substituted by lower alkyl C ₅ -C ₁₂ cycloalkyl, such as the following compounds:

(3RS,4RS)-1-cyclononyl-4-(2-hydroxy-phenyl)piperidin-3-ol hydrochloride (1:1);

1-cyclodecyl-4-(2-methoxy-phenyl)-piperidine hydrochloride (1:1);

(3RS,4RS)-1-cyclodecyl-4-(2-isopropyl-phenyl)piperidin-3-ol hydrochloride (1:1);

(3RS,4RS)-4-(2-Hydroxy-phenyl)-1-(cis- and (trans-4-isopropylcyclohexyl)-piperidin-3-ol hydrochloride (1:1);

2-(1-cyclodecyl-piperidin-4-yl)-phenol hydrochloride (1:1);

(3RS,4RS)-1-cyclodecyl-4-(2-methoxy-phenyl)-piperidin-3-ol hydrochloride (1:1);

1-cyclodecyl-4-cyclohexyl-piperidine hydrochloride (1:1);

(3RS,4RS)-1-cyclononyl-4-(2-methoxy-phenyl)-piperidin-3-ol hydrochloride (1:1);

(3RS,4RS)-4-(2-allyloxy-phenyl)-1-cyclodecyl-piperidin-3-ol hydrochloride (1:1);

1-cyclodecyl-4-phenyl-piperidine hydrochloride (1:1);

(3RS,4RS)-1-cyclononyl-4-(2-isopropyl-phenyl)-piperidin-3-ol hydrochloride (1:1); and

(3RS,4RS)-1-Cyclodecyl-4-(2-hydroxy-phenyl)-piperidin-3-ol hydrochloride (1:1).

Objects of the present invention are the novel compounds of formula I as such and their pharmaceutically acceptable acid addition salts, racemic mixtures and their corresponding enantiomers, the preparation of said compounds, medicaments comprising them and their production as well as said compounds Use in the control or prevention of disease, especially the aforementioned diseases or disease states.

Regardless of whether the general terms used in this specification appear alone or in combination, the following definitions apply.

The term "lower alkyl" as used herein refers to a straight or branched chain alkyl group containing 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, 2 -Butyl, tert-butyl.

Compounds of formula I and their pharmaceutically acceptable acid addition salts can be prepared by methods known in the art, for example by the methods described hereinafter, which comprise the compound of formula II With formula Ⅳ compound Reductive amination is performed wherein R ¹ , R ² and R ³ are as described above.

The amination occurs in two steps, where an intermediate imine is first formed and then further reduced in the presence of a reducing agent such as sodium cyanoborohydride, molecular hydrogen or nickel.

Amination reagent II can be prepared by known methods, e.g. by hydrogenation, starting from compounds of formula III:

Wherein R ² and R ³ are as above and when R ³ is cycloalkyl or phenyl substituted by -O-CH ₂ -C ₆ H ₅ , during the reaction process -CH ₂ -C ₆ H ₅ disconnect.

The reaction takes place in the presence of hydrogen and a suitable hydrogenation catalyst such as palladium on activated carbon.

For example, a cycloalkane wherein ^R2 is hydroxyl and/or ^R3 is cycloalkane substituted by hydroxyl or halogen can be prepared by reaction with haloalkane, haloalkene, phenylalkyl halide or lower alcohol in the presence of an inert solvent such as anhydrous tetrahydrofuran. A compound of formula I with a radical or phenyl group is converted to wherein R ² is lower alkoxy, lower alkenyloxy or lower alkyl and/or R ³ is lower alkoxy, lower alkenyloxy, lower alkyl or -O-(CH ₂ ) _n -C ₆ H ₅ substituted cycloalkyl or phenyl compound of formula I.

The compound of formula III can be obtained according to literature methods (for example, Juan C. Jean and Lawrence D. Wise, J. Heterocyclic Chem. 1987, 24, 1317-1319).

Compounds of formula I can be converted, if desired, into their pharmaceutically acceptable acid addition salts. Said salts can be obtained at room temperature by methods known per se and familiar to any person skilled in the art. Not only salts with inorganic acids but also salts with organic acids are included. Hydrochloride, hydrobromide, sulfate, nitrate, citrate, acetate, maleate, succinate, methanesulfonate, p-toluenesulfonate, etc. are examples of such salts .

As stated above, the compounds of formula I and their pharmaceutically acceptable acid addition salts possess valuable pharmacodynamic properties. It has been found that the compounds of the present invention are agonists/antagonists of OFQ receptors and are effective in memory and attention deficits, psychiatric, neurological and physiological diseases such as anxiety and stress disorders, depression, caused by Alzheimer's disease or other dementias such as vascular Memory loss due to dementia and AIDS dementia syndrome, Parkinson's disease, epilepsy and convulsions, symptoms of acute and/or chronic painful disorders, withdrawal symptoms of addictive drugs and reduction of their abuse/craving, control of water balance , Na ⁺ excretion and arterial blood pressure in animal models of diseases and metabolic diseases such as obesity.

The compounds were studied according to the assay provided below. Method for OFQ-R Binding Assay

cell culture

HEK-293 cells adapted for suspension growth (293s) were cultured in HL medium supplemented with 2% FBS. Cells (FEBS Lett.347,284-288,1994) were transfected with rat OFQ receptor cDNA (LC132), which was cloned in the expression vector pCEP4 (Invitrogen , SanDiego, CA, USA). Transfected cells were selected in the presence of hygromycin (1000 U/ml) (Calbiochem, San Diego, CA, USA). OFQ-R expression in collected resistant cells was determined by [3H]-OFQ (Amersham PLC, Buckinghamshire, England) binding. These cells (293s-OFQ-R) were expanded for large scale culture and membrane preparation.

Membrane preparation

293s-OFQ-R cells were collected by centrifugation, washed 3 times with phosphate-buffered saline (PBS), then resuspended in buffer A (50 mM Tris-HCl, pH 7.8, 5 mM MgCl ₂ , 1 mMEGTA) and homogenized with a tissue homogenizer. Crushing (30 seconds, gear 4, Pt 20, Kinematica, Krlens-Lucern, Switzerland). The total membrane fraction was obtained by centrifugation at 49000 xg at 4°C. This process was repeated twice and the pellet was resuspended in Buffer A. Aliquots were stored at -70°C and protein concentrations were determined using BCA ^™ protein assay reagents (Pierce, Rockford, IL) according to the manufacturer's recommendations.

binding assay

[ ³ H]-OFQ competition studies were performed using 77 μg of membrane protein in 0.5 ml final volume of buffer A plus 0.1% BSA and 0.01% bacitracin (Boehringer-Mannheim, Mannheim, Germany) for 1 hour at room temperature. Non-specific binding was determined using 50 nM unlabeled OFQ. The assay was terminated by Whatman GF/C filter membrane (Unifilter-96, CanberraPackard SA, Zurich, Switzerland), previously, the filter membrane was washed with 0.3% polyethyleneimine (Sigma, ST. Sigma) pretreatment for 1 hour. The filter was washed 6 times with 1 ml of ice-cold 50 mM Tris-HCl pH 7.5. After addition of 40 [mu]l Microscint 40 (Canberra Packard), the retained radioactivity was recorded using a Packard Top-Count microplate scintillation counter. Compound effects were assayed in triplicate using at least 6 concentrations and assayed in duplicate. _IC50 values were determined by curve fitting and converted to Ki values using the method of Cheng and Prusoff (Blochem. Pharmacol., 22, 3099, 1973).

The affinity to the OFQ-receptor expressed in pKi is in the range of 6.0-8.0, for example the pKi of the compounds mentioned below are as follows: Example OFQ 4 7.5 36 7.0 19 6.5

4(3RS,4RS)-1-cyclononyl-4-(2-hydroxy-phenyl)-piperidin-3-ol hydrochloride (1:1)36(3RS,4RS)-1-cyclodecyl -4-(2,6-Dimethoxy-phenyl)-piperidin-3-ol hydrochloride (1:1)

19(3RS,4RS)-4-(2-Methoxy-phenyl)-1-(cis- and (trans-4-isopropyl-cyclohexyl)-piperidin-3-ol hydrochloride (1 : 1) mixture

The compounds of the formula I and their pharmaceutically acceptable acid addition salts can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, eg in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, rectal administration, for example in the form of suppositories, or parenteral administration, for example in the form of injection solutions, is also possible.

The compounds of formula I and their pharmaceutically acceptable acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used as excipients such as tablets, dragees and hard gelatine capsules.

Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like.

Suitable excipients for the production of solutions and syrups are, for example, water, polyols, sucrose, inert sugars, dextrose and the like.

Excipients suitable for the preparation of injections are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like. Excipients suitable for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

The pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may furthermore contain other therapeutically valuable substances as well.

The dosage may vary within wide limits and should, of course, be tailored to the requirements of the individual in each particular disease state. In general, in the case of oral administration, a dosage of about 10-1000 mg per person per day of the compound of general formula I should be suitable, although the above upper limit may be exceeded when necessary.

The following examples illustrate but do not limit the invention in any way.

Example 12-(1-cyclodecyl-piperidin-4-yl)-phenol hydrochloride (1:1) a), 1-benzyl-4-(2-benzyloxy-phenyl)-1 ,2,3,6-Tetrahydropyridine

According to the literature method (Juan C.Jean and Lawrence D.Wise, J.Heterocyclic Chem.1987,24,1317-1319), start from 2-benzyloxybromobenzene instead of 2-bromomethoxybenzene by two steps The title compound was prepared in comparable yields. The product was obtained as a light brown oil.

