MXPA01002152A - Piperidine derivatives - Google Patents

Abstract

The present invention relates to compoundsof general formula (I), wherein R1 is tetrahydronaphtyl;or -(CH2)n-C6H5-R4 wherein n is 0-4 and R4 is H, lower alkyl, or lower alkoxy;or C5-C12 cycloalkyl, optionally substituted by lower alkyl;R2 is H, OH, lower alkoxy, lower alkenyloxy or lower alkyl;R3 is C5-C7 cycloalkyl or phenyl, optionally substituted by OH, halogen, lower alkoxy, lower alkenyloxy, lower alkyl or -O-(CH2)n-C6H5 wherein n is 0-3;and their pharmaceutically acceptable acid addition salts. The compounds of general formula (I) 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 conditions, withdrawal symptoms of addictive drugs and reduction of their abuse/craving, control of water balance, Na+ excretion, arterial blood pressure disorders and metabolic disorders such as obesity.

Description

PIPERIDINE DERIVATIVES Field of Invention The present invention relates to new compounds of the general formula where R1 is tetrahydronaphthyl; or - (CH2) nC6H5-R4 wherein n is 0-4 and R4 is H, lower alkyl or lower alkoxy; or C5-C cycloalkyl? , optionally substituted by lower alkyl; R is H, OH, lower alkoxy, lower alkenyloxy or lower alkyl; Ref: 127385 R3 is C5-C7 cycloalkyl or phenyl, optionally substituted by OH, halogen, lower alkoxy, lower alkenyloxy, lower alkyl or -0- (CH2) n-C6H5 wherein n is 0-3; and its pharmaceutically acceptable acid addition salts.

Description of the invention.

The compounds of formula I and their salts are distinguished by their valuable therapeutic properties. It has surprisingly been found that the compounds of the present invention are OFQ receptor agonists / ant agonists. Accordingly they will be useful in the treatment of memory and attention deficits, psychiatric, neurological and physiological disorders, especially, but not limited to, improvement of anxiety symptoms and tension 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 seizures, acute and / or chronic pain conditions, withdrawal symptoms of addictive drugs and reduction of their abuse / desire, water balance control, Na + excretion and blood pressure disorders and metabolic disorders such as obesity.

The FQ orphanin (OFQ), a seventeen amino acid peptide (FGGFTGARKSARKLANQ), has been isolated from the brain of the rat and is a natural ligand for a coupled G-protein receptor (OFQ-R), found at high levels in the tissue of the brain.

The OFQ exhibits agonist activity in OFQ-R both in vitro and in vivo.

Julius (Nature 377,476, [1995]) discusses the discovery of OFQ by noting that this peptide shares the greatest sequential similarity with dynorphin A, an endogenous ligand established for opiate receptors. OFQ inhibits adenylate cyclase in CHO cells (LC 132+) in culture and induces hyperalgesia when administered intra-cerebroventricularly to mice. The results table indicates that this heptadecapeptide is an endogenous agonist of the LC 132 receptor and appears to have pro-nociceptive properties. It has been described that when injected intra-cerebroventricularly in mice, OFQ slows locomotor activity and induces hyperalgesia and it has been concluded that OFQ can act as a brain neurotransmitter to modulate nociceptive and locomotor behavior.

Preferred examples are compounds of formula I wherein R 1 is C 5 -C 2 cycloalkyl, optionally substituted by lower alkyl, for example the following compounds: (3RS, 4RS) -l-cyclononyl-4 - (2-hydroxy-phenyl) piperidin-3-ol hydrochloride (1: 1); L-cyclodecyl-4 - (2-meth oxy-phenyl) piperidine hydrochloride (1: 1); (3RS, 4 RS) -1-cyclodecyl-4- (2-isopropyl-phenyl) piperidin-3-ol (1: 1) hydrochloride; (3RS, 4RS) -4- (2-hydroxy-phenyl) -1- (cis-y- (trans-4-isopropylcyclohexyl) -piperidin-3-ol (1: 1) hydrochloride; 2- (l-cyclodecyl-piperidin-4-yl) phenol hydrochloride (1: 1); (3RS, 4 RS) -l-cyclodecyl-4 - (2-methoxy-phenyl) -piperidin-3-ol (1: 1) hydrochloride; L-cyclodecyl-4-cyclohexyl-piperidine hydrochloride (1: 1); (3RS, 4RS) -1-cyclononyl-4 - (2-methoxy-phenyl) -piperidin-3-ol (1: 1) hydrochloride; Hydrochloride of (3RS, 4 RS) -4 - (2-ali loxypheni-1) -1-cyclodecyl-piperidin-3-ol (1: 1); 1-Cyclodecyl-4-phenyl-piperidine hydrochloride (1: 1); (3RS, 4 RS) -l-cyclononyl-4 - (2-isopropyl-phenyl) -piperidin-3-ol (1: 1) hydrochloride; and (3RS, 4RS) -l-cyclodecyl-4 - (2-hydroxy-phenyl) piperidin-3-ol hydrochloride (1: 1).