MS m/e (%): 356 (M+H ⁺ , 100). b), 2-piperidin-4-yl-phenol

Add 7.0g of 10% palladium-coated activated carbon to 37.3g (0.105mol) of 1-benzyl-4-(2-benzyloxy-phenyl)-1,2,3,6-tetrahydropyridine in 380ml of methanol in solution. The reaction mixture was hydrogenated (room temperature, 5 bar) until the theoretical amount of hydrogen was consumed (ca. 20 h). The catalyst was filtered and washed with methanol (3 x 50ml). The filtrate was evaporated in vacuo and flash chromatography gave 14.8 g (80%) of the title compound as a light brown foam.

MS m/e (%): 177 (M ⁺ , 100). c), 2-(1-cyclodecyl-piperidin-4-yl)-phenol

8.0 g (28 mmol) of tetraisopropyl orthotitanate were added to a suspension of 1.0 g (5.64 mmol) of 2-piperidin-4-ylphenol in 870 mg (5.64 mmol) of cyclodecanone. After stirring at room temperature for 4 days, a viscous oil was obtained. A solution of 250 mg (3.95 mmol) sodium cyanoborohydride in 4 ml ethanol was added dropwise over 3-4 minutes. Stirring was continued at room temperature for 2 h and 10 ml of 2.5 M ammonia ethanol solution was added. The precipitate was filtered and the filtrate was evaporated. The residue was purified by flash chromatography to give 1.37 g (77%) of the title compound as a pale yellow foam.

MS m/e (%): 316 (M+H ⁺ , 100). d), 2-(1-cyclodecyl-piperidin-4-yl)-phenol hydrochloride (1:1)

1 ml of 2.3N hydrochloric acid in ether was added to a solution of 100 mg (0.32 mmol) 2-(1-cyclodecyl-piperidin-4-yl)-phenol in 20 ml of ether. After stirring for 30 minutes, excess hydrochloric acid and ether were removed in vacuo and the residue was resuspended in 10 ml ether. The precipitate was filtered and washed with ether to give 101 mg (91%) of the title compound as a white powder.

MS m/e (%): 316 (M+H ⁺ , 100).

Example 21-Cyclodecyl-4-(2-methoxy-phenyl)-piperidine hydrochloride (1:1)

At 0°C, 76 mg (0.38 mmol) of potassium bis(trimethylsilyl)amide was added to 100 mg (0.32 mmol) of 2-(1-cyclodecyl-piperidin-4-yl)-phenol (Example 1c) In solution in 1 ml dry tetrahydrofuran. Stirring was continued at this temperature for 1 h and 55 mg (0.38 mmol) iodomethane was added. After stirring at 0°C for 30 minutes, the ice bath was removed and the reaction mixture was allowed to warm to room temperature overnight.

The solvent was removed and the residue was purified by flash chromatography to give 74mg of an oil. The amine was dissolved in 5 ml of ether and 1 ml of 2.3M hydrochloric acid in ether was added dropwise. The precipitate was filtered, washed with ether and dried in vacuo to give 42 mg (36%) of the title compound as a white powder.

MS m/e (%): 330 (M+H ⁺ , 100).

Example 3 4-(2-allyloxy-phenyl)-1-cyclodecyl-piperidine hydrochloride (1:1)

At 0°C, 152 mg (0.76 mmol) of potassium bis(trimethylsilyl)amide was added to 200 mg (0.64 mmol) of 2-(1-cyclodecyl-piperidin-4-yl)-phenol (Example 1c) In solution in 2 ml of anhydrous tetrahydrofuran. Stirring was continued at this temperature for 1 h and 92 mg (0.76 mmol) allyl bromide was added. After stirring at 0°C for 30 minutes, the ice bath was removed and the reaction mixture was allowed to warm to room temperature overnight.

The solvent was removed and the residue was purified by flash chromatography to give 164mg of an oil. The amine was dissolved in 10 ml of ether and 1 ml of 2.3M hydrochloric acid in ether was added dropwise. The precipitate was filtered, washed with ether and dried in vacuo to give 138 mg (55%) of the title compound as a white powder.

MS m/e (%): 356 (M+H ⁺ , 100).

Example 4 (3RS, 4RS)-1-cyclononyl-4-(2-hydroxy-phenyl)-piperidin-3-ol hydrochloride (1:1) a), (3RS, 4RS)-1 -Benzyl-4-(2-benzyloxy-phenyl)-piperidin-3-ol hydrochloride (1:1)

According to the literature method (Juan C.Jean and Lawrence D.Wise, J.Heterocyclic Chem.1987,24,1317-1319), start from 2-benzyloxybromobenzene instead of 2-bromomethoxybenzene by three steps The title compound was prepared in comparable yields. The product was obtained as white crystals.

MS m/e (%): 374 (M+H ⁺ , 100). b), (3RS,4RS)-4-(2-hydroxy-phenyl)-piperidin-3-ol hydrochloride (1:1)

Add 8.5g 10% palladium activated carbon to 46.5g (0.11mol) (3RS, 4RS)-1-benzyl-4-(2-benzyloxy-phenyl)-piperidin-3-alcohol hydrochloride ( 1:1) in a solution in 1100 ml of methanol. The reaction mixture was hydrogenated (room temperature, 5 bar) until the theoretical amount of hydrogen was consumed (ca. 20 h). The catalyst was filtered and washed with methanol (3 x 100ml). The filtrate was evaporated in vacuo and flash chromatography afforded 21.0 g (99%) of the title compound as a white powder.

MS m/e (%): 193 (M ⁺ , 78), 164 (58), 44 (100). c), (3RS,4RS)-4-(2-hydroxy-phenyl)-piperidin-3-ol

Add 1.5 g of sodium carbonate to a solution of 3.17 g (1.38 mmol) (3RS, 4RS)-4-(2-hydroxy-phenyl)-piperidin-3-ol hydrochloride (1:1) in 30 ml of methanol middle. After stirring at room temperature for 1 h, the sodium salt was filtered and washed with 10 ml of ethanol. The filtrate was concentrated, diluted with ethanol and filtered again. The filtrate was evaporated to give 2.7 g (quant.) of the title compound as a white solid.

MS m/e (%): 194 (M+H ⁺ , 100). d), (3RS,4RS)-1-cyclononyl-4-(2-hydroxy-phenyl)-piperidin-3-ol

Add 3.80g (13mmol) tetraisopropyl orthotitanate to 520mg (2.69mmol) (3RS, 4RS)-4-(2-hydroxyl-phenyl)-piperidin-3-alcohol in 380mg (1.55mmol) ring in suspension in nonanone. After stirring at room temperature for 2 days, a viscous oil was obtained. A solution of 120 mg (1.9 mmol) sodium cyanoborohydride in 1 ml ethanol was added dropwise over 3-4 minutes. Stirring was continued at room temperature for 6 h and 2 ml of 2.5M ammonia in ethanol was added. The precipitate was filtered and the filtrate was evaporated. The residue was purified by flash chromatography to give 435 mg (51%) of the title compound as a pale yellow foam.

MS m/e (%): 318 (M+H ⁺ , 100). e), (3RS,4RS)-1-cyclononyl-4-(2-hydroxy-phenyl)-piperidin-3-ol hydrochloride (1:1)

Add 1ml of 2.3N hydrochloric acid in ether to 100mg (0.32mmol) (3RS, 4RS)-1-cyclononyl-4-(2-hydroxy-phenyl)-piperidin-3-ol in 10ml of ether in the solution. After stirring for 30 minutes, excess hydrochloric acid and ether were removed in vacuo and the residue was resuspended in 10 ml ether. The precipitate was filtered and washed with ether to give 98 mg (88%) of the title compound as a white powder.

MS m/e (%): 318 (M+H ⁺ , 100).

Example 5 (3RS,4RS)-1-cyclononyl-4-(2-methoxy-phenyl)-piperidin-3-ol hydrochloride (1:1)

At 0°C, add 85 mg (0.42 mmol) of bis(trimethylsilyl) potassium amide to 110 mg (0.35 mmol) of (3RS, 4RS)-1-cyclononyl-4-(2-hydroxy-phenyl )-piperidin-3-ol (Example 4d) in 1 ml of anhydrous THF in solution. Stirring was continued at this temperature for 1 h and 59 mg (0.42 mmol) iodomethane was added. After stirring at 0°C for 30 minutes, the ice bath was removed and the reaction mixture was allowed to warm to room temperature overnight.

The solvent was removed and the residue was purified by flash chromatography to give 74mg of an oil. The amine was dissolved in 5 ml of ether and 1 ml of 2.3M hydrochloric acid in ether was added dropwise. The precipitate was filtered, washed with ether and dried in vacuo to give 70 mg (54%) of the title compound as a white powder.

MS m/e (%): 332 (M+H ⁺ , 100).

Example 6 (3RS, 4RS)-1-cyclononyl-4-(2-hydroxy-phenyl)-piperidin-3-ol hydrochloride (1:1)

Add 4.58 g (16.1 mmol) tetraisopropyl orthotitanate to 2.5 g (12.9 mmol) (3RS,4RS)-4-(2-hydroxy-phenyl)-piperidin-3-ol (Example 4c) In suspension in 2.00 g (12.9 mmol) cyclodecanone. After stirring overnight at room temperature, a viscous oil was obtained. A solution of 570 mg (9 mmol) sodium cyanoborohydride in 10 ml ethanol was added dropwise within 1 minute. Stirring was continued overnight at room temperature and 50 ml of 1N hydrochloric acid solution were added. After 30 minutes, the precipitate was filtered and washed with 1N hydrochloric acid solution to give 2.81 g (59%) of the title compound as a light brown foam. MS m/e (%): 332 (M+H ⁺ , 100).

Example 7

(3RS,4RS)-1-cyclodecyl-4-(2-ethoxy-phenyl)-piperidin-3-ol hydrochloride (1:1)a), (3RS,4RS)-1- Cyclodecyl-4-(2-hydroxy-phenyl)-piperidin-3-ol

Add 1.5g of sodium carbonate to 570mg (1.55mmol) (3RS, 4RS)-1-cyclodecyl-4-(2-hydroxyl-phenyl)-piperidin-3-alcohol hydrochloride (1:1)( Example 6) In solution in 20 ml ethanol. After stirring at room temperature for 1 h, the sodium salt was filtered and washed with 10 ml of ethanol. The filtrate was evaporated to give 510 mg (quant.) of the title compound as a white solid.

MS m/e (%): 332 (M+H ⁺ , 100). b), (3RS,4RS)-1-cyclodecyl-4-(2-ethoxy-phenyl)-piperidin-3-ol

At 0°C, add 147 mg (0.74 mmol) of bis(trimethylsilyl) potassium amide to 204 mg (0.62 mmol) of (3RS, 4RS)-1-cyclodecanyl-4-(2-hydroxy-phenyl )-piperidin-3-ol in a solution in 1 ml of anhydrous tetrahydrofuran. Stirring was continued at this temperature for 1 h and 74 mg (0.68 mmol) bromoethane was added. After stirring at 0°C for 30 minutes, the ice bath was removed and the reaction mixture was allowed to warm to room temperature overnight.

Removal of the solvent and purification of the residue by flash chromatography gave 51 mg (23%) of the title compound as a colorless oil.

MS m/e (%): 360 (M+H ⁺ , 100). c), (3RS,4RS)-1-cyclodecyl-4-(2-ethoxy-phenyl)-piperidin-3-ol hydrochloride (1:1)

Add 0.2ml of 2.5N hydrochloric acid ether solution to 7mg (0.02mmol) (3RS, 4RS)-1-cyclodecyl-4-(2-ethoxy-phenyl)-piperidin-3-ol in solution in 1 ml of diethyl ether. After stirring for 30 minutes, excess hydrochloric acid and ether were removed in vacuo and the residue was resuspended in 2 ml ether. The precipitate was filtered and washed with diethyl ether to give 7 mg (quantitative) of the title compound as white crystals.

MS m/e (%): 360 (M+H ⁺ , 100).

Example 8 (3RS, 4RS)-1-cyclodecyl-3-ethoxy-4-(2-ethoxy-phenyl)-piperidine hydrochloride (1:1) a), (3RS, 4RS)-1-cyclodecyl-3-ethoxy-4-(2-ethoxy-phenyl)-piperidine

During the isolation and purification of (3RS,4RS)-1-cyclodecyl-4-(2-ethoxy-phenyl)-piperidin-3-ol (Example 7b), the title compound was obtained as a by-product . Flash chromatography gave 93 mg (38 mg) of the title compound as a light brown oil.

MS m/e (%): 388 (M+H ⁺ , 100). b), (3RS,4RS)-1-cyclodecyl-3-ethoxy-4-(2-ethoxy-phenyl)-piperidine hydrochloride (1:1)

Add 0.2ml of 2.5N hydrochloric acid in ether to 10mg (0.025mmol) (3RS, 4RS)-1-cyclodecyl-3-ethoxy-4-(2-ethoxy-phenyl)-piper Pyridine in 1ml ether solution. After stirring for 30 minutes, excess hydrochloric acid and ether were removed in vacuo and the residue was resuspended in 2 ml ether. The precipitate was filtered and washed with diethyl ether to give 10 mg (quantitative) of the title compound as white crystals.

MS m/e (%): 388 (M+H ⁺ , 100).

Example 9 (3RS, 4RS)-4-(2-allyloxy-phenyl)-1-cyclodecyl-piperidin-3-ol hydrochloride (1:1) a), (3RS, 4RS )-4-(2-allyloxy-phenyl)-1-cyclodecyl-piperidin-3-ol

Add 298 mg (2.15 mmol) potassium carbonate and 260 mg (2.15 mmol) allyl bromide to 645 mg (1.96 mmol) (3RS, 4RS)-1-cyclodecyl-4-(2-hydroxy-phenyl)-piperidine -3-ol (Example 7a) in solution in 6 ml of dry acetone. After stirring overnight at 60°C, the product was extracted with ethyl acetate (3 x 10ml), washed with brine, dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 557 mg (76%) of the title compound as a white powder.

MS m/e (%): 372 (M+H ⁺ , 100). b), (3RS,4RS)-4-(2-allyloxy-phenyl)-1-cyclodecyl-piperidin-3-ol hydrochloride (1:1)

Add 2ml of 2.5N hydrobromic acid ether solution to 133mg (0.36mmol) (3RS, 4RS)-4-(2-allyloxy-phenyl)-1-cyclodecyl-piperidin-3-alcohol in 2.5ml of solution in tetrahydrofuran. After stirring for 30 minutes, excess hydrobromic acid and ether were removed in vacuo and the residue was resuspended in 10 ml ether. The precipitate was filtered and washed with diethyl ether to give 100 mg (68%) of the title compound as white crystals.

MS m/e (%): 372 (M+H ⁺ , 100).

Example 10 (3RS,4RS)-4-(2-allyloxy-phenyl)-1-cyclodecyl-3-methoxy-piperidine hydrochloride (1:1)

At 0°C, add 85 mg (0.43 mmol) of bis(trimethylsilyl) potassium amide to 133 mg (0.36 mmol) of (3RS, 4RS)-4-(2-allyloxy-phenyl)-1 - Cyclodecyl-piperidin-3-ol (Example 9a) in solution in 1.5 ml of anhydrous THF. Stirring was continued at this temperature for 1 h and 61 mg (0.43 mmol) iodomethane was added. After stirring at 0°C for 30 minutes, the ice bath was removed and the reaction mixture was allowed to warm to room temperature overnight.

After adding 2ml of water, the product was extracted with ether (3 x 10ml), dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 77mg of an oil. The amine was dissolved in 10 ml of ether and 1 ml of 2.3M hydrochloric acid in ether was added dropwise. The precipitate was filtered, washed with ether and dried in vacuo to give 67 mg (44%) of the title compound as a white powder.

MS m/e (%): 386 (M+H ⁺ , 100).

Example 11 (3RS,4RS)-1-cyclodecyl-3-methoxy-4-(2-propoxy-phenyl)-piperidine hydrochloride (1:1)

Add 10mg of 10% palladium-coated activated carbon to 30mg (0.07mol) (3RS, 4RS)-4-(2-allyloxy-phenyl)-1-cyclodecanyl-3-methoxy-piperidine hydrochloride A solution of the salt (1:1) (Example 10) in 1.5 ml methanol. The reaction mixture was hydrogenated (room temperature, 1 bar) overnight. The catalyst was filtered and washed with methanol (3 x 1 ml). The filtrate was evaporated in vacuo to give 23 mg (77%) of the title compound as a white powder.

MS m/e (%): 388 (M ⁺ , 100).

Example 12 (3RS,4RS)-4-(2-benzyloxy-phenyl)-1-cyclodecanyl-piperidin-3-ol hydrochloride (1:1)

Add 810 mg (5.88 mmol) of potassium carbonate and 370 mg (2.16 mmol) of benzyl bromide to 721 mg (1.96 mmol) of (3RS, 4RS)-1-cyclodecyl-4-(2-hydroxy-phenyl)-piperidine- A solution of 3-alcohol hydrochloride (1:1) (Example 6) in 3 ml of anhydrous dimethylformamide. After stirring overnight at 60°C, the product was extracted with ethyl acetate (3 x 10ml), washed with brine, dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 90 mg of a pale yellow solid. The amine was dissolved in 10 ml of ether and 1 ml of 2.3M hydrochloric acid in ether was added dropwise. The precipitate was filtered, washed with ether and dried in vacuo to give 63 mg (7%) of the title compound as a white powder. MS m/e (%): 422 (M+H ⁺ , 100).

Example 13 (3RS, 4RS)-1-cycloundecyl-4-(2-hydroxy-phenyl)-piperidin-3-ol hydrochloride (1:1) a), (3RS, 4RS) -1-cycloundecyl-4-(2-hydroxy-phenyl)-piperidin-3-ol

Add 2.20 g (7.8 mmol) tetraisopropyl orthotitanate to 300 mg (1.55 mmol) (3RS, 4RS)-4-(2-hydroxy-phenyl)-piperidin-3-ol (Example 4c) in 260mg (1.55mmol) suspension in cycloundecone. After stirring at room temperature for 6 days, a viscous oil was obtained. A solution of 70 mg (1.1 mmol) sodium cyanoborohydride in 1 ml ethanol was added dropwise over 3-4 minutes. Stirring was continued for 6 h at room temperature and 2 ml of 2.5M ammonia in ethanol was added. The precipitate was filtered and the filtrate was evaporated. The residue was purified by flash chromatography to give 138 mg (26%) of the title compound as a pale yellow foam.

MS m/e (%): 346 (M+H ⁺ , 100). b), (3RS,4RS)-1-cycloundecyl-4-(2-hydroxy-phenyl)-piperidin-3-ol hydrochloride (1:1)

Add 0.2ml of 2.3N hydrochloric acid ether solution to 7mg (0.02mmol) (3RS, 4RS)-1-cycloundecyl-4-(2-hydroxyl-phenyl)-piperidin-3-alcohol in solution in 1 ml of diethyl ether. After stirring for 30 minutes, excess hydrochloric acid and ether were removed in vacuo and the residue was resuspended in 1 ml ether. The precipitate was filtered and washed with ether to give 7 mg (quantitative) of the title compound as a white powder.

MS m/e (%): 346 (M+H ⁺ , 100).