The objects of the present invention are new compounds of formula I per se and their pharmaceutically acceptable addition salts, racemic mixtures and their corresponding enantiomers, the preparation of the aforementioned compounds, medicaments containing them and their preparation, as well as the use of the aforementioned compounds in the control or prevention of diseases, especially diseases and disorders of the type indicated above.

The following definitions of the general terms used in the present description are applicable regardless of whether the terms in question appear alone or in combination.

As used herein, the term "lower alkyl" denotes a straight or branched chain alkyl group with 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2- Butyl, t-butyl.

The compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example with the procedures described below, comprising reductive amination of a compound of formula II as a compound of the formula wherein R1, R2 and R3 are as described above.

The amination takes place in two stages where an imine is formed as an intermediate product which additionally undergoes reduction in the presence of a reducing agent such as sodium cyanoborohydride, molecular hydrogen or nickel.

The amination agent II can be prepared by known methods, for example from compounds of formula III by means of a hydrogenation reaction: wherein R2 and R3 are as described above and, in case R3 is cycloalkyl or phenyl substituted by a -0-CH2-CeH5, the dissociation of the -CH2-C6H5 group occurs during the reaction.

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

The compounds of formula I, wherein R 2 is hydroxyl and / or R 3 is cycloalkyl or phenyl substituted by hydroxyl or halogen can be converted to compounds of formula I, wherein R is lower alkoxy, lower alkenyloxy or lower alkyl and / or R3 is cycloalkyl or phenyl substituted by lower alkoxy, lower alkenyloxy, lower alkyl or -0- (CH2) n-C6H5, making them react for example with alkyl halides , alkenyl halides, phenalkyl halides or lower alcohols in an inert solvent such as anhydrous tetrahydrofuran.

The compounds of formula III can be obtained according to procedures of the literature (for example Juan C. Jean and La Rence D. Wise, J. He terocycl i c Chem. 1987, 24, 1317-1319).

If desired, the compounds of formula I can be converted into pharmaceutically acceptable acid addition salts. The salt formation is carried out at room temperature with methods which are known per se and which are familiar to any person skilled in the art. They come into consideration not only salts with inorganic acids but also salts with organic acids. Examples of these salts are hydrochlorides, hydrobromides, sulfates, nitrates, citrates, acetates, maleates, succinates, metal rings, p-toluensulphates and the like.

As indicated above, the compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacodynamic properties. It has been found that the compounds of the present invention are agonists / antagonists of the OFQ receptor and have effects in animal models with memory and attention deficits, psychiatric, neurological and physiological disorders, such as anxiety, tension disorders, depression, memory loss due to to Alzheimer's disease or other dementias such as vascular dementia and AIDS dementia complex, Parkinson's disease, epilepsy and seizures, acute and / or chronic pain conditions, withdrawal symptoms of addictive drugs and reduction of their abuse / desire, control of water balance, Na + excretion, blood pressure disorders and metabolic disorders such as obesity.

The compounds were investigated in accordance with the tests given below: Methods of Ligament Test of OFQ-R Cell culture HEK-293 cells adapted to growth in suspension (293s) cultured in HL medium plus 2% FBS were cultured. Cells were transfected with cDNA (LC132) rat OFQ receptor, FEBS Lett. 347, 284-288, 1994, cloned in the pCEP4 expression vector (Invitrogen, San Diego, CA, USA) using lipofectin (Life Technologies, Betehesda, MD, USA). The transfected cells were selected in the presence of hydromycin (1000 U / ml) (Calbiochem, San Diego, CA, USA). A pool of resistant cells was tested for OFQ-R expression by [3H] -OFQ binding (Amersham PLC, Buckinghamshire, England). These cells (293s-OFQ-R) were expanded for large-scale culture and membrane preparation.

Preparation of membranes 293s-OFQ-R cells were harvested by centrifugation, washed 3 times with phosphate buffered saline solution (PBS) before resuspension in buffer A (50 mM Tris-HCl, pH 7.8, 5 mM MgCl 2, 1 mM EGTA) and disruption with tissue homogenizer (30 seconds, fixation 4, Pt 20, Kinematica, Kriens-Lucern, Switzerland). A total membrane fraction was obtained by centrifugation at 49,000 x g at 4 ° C. This procedure was repeated twice and the pelletizing was resuspended in buffer A. Aliquots were stored at -70 ° C and protein concentrations were determined using the BCA ™ protein assay reagent (Pierce, Rockford, IL) following the manufacturer's recommendations.

Link analysis Competition studies of [3HJ-OFQ with membrane protein of 77 μg in a final assay volume of 0.5 ml of buffer solution A plus 0.1% BSA and 0.01% bacitracin were carried out ( Boehringer-Mannheim, Mannheim, Germany) for one hour at room temperature. 50 nM of OFQ was used without signaling to define non-specific binding. The tests were terminated by filtration through Whatman GF / C filters (Unifilter-96, Canberra Packard SA, Zurich, Switzerland) previously treated with 0.3% polyethyleneimine (Sigma, San Luis, MO, USA) and 0.1 % BSA (Sigma) for 1 hour. The filters were washed 6 times with 1 ml of ice cold 50 mM tris-HCl at a pH of 7.5. The radioactivity retained was counted on a Packard Top-Count microplate scintillation counter after the addition of 40 μl of Microscint 40 (Canberra Packard). The effects of the compounds were determined using at least 6 concentrations in triplicate, and were determined twice. The IC50 values were determined by curve coupling and these values were converted to KS values with the method of Cheng and Prusoff, Biochem. Pharmacol., 22, 3099, 1973.