Example 14 (3RS,4RS)-1-cycloundecyl-4-(2-methoxy-phenyl)-piperidin-3-ol hydrochloride (1:1)

At 0°C, add 65 mg (0.34 mmol) of bis(trimethylsilyl) potassium amide to 110 mg (0.31 mmol) of (3RS, 4RS)-1-cycloundecyl-4-(2-hydroxy- A solution of phenyl)-piperidin-3-ol (Example 13a) in 1 ml of anhydrous THF. Stirring was continued at this temperature for 1 h and 48 mg (0.34 mmol) iodomethane was added. After stirring at 0°C for 30 minutes, the ice bath was removed and the reaction mixture was allowed to warm to room temperature overnight.

After adding 2ml of water, the product was extracted with diethyl ether (3 x 10ml), dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 70mg of an oil. The amine was dissolved in 5 ml of ether and 1 ml of 2.3M hydrochloric acid in ether was added dropwise. The precipitate was filtered, washed with ether and dried in vacuo to give 65 mg (55%) of the title compound as a white powder.

MS m/e (%): 360 (M+H ⁺ , 100).

Example 15 (3RS, 4RS)- and (3SR, 4SR)-4-(2-hydroxyl-phenyl)-1-[(RS)-1,2,3,4-tetrahydro-naphthalene-2-yl ]-piperidin-3-ol hydrochloride (1:1) mixture a), (3RS,4RS)- and (3SR,4SR)-4-(2-hydroxy-phenyl)-1-[(RS )-1,2,3,4-tetrahydro-naphthalen-2-yl]-piperidin-3-ol mixture

2.20 g (7.8 mmol) tetraisopropyl orthotitanate were added to 300 mg (1.55 mmol) (3RS, 4RS)-4-(2-hydroxy-phenyl)-piperidin-3-ol (Example 4c) and 230mg (1.55mmol) in the mixture of β-tetralone. After stirring at room temperature for 5 days, a viscous oil was obtained. A solution of 70 mg (1.1 mmol) sodium cyanoborohydride in 1 ml ethanol was added dropwise over 3-4 minutes. Stirring was continued for 6 h at room temperature and 2 ml of 2.5M ammonia in ethanol was added. The precipitate was filtered and the filtrate was evaporated. The residue was purified by flash chromatography to give 100 mg (20%) of the title compound as a light brown foam.

MS m/e (%): 324 (M+H ⁺ , 100). b), (3RS,4RS)- and (3SR,4SR)-4-(2-hydroxy-phenyl)-1-[(RS)-1,2,3,4-tetrahydro-naphthalen-2-yl ]-piperidin-3-ol hydrochloride (1:1) mixture

Add 0.2ml of 2.3N hydrochloric acid in ether to 7mg (0.02mmol) (3RS, 4RS)- and (3SR, 4SR)-4-(2-hydroxyl-phenyl)-1-[(RS)-1 , 2,3,4-Tetrahydro-naphthalen-2-yl]-piperidin-3-ol in a solution in 1 ml of ether. After stirring for 30 minutes, excess hydrochloric acid and ether were removed in vacuo and the residue was resuspended in 1 ml ether. The precipitate was filtered and washed with ether to give 7 mg (quantitative) of the title compound as a white powder.

MS m/e (%): 324 (M+H ⁺ , 100).

Example 16 (3RS, 4RS)- and (3SR, 4SR)-4-(2-methoxy-phenyl)-1-[(RS)-1,2,3,4-tetrahydro-naphthalene-2 - Base]-piperidin-3-ol hydrochloride (1:1) mixture

At 0°C, add 55 mg (0.27 mmol) of bis(trimethylsilyl) potassium amide to 78 mg (0.24 mmol) of (3RS, 4RS)- and (3SR, 4SR)-4-(2-hydroxy-benzene base)-1-[(RS)-1,2,3,4-tetrahydro-naphthalen-2-yl]-piperidin-3-ol (Example 15a) in a solution of the mixture in 0.8 ml of anhydrous tetrahydrofuran . Stirring was continued at this temperature for 1 h and 38 mg (0.27 mmol) iodomethane was added. After stirring at 0°C for 30 minutes, the ice bath was removed and the reaction mixture was allowed to warm to room temperature overnight.

After adding 2ml of water, the product was extracted with diethyl ether (3 x 10ml), dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 38 mg of foam. The amine was dissolved in 3 ml of ether and 1 ml of 2.3M hydrochloric acid in ether was added dropwise. The precipitate was filtered, washed with ether and dried in vacuo to give 40 mg (44%) of the title compound as a light brown powder.

MS m/e (%): 338 (M+H ⁺ , 100).

Example 17 (3RS, 4RS)- and (3SR, 4SR)-4-(2-hydroxyl-phenyl)-1-[(RS)-1,2,3,4-tetrahydro-naphthalen-1-yl ]-piperidin-3-ol hydrochloride (1:1) mixture a), (3RS,4RS)- and (3SR,4SR)-4-(2-hydroxy-phenyl)-1-[(RS )-1,2,3,4-tetrahydro-naphthalen-1-yl]-piperidin-3-ol mixture

2.20 g (7.8 mmol) tetraisopropyl orthotitanate were added to 300 mg (1.55 mmol) (3RS, 4RS)-4-(2-hydroxy-phenyl)-piperidin-3-ol (Example 4c) and 230mg (1.55mmol) in the mixture of α-tetralone. After stirring at room temperature for 5 days, a viscous oil was obtained. A solution of 70 mg (1.1 mmol) sodium cyanoborohydride in 1 ml ethanol was added dropwise over 3-4 minutes. Stirring was continued at room temperature for 6 h and 2 ml of 2.5M ammonia in ethanol was added. The precipitate was filtered and the filtrate was evaporated. The residue was purified by flash chromatography to give 29 mg (6%) of the title compound as a light brown foam.

MS m/e (%): 324 (M+H ⁺ , 100). b), (3RS,4RS)- and (3SR,4SR)-4-(2-hydroxy-phenyl)-1-[(RS)-1,2,3,4-tetrahydro-naphthalen-1-yl ]-piperidin-3-ol hydrochloride (1:1) mixture

Add 0.2ml of 2.3N hydrochloric acid in ether to 4mg (0.01mmol) (3RS, 4RS)- and (3SR, 4SR)-4-(2-hydroxyl-phenyl)-1-[(RS)-1 , 2,3,4-Tetrahydro-naphthalen-1-yl]-piperidin-3-ol in a solution in 1 ml of ether. After stirring for 30 minutes, excess hydrochloric acid and ether were removed in vacuo and the residue was resuspended in 1 ml ether. The precipitate was filtered and washed with ether to give 4 mg (quant.) of the title compound as a white powder.

MS m/e (%): 324 (M+H ⁺ , 100).

Example 18 (3RS, 4RS)-4-(2-hydroxyl-phenyl)-1-(cis-and (trans-4-isopropyl-cyclohexyl)-piperidin-3-alcohol hydrochloride (1 : a mixture of 1), (3RS,4RS)-4-(2-hydroxy-phenyl)-1-(cis- and (trans-4-isopropyl-cyclohexyl)-piperidin-3-ol mixture

Add 9.16 g (32.2 mmol) tetraisopropyl orthotitanate to 2.5 g (12.9 mmol) (3RS,4RS)-4-(2-hydroxy-phenyl)-piperidin-3-ol (Example 4c) In suspension in 1.88 g (12.9 mmol) 4-isopropylcyclohexanone. After stirring overnight at room temperature, a viscous oil was obtained. A solution of 570 mg (9 mmol) sodium cyanoborohydride in 10 ml ethanol was added dropwise within 1 minute. Stirring was continued overnight at room temperature and 50 ml of 1M hydrochloric acid solution were added. After 30 minutes, the precipitate was filtered and washed with 1N hydrochloric acid solution to give 1.51 g of a white solid. The mother liquor was extracted with dichloromethane and the extract was combined with the first precipitate. Purification by flash chromatography afforded 1.90 g (46%) of the title compound as a white solid.

MS m/e (%): 318 (M+H ⁺ , 100). b), (3RS, 4RS)-4-(2-hydroxy-phenyl)-1-(cis- and (trans-4-isopropyl-cyclohexyl)-piperidin-3-ol hydrochloride (1 : 1) mixture

Add 0.2ml of 2.5N hydrochloric acid in ether to 10mg (0.03mmol) (3RS, 4RS)--4-(2-hydroxy-phenyl)-1-(cis-and (trans-4-isopropyl -cyclohexyl)-piperidin-3-ol in 1 ml of ether. After stirring for 30 minutes, the excess hydrochloric acid and ether were removed in vacuo and the residue was resuspended in 1 ml of ether. The precipitate was filtered and washed with ether Washing gave 10 mg (quantitative) of the title compound as a white powder.

MS m/e (%): 318 (M+H ⁺ , 100).

Example 19 (3RS, 4RS)-4-(2-methoxy-phenyl)-1-(cis-and (trans-4-isopropyl-cyclohexyl)-piperidin-3-ol hydrochloride (1:1) mixture

At 0°C, add 103 mg (0.52 mmol) of bis(trimethylsilyl) potassium amide to 75 mg (0.24 mmol) of (3RS, 4RS)-4-(2-hydroxyl-phenyl)-1-(cis - and (trans-4-isopropyl-cyclohexyl)-piperidin-3-ol (Example 18a) in a solution in 1 ml of anhydrous THF. Stirring was continued at this temperature for 1 h and 70 mg (0.49 mmol) were added Iodomethane. After stirring at 0°C for 30 minutes, the ice bath was removed and the reaction mixture was allowed to warm to room temperature overnight.

The solvent was removed and the residue was purified by flash chromatography to give 7mg of an oil. The amine was dissolved in 1 ml of ether and 0.2 ml of 2.3M hydrochloric acid in ether was added dropwise. The precipitate was filtered, washed with ether and dried in vacuo to give 7 mg (8%) of the title compound as a white powder.

MS m/e (%): 332 (M+H ⁺ , 100).

Example 20 (3RS, 4RS)-4-(2-allyloxy-phenyl)-1-(cis-and (trans-4-isopropyl-cyclohexyl)-piperidin-3-alcohol hydrochloride A mixture of salts (1:1) a), (3RS,4RS)-4-(2-allyloxy-phenyl)-1-(cis- and (trans-4-isopropyl-cyclohexyl)- Mixture of piperidin-3-ols

Add 610mg (4.4mmol) of potassium carbonate and 320mg (2.64mmol) of allyl bromide to 700mg (2.2mmol) of (3RS, 4RS)-4-(2-hydroxyl-phenyl)-1-(cis-and (trans -4-isopropyl-cyclohexyl)-piperidin-3-ol (Example 18a) in 3 ml of anhydrous dimethylformamide solution. Stir overnight at 60 ° C, remove the solvent and pass the residue through Purification by flash chromatography gave 125 mg (16%) of the title compound as a colorless foam.

MS m/e (%): 358 (M+H ⁺ , 100). b), (3RS, 4RS)-4-(2-allyloxy-phenyl)-1-(cis- and (trans-4-isopropyl-cyclohexyl)-piperidin-3-ol hydrochloride Salt (1:1) mixture

Add 0.2ml of 2.3N hydrochloric acid in ether to 5mg (0.014mmol) (3RS, 4RS)-4-(2-allyloxy-phenyl)-1-(cis-and (trans-4-iso Propyl-cyclohexyl)-piperidin-3-ol in 1 ml of ether. After stirring for 30 minutes, excess hydrochloric acid and ether were removed in vacuo and the residue was resuspended in 1 ml of ether. The precipitate was filtered And washed with diethyl ether to obtain 5 mg (quantitative) of the title compound as a white powder.

MS m/e (%): 358 (M+H ⁺ , 100).

Example 21 (3RS, 4RS)-4-(2-allyloxy-phenyl)-1-(cis-and (trans-4-isopropyl-cyclohexyl)-3-methoxy-piperidine Hydrochloride (1:1) mixture

At 0°C, add 33 mg (0.17 mmol) of bis(trimethylsilyl) potassium amide to 50 mg (0.14 mmol) of (3RS, 4RS)-4-(2-allyloxy-phenyl)-1 -(cis- and (trans-4-isopropyl-cyclohexyl)-piperidin-3-ol mixture (Example 20a) in solution in 0.5 ml of anhydrous tetrahydrofuran. Stirring was continued at this temperature for 1 h and addition 24 mg (0.17 mmol) iodomethane. After stirring at 0° C. for 30 minutes, the ice bath was removed and the reaction mixture was allowed to warm to room temperature overnight.

After adding 2ml of water, the product was extracted with diethyl ether (3 x 10ml), dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 30mg of an oil. The amine was dissolved in 2 ml of ether and 0.5 ml of 2.3M hydrochloric acid in ether was added dropwise. The precipitate was filtered, washed with ether and dried in vacuo to give 32 mg (56%) of the title compound as a white powder.

MS m/e (%): 372 (M+H ⁺ , 100).

Example 22 (3RS, 4RS)-4-(2-benzyloxy-phenyl)-1-(cis-and (trans-4-isopropyl-cyclohexyl)-piperidin-3-ol hydrochloride (1:1) mixture a), (3RS,4RS)-4-(2-benzyloxy-phenyl)-1-(cis- and (trans-4-isopropyl-cyclohexyl)-piperidine -3-ol mixture

Add 912 mg (6.6 mmol) of potassium carbonate and 450 mg (2.64 mmol) of benzyl bromide to 397 mg (1.25 mmol) of (3RS, 4RS)-4-(2-hydroxyl-phenyl)-1-(cis-and (trans- 4-Isopropyl-cyclohexyl)-piperidin-3-ol mixture (Example 18a) in 3 ml of anhydrous dimethylformamide solution. Stir overnight at 60° C., remove the solvent and pass the residue through Purification by flash chromatography gave 228 mg (45%) of the title compound as a colorless foam.

MS m/e (%): 408 (M+H ⁺ , 100). b), (3RS,4RS)-4-(2-benzyloxy-phenyl)-1-(cis- and (trans-4-isopropyl-cyclohexyl)-piperidin-3-ol hydrochloride (1:1) mixture

Add 0.2ml of 2.3N hydrochloric acid in ether to 7mg (0.017mmol) (3RS, 4RS)-4-(2-benzyloxy-phenyl)-1-(cis-and (trans-4-isopropyl base-cyclohexyl)-piperidin-3-ol in 1 ml of diethyl ether. After stirring for 30 minutes, excess hydrochloric acid and diethyl ether were removed in vacuo and the residue was resuspended in 1 ml of diethyl ether. The precipitate was filtered and washed with Ether washing gave 7 mg (quantitative) of the title compound as a white powder.

MS m/e (%): 408 (M+H ⁺ , 100).

Example 23 (3RS, 4RS)-1-benzyl-3-methoxy-4-(2-methoxy-phenyl)-piperidine hydrochloride (1:1) a), (3RS, 4RS )-1-benzyl-4-(2-methoxy-phenyl)-piperidin-3-ol

Following the literature procedure (Juan C. Jean and Lawrence D. Wise, J. Heterocyclic Chem. 1987, 24, 1317-1319), the title compound was prepared in comparable yields in three steps starting from 2-bromomethoxybenzene. The product was obtained as a white powder.

MS m/e (%): 298 (M+H ⁺ , 100). b), (3RS,4RS)-1-benzyl-3-methoxy-4-(2-methoxy-phenyl)-piperidine hydrochloride (1:1)

At 0°C, add 126 mg (0.6 mmol) of bis(trimethylsilyl) potassium amide to 149 mg (0.5 mmol) of (3RS, 4RS)-1-benzyl-4-(2-methoxy-benzene base)-piperidin-3-ol in a solution in 1.5 ml of anhydrous tetrahydrofuran. Stirring was continued at this temperature for 1 h and 85 mg (0.6 mmol) iodomethane was added. After stirring at 0°C for 30 minutes, the ice bath was removed and the reaction mixture was allowed to warm to room temperature overnight.

After adding 2ml of water, the product was extracted with diethyl ether (3 x 10ml), dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 128mg of an oil. The amine was dissolved in 10 ml of ether and 1 ml of 2.3M hydrochloric acid in ether was added dropwise. The precipitate was filtered, washed with ether and dried in vacuo to give 130 mg (75%) of the title compound as a white powder.

MS m/e (%): 312 (M+H ⁺ , 100).

Example 24 (3RS, 4RS)-3-methoxy-1-(2-methoxy-phenyl)-4-(2-methoxy-phenyl)piperidine hydrochloride (1:1) a), (3RS,4RS)-3-methoxy-4-(2-methoxy-phenyl)-piperidine

Add 1.0g 10% palladium-coated activated carbon to 4.03g (11.6mol) (3RS, 4RS)-1-benzyl-3-methoxy-4-(2-methoxy-phenyl)-piperidine hydrochloride A solution of the salt (1:1) (Example 23b) in 100 ml methanol. The reaction mixture was hydrogenated (room temperature, 1 bar) for 20 h. The catalyst was filtered and washed with methanol (3 x 10ml). The filtrate was concentrated to a total volume of about 50ml and 1.3g of sodium carbonate was added. After stirring the suspension for a further 2 h, the solvent was removed under reduced pressure and the residue was resuspended in 50 ml of dichloromethane. The inorganic salts were filtered and the filtrate evaporated to give 2.20 g (74%) of the title compound as a pale yellow oil.

MS m/e (%): 221 (M ⁺ , 17), 189 (100), 178 (62). b), (3RS, 4RS)-3-methoxy-1-(2-methoxy-benzyl)-4-(2-methoxy-phenyl)-piperidine hydrochloride (1:1 )

Add 75mg (0.55mmol) 2-methoxybenzaldehyde to 111mg (0.5mmol) (3RS, 4RS)-3-methoxy-4-(2-methoxy-phenyl)-piperidine in 1.5ml solution in methanol. The reaction mixture was stirred at room temperature for 5 minutes and 63 mg (1.0 mmol) sodium cyanoborohydride was added dropwise. After reacting overnight, 1 ml of 2.3M methanolic hydrochloric acid was added. The reaction mixture was evaporated, redissolved in 5 ml of water and washed with ether. The aqueous solution was adjusted to pH 10 by the addition of solid potassium hydroxide and extracted with dichloromethane, dried (magnesium sulfate), evaporated and purified by flash chromatography to give 100 mg of an oil. The amine was dissolved in 10 ml of ether and 1 ml of 2.3M hydrochloric acid in ether was added dropwise. The precipitate was filtered, washed with ether and evaporated to dryness in vacuo to give 70 mg (35%) of the title compound as a white powder.

MS m/e (%): 342 (M+H ⁺ , 100).

Example 25 (3RS,4RS)-3-methoxy-4-(2-methoxy-phenyl)-1-(3-phenyl-propyl)piperidine hydrochloride (1:1)

Add 74 mg (0.55 mmol) 3-phenylpropanal to 111 mg (0.5 mmol) (3RS,4RS)-3-methoxy-4-(2-methoxy-phenyl)-piperidine (Example 24a) in solution in 1.5 ml of methanol. The reaction mixture was stirred at room temperature for 5 minutes and 63 mg (1.0 mmol) sodium cyanoborohydride was added. After reacting overnight, 1 ml of 2.3M methanolic hydrochloric acid was added. The reaction mixture was evaporated, redissolved in 5 ml of water and washed with ether. The aqueous solution was adjusted to pH 10 by the addition of solid potassium hydroxide and extracted with dichloromethane, dried (magnesium sulfate) and evaporated to give 155mg of an oil. The amine was dissolved in 10 ml of ether and 1 ml of 2.3M hydrochloric acid in ether was added dropwise. The precipitate was filtered, washed with ether and evaporated to dryness in vacuo to give 150 mg (80%) of the title compound as a white powder.

MS m/e (%): 340 (M+H ⁺ , 100).

Example 26 (3RS,4RS)-1-(4-tert-butyl-benzyl)-3-methoxy-4-(2-methoxy-phenyl)piperidine hydrochloride (1:1)

Add 89 mg (0.55 mmol) of 4-tert-butylbenzaldehyde to 111 mg (0.5 mmol) of (3RS, 4RS)-3-methoxy-4-(2-methoxy-phenyl)-piperidine (Example 24a) In solution in 1.5 ml methanol. The reaction mixture was stirred at room temperature for 5 minutes and 63 mg (1.0 mmol) sodium cyanoborohydride was added. After reacting overnight, 1 ml of 2.3M methanolic hydrochloric acid was added. The reaction mixture was evaporated, redissolved in 5 ml of water and washed with ether. The aqueous solution was adjusted to pH 10 by the addition of solid potassium hydroxide and extracted with dichloromethane, dried (magnesium sulfate) and evaporated to give 100 mg of an oil. The amine was dissolved in 10 ml of ether and 1 ml of 2.3M hydrochloric acid in ether was added dropwise. The precipitate was filtered, washed with ether and evaporated to dryness in vacuo to give 110 mg (55%) of the title compound as a white powder.

MS m/e (%): 368 (M+H ⁺ , 100).

Example 27 (3RS,4RS)-3-allyloxy-1-benzyl-4-(2-methoxy-phenyl)-piperidine hydrochloride (1:1)

At 0°C, add 126 mg (0.6 mmol) of bis(trimethylsilyl) potassium amide to 149 mg (0.5 mmol) of (3RS, 4RS)-1-benzyl-4-(2-methoxy-benzene base)-piperidin-3-ol (Example 23a) in 1.5 ml of anhydrous THF. Stirring was continued at this temperature for 1 h and 73 mg (0.6 mmol) allyl bromide was added. After stirring at 0°C for 30 minutes, the ice bath was removed and the reaction mixture was allowed to warm to room temperature overnight.

After adding 2ml of water, the product was extracted with diethyl ether (3 x 10ml), dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 149mg of an oil. The amine was dissolved in 10 ml of ether and 1 ml of 2.3M hydrochloric acid in ether was added dropwise. The precipitate was filtered, washed with ether and dried in vacuo to give 150 mg (80%) of the title compound as a white powder.

MS m/e (%): 338 (M+H ⁺ , 100).

Example 28 (3RS, 4RS)-1-cyclodecyl-4-(2-methoxy-phenyl)-piperidin-3-ol hydrochloride (1:1) a), (3RS, 4RS) -4-(2-Methoxy-phenyl)-piperidin-3-ol hydrochloride (1:1)

5.95g (20mmol) (3RS, 4RS)-1-benzyl-4-(2-methoxy-phenyl)-piperidin-3-alcohol (embodiment 23a) in the ethanol solution of 100ml 1N hydrochloric acid The solution in was stirred for 30 minutes. The solvent and excess hydrochloric acid were removed in vacuo. The residue was dissolved in 100ml of methanol and 1.5g of 10% palladium on activated carbon was added. The reaction mixture was hydrogenated (room temperature, 1 bar) for 20 h. The catalyst was filtered and washed with methanol (3 x 10ml). The filtrate was evaporated in vacuo to give 4.7 g (96%) of the title compound as a white powder.

MS m/e (%): 207 (M ⁺ , 19), 178 (100).

b), (3RS,4RS)-4-(2-methoxy-phenyl)-piperidin-3-ol

Add 2.1 g of sodium carbonate to 4.7 g (20 mmol) of (3RS, 4RS)-4-(2-methoxy-phenyl)-piperidin-3-ol hydrochloride (1:1) in 40 ml of methanol in solution. After stirring at room temperature for 1 h, the sodium salt was filtered and washed with 10 ml methanol. The filtrate was concentrated, diluted with 2-propanol and filtered again. The filtrate was evaporated to give 4.10 g (quant.) of the title compound as a white solid.

MS m/e (%): 208 (M+H ⁺ , 100). c), (3RS,4RS)-1-cyclodecyl-4-(2-methoxy-phenyl)-piperidin-3-ol

Add 7.12g (25mmol) tetraisopropyl orthotitanate to 4.14g (20mmol) (3RS, 4RS)-4-(2-methoxy-phenyl)-piperidin-3-ol in 3.09g (20mmol ) in suspension in cyclodecanone. After stirring overnight at room temperature, a viscous oil was obtained. A solution of 880 mg (14 mmol) sodium cyanoborohydride in 20 ml ethanol was added dropwise over 3-4 minutes. Stirring was continued at room temperature for 48 h and 10 ml of 25% hydrochloric acid was added. After 30 minutes, the precipitate was filtered and 200 ml of 2.5M ammonia in ethanol was added. The precipitate was filtered again and the filtrate was evaporated. The residue was purified by flash chromatography to give 5.40 g (78%) of a pale yellow oil which crystallized on standing at room temperature.

MS m/e (%): 346 (M+H ⁺ , 100). d), (3RS,4RS)-1-cyclodecyl-4-(2-methoxy-phenyl)-piperidin-3-ol hydrochloride (1:1)

Add 2ml of 2.5N hydrochloric acid in ether to 270mg (0.78mmol) of (3RS, 4RS)-1-cyclodecyl-4-(2-methoxy-phenyl)-piperidin-3-ol in ether (10ml) solution. After stirring for 30 minutes, excess hydrochloric acid and ether were removed in vacuo and the residue was resuspended in 20 ml ether. The precipitate was filtered and washed with diethyl ether to give 298 mg (quant.) of the title compound as a white powder.

MS m/e (%): 346 (M+H ⁺ , 100).

Example 29 (3RS,4RS)-3-methoxy-1-cyclodecyl-4-(2-methoxy-phenyl)-piperidine hydrochloride (1:1)

At 0°C, add 126 mg (0.6 mmol) of bis(trimethylsilyl) potassium amide to 173 mg (0.5 mmol) of (3RS, 4RS)-1-cyclodecyl-4-(2-methoxy- phenyl)-piperidin-3-ol (Example 28c) in anhydrous THF (1.5ml). Stirring was continued at this temperature for 1 h and 85 mg (0.6 mmol) iodomethane was added. After stirring at 0°C for 30 minutes, the ice bath was removed and the reaction mixture was allowed to warm to room temperature overnight.

After adding 2ml of water, the product was extracted with diethyl ether (3 x 10ml), dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 120mg of an oil. The amine was dissolved in 10 ml of ether and 1 ml of 2.3M hydrochloric acid in ether was added dropwise. The precipitate was filtered, washed with ether and dried in vacuo to give 133 mg (67%) of the title compound as a white powder.

MS m/e (%): 360 (M+H ⁺ , 100).

Example 30 (3RS, 4RS)-3-allyloxy-1-cyclodecyl-4-(2-methoxy-phenyl)-piperidine hydrochloride (1:1) a), (3RS ,4RS)-3-allyloxy-1-cyclodecyl-4-(2-methoxy-phenyl)-piperidine

At 0°C, add 256 mg (1.2 mmol) of bis(trimethylsilyl) potassium amide to 146 mg (1.0 mmol) of (3RS, 4RS)-1-cyclodecyl-4-(2-methoxy- phenyl)-piperidin-3-ol (Example 28c) in anhydrous THF (3.0ml). Stirring was continued at this temperature for 1 h and 145 mg (1.2 mmol) allyl bromide was added. After stirring at 0°C for 30 minutes, the ice bath was removed and the reaction mixture was allowed to warm to room temperature overnight.

After adding 4ml of water, the product was extracted with diethyl ether (3 x 20ml), dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 280 mg (73%) of the title compound as a colorless oil.

MS m/e (%): 386 (M+H ⁺ , 100). b), (3RS,4RS)-3-allyloxy-1-cyclodecyl-4-(2-methoxy-phenyl)-piperidine hydrochloride (1:1)

Add 1ml of 2.3M hydrochloric acid in ether to 100mg (0.26mmol) (3RS, 4RS)-3-allyloxy-1-cyclodecyl-4-(2-methoxy-phenyl)-piper Pyridine in ether (10ml) solution. The precipitate was filtered, washed with ether and dried in vacuo to give 109 mg (quantitative) of the title compound as a white powder.

MS m/e (%): 386 (M+H ⁺ , 100).

Example 31 (3RS,4RS)-1-cyclodecyl-4-(2-methoxy-phenyl)-3-propoxy-piperidine hydrochloride (1:1)

Add 40mg 10% palladium activated carbon to 77mg (0.2mol) (3RS, 4RS)-3-allyloxy-1-cyclodecyl-4-(2-methoxy-phenyl)-piperidine (implementation Example 30a) in solution in 10 ml ethyl acetate. The reaction mixture was hydrogenated (room temperature, 1 bar) for 20 h. The catalyst was filtered and washed with ethyl acetate (3 x 1 ml). The filtrate was evaporated in vacuo to give 78 mg of an oil. The amine was dissolved in 10 ml of ether and 1 ml of 2.3M hydrochloric acid in ether was added dropwise. The precipitate was filtered, washed with ether and dried in vacuo to give 85 mg (quantitative) of the title compound as a white powder.

MS m/e (%): 388 (M ⁺ , 100).

Example 32 (3RS, 4RS)-1-cyclodecyl-4-(2-isopropyl-phenyl)-piperidin-3-ol hydrochloride (1:1) a), (3RS, 4RS) -1-Benzyl-4-(2-isopropyl-phenyl)-piperidin-3-ol

According to the literature method (Juan C.Jean and Lawrence D.Wise, J.Heterocyclic Chem.1987,24,1317-1319), start from 2-bromoisopropylbenzene instead of 2-bromomethoxybenzene through three steps The title compound was prepared in comparable yields. The product was obtained as a white solid.

MS m/e (%): 310 (M+H ⁺ , 100). b), (3RS,4RS)-4-(2-isopropyl-phenyl)-piperidin-3-ol hydrochloride (1:1)

A solution of 10.9 g (32 mmol) (3RS, 4RS)-1-benzyl-4-(2-isopropyl-phenyl)-piperidin-3-ol in 100 ml 1N hydrochloric acid ethanol solution was stirred for 30 minutes . The solvent and excess hydrochloric acid were removed in vacuo. The residue was dissolved in 300ml of methanol and 2.4g of 10% palladium on activated carbon was added. The reaction mixture was hydrogenated (room temperature, 5 bar) for 20 h. The catalyst was filtered and washed with methanol (3 x 50ml). The filtrate was evaporated in vacuo to give 5.9 g (74%) of the title compound as a white powder.

MS m/e (%): 219 (M ⁺ , 17), 202 (21), 190 (39), 172 (42), 44 (100). c), (3RS,4RS)-4-(2-isopropyl-phenyl)-piperidin-3-ol

Add 3.6g of sodium carbonate to 5.75g (22.6mmol) of (3RS, 4RS)-4-(2-isopropyl-phenyl)-piperidin-3-alcohol hydrochloride (1:1) in ethanol (150ml ) in the suspension. After stirring at room temperature for 2 h, the sodium salt was filtered and washed with 10 ml of ethanol. The filtrate was concentrated, diluted with 2-propanol and filtered again. The filtrate was evaporated to give 4.93 g (quant.) of the title compound as a white solid.

MS m/e (%): 220 (M+H ⁺ , 100). d), (3RS,4RS)-1-cyclodecyl-4-(2-isopropyl-phenyl)-piperidin-3-ol

Add 3.24g (11.4mmol) tetraisopropyl orthotitanate to 500mg (2.28mmol) (3RS, 4RS)-4-(2-isopropyl-phenyl)-piperidin-3-ol in 350mg (2.28 mmol) in suspension in cyclodecanone. After stirring at room temperature for 5 days, a viscous oil was obtained. A solution of 100 mg (1.59 mmol) sodium cyanoborohydride in ethanol (2 ml) was added dropwise over 3-4 minutes. Stirring was continued at room temperature for 4 h and 25 ml of 2.3N hydrochloric acid ethanol solution was added. After heating at 60 °C for 3 h, the solution was adjusted to pH 8 by adding 25% sodium hydroxide solution and filtered. The filtrate was extracted with ethyl acetate, the organic phase was washed with brine, dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to afford 415 mg (51%) of the title compound as a white solid.

MS m/e (%): 358 (M+H ⁺ , 100). e), (3RS,4RS)-1-cyclodecyl-4-(2-isopropyl-phenyl)-piperidin-3-ol hydrochloride (1:1)

Add 0.3ml of 2.3M hydrochloric acid in ethanol to 30mg (0.08mmol) (3RS, 4RS)-1-cyclodecyl-4-(2-isopropyl-phenyl)-piperidin-3-ol in solution in 3 ml of ethanol. The solution was stirred at room temperature for 30 minutes and evaporated. The residue was suspended in ether and stirred for 1 h. The precipitate was filtered, washed with ether and dried in vacuo to give 23 mg (70%) of the title compound as a white powder.

MS m/e (%): 358 (M+H ⁺ , 100).

Example 33 (3RS,4RS)-1-cyclodecyl-4-(2-isopropyl-phenyl)-3-methoxy-piperidine hydrochloride (1:1)

At 0°C, add 134 mg (0.67 mmol) of bis(trimethylsilyl) potassium amide to 200 mg (0.56 mmol) of (3RS, 4RS)-1-cyclodecyl-4-(2-isopropyl- A solution of phenyl)-piperidin-3-ol (Example 32d) in 2 ml of anhydrous THF. Stirring was continued at this temperature for 1 h and 80 mg (0.56 mmol) iodomethane was added. After stirring at 0°C for 30 minutes, the ice bath was removed and the reaction mixture was allowed to warm to room temperature overnight.

After adding 2ml of water, the product was extracted with diethyl ether (3 x 10ml), dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 50mg of an oil. The amine was dissolved in 10 ml of ether and 1 ml of 2.3M hydrochloric acid in ether was added dropwise. The precipitate was filtered, washed with ether and dried in vacuo to give 34 mg (15%) of the title compound as a white powder.

MS m/e (%): 372 (M+H ⁺ , 100).

Example 34 (3RS,4RS)-1-cyclononyl-4-(2-isopropyl-phenyl)-piperidin-3-ol hydrochloride (1:1)

Add 1.29 g (4.56 mmol) tetraisopropyl orthotitanate to 200 mg (0.91 mmol) (3RS, 4RS)-4-(2-isopropyl-phenyl)-piperidin-3-ol (Example 32c ) in suspension in 160 mg (1.14 mmol) cyclononanone. After stirring at room temperature for 6 days, a viscous oil was obtained. A solution of 24 mg (0.64 mmol) sodium borohydride in ethanol (2 ml) was added dropwise over 3-4 minutes. Stirring was continued at room temperature for 1 h and 10 ml of 2.3N hydrochloric acid in ethanol was added. After heating at 60 °C for 4 h, the solution was adjusted to pH 8 by adding 25% sodium hydroxide solution and filtered. The filtrate was extracted with ethyl acetate, the organic phase was washed with brine, dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 160 mg of a pale yellow oil. The amine was dissolved in 10 ml of ethanol and 1 ml of 2.3M hydrochloric acid in ethanol was added dropwise. The solution was stirred at room temperature for 30 minutes and evaporated, the residue was suspended in ether and stirred for 1 hour. The precipitate was filtered, washed with ether and dried in vacuo to give 175 mg (51%) of the title compound as a white powder.

MS m/e (%): 344 (M+H ⁺ , 100).

Example 35 1-cyclodecyl-4-(2,6-dimethoxy-phenyl)-piperidine hydrochloride (1:1)a), 1-benzyl-4-(2,6-di Methoxy-phenyl)-1,2,3,6-tetrahydro-piperidine

According to the literature method (Juan C.Jean and Lawrence D.Wise, J.Heterocyclic Chem.1987,24,1317-1319), start from 1,2-dimethoxyphen-2-ylmagnesium bromide in two steps instead of The title compound was prepared in comparable yields starting from 2-methoxyphenylmagnesium bromide. The product was obtained as white needles.

MS m/e (%): 310 (M+H ⁺ , 100). b), 4-(2,6-dimethoxy-phenyl)-piperidine

3.4g (11mmol) 1-benzyl-4-(2,6-dimethoxy-phenyl)-1,2,3,6-tetrahydro-piperidine in 100ml 1N hydrochloric acid ethanol solution The solution was stirred for 30 minutes. The solvent and excess hydrochloric acid were removed in vacuo. The residue was dissolved in 110 ml of methanol and 0.9 g of 10% palladium on activated carbon was added. The reaction mixture was hydrogenated (room temperature, 5 bar) for 20 h. The catalyst was filtered and washed with methanol (3 x 50ml). The filtrate was evaporated in vacuo and the product was purified by flash chromatography to give 1.34 g (57%) of the title compound as a white powder.

MS m/e (%): 222 (M+H ⁺ , 100). c), 1-cyclodecyl-4-(2,6-dimethoxy-phenyl)-piperidine hydrochloride (1:1)

Add 1.28g (4.52mmol) tetraisopropyl orthotitanate to 200mg (0.9mmol) 4-(2,6-dimethoxy-phenyl)-piperidine in 140mg (0.9mmol) cyclodecanone in suspension. After stirring at room temperature for 4 days, a viscous oil was obtained. A solution of 40 mg (0.63 mmol) sodium cyanoborohydride in 1 ml ethanol was added dropwise over 3-4 minutes. Stirring was continued at room temperature for 5 h and 10 ml of 2.3N hydrochloric acid in ethanol was added. After heating at 60 °C for 3 h, the solution was adjusted to pH 8 by adding 25% sodium hydroxide solution and filtered. The filtrate was extracted with ethyl acetate, the organic phase was washed with brine, dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to obtain 18 mg of white crystals. The amine was dissolved in 10 ml of ether and 1 ml of 2.3M hydrochloric acid in ether was added dropwise. The solution was stirred at room temperature for 30 minutes and evaporated. The residue was resuspended in ether and dried in vacuo to give 20 mg (6%) of the title compound as a white powder.

MS m/e (%): 360 (M+H ⁺ , 100).

Example 36 (3RS, 4RS)-1-cyclodecyl-4-(2,6-dimethoxy-phenyl)-piperidin-3-ol hydrochloride (1:1) a), (3RS ,4RS)-1-benzyl-4-(2,6-dimethoxy-phenyl)-piperidin-3-ol hydrochloride (1:1)

According to the literature method (Juan C.Jean and Lawrence D.Wise, J.Heterocyclic Chem.1987,24,1317-1319), start from 1,3-methoxyphen-2-ylmagnesium bromide in three steps instead of from 2-Methoxyphenylmagnesium bromide initially prepared the title compound in comparable yields. The product was obtained as white crystals.

MS m/e (%): 328 (M+H ⁺ , 100). b), (3RS,4RS)-4-(2,6-dimethoxy-phenyl)-piperidin-3-ol hydrochloride (1:1)

Add 600mg of 10% palladium-coated activated carbon to 2.9g (8mmol) (3RS, 4RS)-1-benzyl-4-(2,6-dimethoxy-phenyl)-piperidin-3-alcohol hydrochloride (1:1) in methanol (80ml) solution. The reaction mixture was hydrogenated (room temperature, 5 bar) until the theoretical amount of hydrogen was consumed (ca. 20 h). The catalyst was filtered and washed with methanol (3 x 20ml). The filtrate was evaporated in vacuo to give 1.88 g (87%) of the title compound as a pale yellow powder.

MS m/e (%): 237 (M ⁺ , 27), 208 (100). c), (3RS,4RS)-4-(2,6-dimethoxy-phenyl)-piperidin-3-ol

Add 1.0 g of sodium carbonate to 1.78 g (6.53 mmol) of (3RS, 4RS)-4-(2,6-dimethoxy-phenyl)-piperidin-3-ol hydrochloride (1:1) in solution in 25ml of ethanol. After stirring at room temperature for 2 h, the sodium salt was filtered and washed with 10 ml of ethanol. The filtrate was concentrated, diluted with 2-propanol and filtered again. The filtrate was evaporated to give 1.46 g (quant.) of the title compound as a pale yellow solid.

MS m/e (%): 238 (M+H ⁺ , 100). d), (3RS,4RS)-1-cyclodecyl-4-(2,6-dimethyl-phenyl)-piperidin-3-ol

Add 3.0 g (10.5 mmol) tetraisopropyl orthotitanate to 500 mg (2.1 mmol) (3RS, 4RS)-4-(2,6-dimethoxy-phenyl)-piperidin-3-ol in 325mg (2.1mmol) in suspension in cyclodecanone. After stirring at room temperature for 4 days, a viscous oil was obtained. A solution of 93 mg (1.5 mmol) sodium cyanoborohydride in 1.5 ml ethanol was added dropwise over 3-4 minutes. Stirring was continued at room temperature for 2 h and 25 ml of 2.3N hydrochloric acid in ethanol was added. After heating at 60 °C for 2 h, it was adjusted to pH 8 by adding 25% sodium hydroxide solution and filtered. The filtrate was extracted with ethyl acetate, the organic phase was washed with brine, dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 218 mg (27%) of the title compound as a yellow oil.

MS m/e (%): 376 (M+H ⁺ , 100). e), (3RS,4RS)-1-cyclodecyl-4-(2,6-dimethoxy-phenyl)-piperidin-3-ol hydrochloride (1:1)

Add 0.3ml dropwise to a solution of 30mg (0.08mmol) (3RS, 4RS)-1-cyclodecyl-4-(2,6-dimethoxyphenyl)-piperidin-3-ol in 3ml ethanol 2.3M hydrochloric acid ethanol solution. The solution was stirred at room temperature for 30 minutes and evaporated. The residue was suspended in ether and stirred for 1 hour. The precipitate was filtered off, washed with ether and dried in vacuo to afford 21 mg (61%) of the title compound as a white powder.

MS m/e (%): 376 (M+H ⁺ , 100).

Example 37 1-Cyclodecyl-4-phenyl-piperidine hydrochloride (1:1)

1.76 g (6.2 mmol) of tetraisopropyl orthotitanate were added to a suspension of 200 mg (1.24 mmol) of 4-phenylpiperidine in 230 mg (1.49 mmol) of cyclodecanone. After stirring at room temperature for 5 days, a viscous oil was obtained. A solution of 235 mg (6.2 mmol) sodium borohydride in 10 ml ethanol was added dropwise over 3-4 minutes. Stirring was continued at room temperature for 2 h and 10 ml of concentrated ammonia solution was added. The inorganic precipitate was removed by filtration and washed with dichloromethane. The filtrate was extracted with dichloromethane, the organic phase was washed with brine, dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 270 mg of a yellow solid. The amine was dissolved in 10 ml of ethanol and 1 ml of 2.3M hydrochloric acid in ethanol was added dropwise. The solution was stirred at room temperature for 30 minutes and evaporated. The residue was resuspended in ether and stirred for 1 h. The precipitate was filtered, washed with ether and dried in vacuo to give 200 mg (48%) of the title compound as a white powder.

MS m/e (%): 300 (M+H ⁺ , 100).

Example 38 1-Cyclodecyl-4-cyclohexyl-piperidine hydrochloride (1:1)

1.67 g (6.0 mmol) of tetraisopropyl orthotitanate were added to a suspension of 200 mg (1.12 mmol) of 4-cyclohexylpiperidine in 220 mg (1.43 mmol) of cyclodecanone. After stirring at room temperature for 5 days, a viscous oil was obtained. A solution of 225 mg (6.0 mmol) sodium borohydride in 10 ml ethanol was added dropwise over 3-4 minutes. Stirring was continued at room temperature for 2 h and 10 ml of concentrated ammonia solution was added. The inorganic precipitate was filtered and washed with dichloromethane. The filtrate was extracted with dichloromethane, the organic phase was washed with brine, dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 80 mg of a pale yellow solid. The amine was dissolved in 10 ml of ethanol and 1 ml of 2.3M hydrochloric acid in ethanol was added dropwise. The solution was stirred at room temperature for 30 minutes and evaporated. The residue was resuspended in ether and stirred for 1 h. The precipitate was filtered, washed with ether and dried in vacuo to give 78 mg (19%) of the title compound as a white powder.

MS m/e (%): 305 (M ⁺ , 18), 206 (100).

Claims (11)

1. Compounds of general formula I and their addition salts with pharmaceutically acceptable acids

in: R ¹ is tetrahydronaphthyl; Or -(CH ₂ ) _n -C ₆ H ₅ -R ₄ , wherein n is 0-4 and R ⁴ is H, lower alkyl or lower alkoxy; Or C ₅ -C ₁₂ cycloalkyl unsubstituted or substituted by lower alkyl; R ² is H, OH, lower alkoxy, lower alkenyloxy or lower alkyl; R ³ is C ₅ -C ₇ cycloalkyl or phenyl which is unsubstituted or substituted by a substituent, and the substituent is OH, halogen, lower alkoxy, lower alkenyloxy, lower alkyl or -O- (CH ₂ ) _n -C ₆ H ₅ , wherein n is 0-3. 2. The compound of claim 1, wherein R ¹ is C ₅ -C ₁₂ cycloalkyl which may be substituted or not substituted by lower alkyl. 3. The compound of claim 2 which is (3RS,4RS)-1-cyclononyl-4-(2-hydroxy-phenyl)piperidin-3-ol; 1-cyclodecyl-4-(2-methoxy-phenyl)-piperidine; (3RS,4RS)-1-cyclodecyl-4-(2-isopropyl-phenyl)piperidin-3-ol; (3RS,4RS)-4-(2-Hydroxy-phenyl)-1-(cis- and (trans-4-isopropylcyclohexyl)-piperidin-3-ol; 2-(1-cyclodecyl-piperidin-4-yl)-phenol; (3RS,4RS)-1-cyclodecyl-4-(2-methoxy-phenyl)-piperidin-3-ol; 1-cyclodecyl-4-cyclohexyl-piperidine; (3RS,4RS)-1-cyclononyl-4-(2-methoxy-phenyl)-piperidin-3-ol; (3RS,4RS)-4-(2-allyloxy-phenyl)-1-cyclodecyl-piperidin-3-ol; 1-cyclodecyl-4-phenyl-piperidine; (3RS,4RS)-1-cyclononyl-4-(2-isopropyl-phenyl)-piperidin-3-ol; and (3RS,4RS)-1-Cyclodecyl-4-(2-hydroxy-phenyl)-piperidin-3-ol. 4. Compounds according to any one of claims 1-3, for use as therapeutically active substances, in particular for the treatment of memory and attention deficits, psychiatric, neurological and physiological diseases such as anxiety and stress disorders, depression, caused by premature aging Memory loss due to dementia or other dementias such as vascular dementia and AIDS dementia syndrome, Parkinson's disease, epilepsy and convulsions, acute and/or chronic painful disorders, withdrawal symptoms of addictive drugs and reduction of their abuse/craving , control of water balance, Na ⁺ excretion and arterial blood pressure diseases and metabolic diseases such as obesity. 5. A medicament containing one or more compounds according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof. 6. The medicament of claim 5 for the treatment of Orphanin FQ (OFQ) receptor related diseases, said diseases include memory and attention deficit, psychiatric, neurological and physiological diseases such as anxiety and stress disorders, depression, by Memory loss in Alzheimer's disease or other dementias such as vascular dementia and AIDS-related dementia syndrome, Parkinson's disease, epilepsy and convulsions, acute and/or chronic pain disorders, withdrawal symptoms of addictive drugs and reduction of their abuse / Appetite, control of water balance, Na ⁺ excretion and arterial blood pressure diseases and metabolic diseases such as obesity. 7. The preparation method of the compound of formula I defined in claim 1, which method comprises the compound of formula II

With formula Ⅳ compound

Reductive amination is carried out, wherein R ¹ , R ² and R ³ are as defined in claim 1. 8. Use of one or more compounds according to claims 1-3 or a pharmaceutically acceptable salt thereof for the preparation of a medicament. 9. The use of claim 8 for the preparation of a medicament for the treatment of memory and attention deficits, psychiatric, neurological and physiological diseases such as anxiety and tension disorders, depression, caused by Alzheimer's disease or other dementias such as Memory loss due to vascular dementia and AIDS dementia syndrome, Parkinson's disease, epilepsy and convulsions, acute and/or chronic painful disorders, withdrawal symptoms of addictive drugs and reduction of their abuse/craving, control of water balance, Na ⁺ excretion and arterial blood pressure diseases and metabolic diseases such as obesity. 10. Compounds of general formula I obtainable by the process of claim 7 or equivalents. 11. The invention substantially as herein described.