The affinity of the OFQ receptor, given as pKi, is in the range of 6.0 to 8.0, for example the pKi for the compounds mentioned below is as follows: 4 (3RS, 4RS) -l-cyclononyl-4 - (2-hydroxy-phenyl) -piperidin-3-ol hydrochloride (1: 1) 36 (3RS, 4RS) -l-cyclodecyl-4- (2,6-dimethoxy-phenyl) -piperidin-3-ol hydrochloride (1: 1) 19 Mixture of (3RS, 4 RS) -4-methoxy-phenyl) -1- (cis- and - (trans-4-isopropyl-cyclohexy-1) piperidin-3-ol (1: 1) hydrochloride.

The compounds of formula I, as well as 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, for example in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can be carried out rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions.

The compounds of formula I and their pharmaceutically usable 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 its derivatives, talc, stearic acid or its salts, etc. they can be used as these excipients, for example for tablets, dragees and hard gelatine capsules.

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

Suitable excipients for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.

Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid polyols, etc.

In addition, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffer solutions, masking agents or antioxidants. They may also still contain other therapeutically valuable substances.

The dosage can vary within wide limits and, obviously, will be adjusted to the individual requirements in each particular case. In general, in the case of oral administration, a daily dose of about 10 to 1000 mg per person of a compound of general formula I should be appropriate, although the above upper limit may also be exceeded when considered appropriate.

The following examples illustrate the present invention, but should not be construed as limiting in any way.

Example 1 2- (l-cyclodecyl-piperidin-4-yl) phenol hydrochloride (1: 1) a) 1-Benzyl-4- (2-benzyloxy-phenyl) -1,2,3,6-tetrahydro-pyridine The title compound was prepared in a comparable yield according to a literature procedure (Juan C. Jean and Lawrence D. Wise, J. Heterocyclic Chem. 1987, 24, 1317-1319) in two steps from 2- benzyloxy-bromobenzene instead of 2-bromoanisol. The product was obtained in the form of a light brown oil.

MS m / e (%): 356 (M + H +, 100) b) 2-piperidin-4-yl-phenol To a solution of 37.6 g (0.105 mol) of 1-benzyl-4- (2-benzyloxy-phenyl) -1,2,3,6-tetrahydro-pyridine in 380 ml of methanol was added 7.0 g of 10% palladium on activated carbon. The reaction mixture was hydrogenated (room temperature, 5 bar) until the theoretical amount of hydrogen was collected (about 20 hours). The catalyst was filtered off and washed three times with 50 ml portions of methanol. The filtrate was evaporated in vacuo and purified by flash chromatography, which gave 14.8 g (80%) of the title compound as a light brown foam.

MS m / e (%): 177 (M +, 100). c) 2- (l-cyclodecyl-piperidin-4-yl) -phenol To a suspension of 1.0 g (5.64 mmol) of 2-piperidin-4-yl-phenol in 870 mg (5.64 mmol) of cyclodecanone was added 8.0 g (28 mmol) of tetraisopropyl orthotite. . After stirring for 4 days at room temperature, a viscous oil was obtained. A solution of 250 mg (3.95 mmol) of sodium cyanoborohydride in 4 ml of ethanol was added dropwise within 3-4 minutes. Stirring was continued for 2 hours at room temperature and 10 ml of 2.5 M ammonia in ethanol was added. The residue was purified by flash chromatography, which gave 1.37 g (77%) of the title compound as a light yellow foam.

MS m / e (%): 316 M + H +, 100). d) 2- (l-cyclodysilyl-piperidin-4-yl-phenol hydrochloride (1: 1) To a solution of 100 mg (0.32 mmol) of 2- (1-cyclodecyl-piperidin-4-yl) -phenol in 20 ml of ether was added 1 ml of 2.3 N hydrochloric acid in ether. After stirring for 30 minutes, the excess hydrochloric acid and ether were removed in vacuo and the residue was resuspended in 10 ml of ether. Filtration of the precipitate and washing with ether gave 101 mg (91%) of the title compound as a white powder.

MS m / e (%): 316 (M + H +, 100).

Example 2 L-cyclodecyl-4- (2-methoxy-phenyl) piperidine hydrochloride (1: 1) To a solution of 100 mg (0.32 mmol) of 2- (12-cyclodecyl-piperidin-4-yl) -phenol (example le) in 1 ml of anhydrous tetrahydrofuran at 0 ° C was added 76 mg (0, 38 mmol) of potassium bis (trimethylsilyl) amide. Stirring was continued for 1 hour at this temperature and 55 mg (0.38 mmol) of methyl iodide was added. After stirring for 30 minutes at 0 ° C, 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, which gave 74 mg of an oil. The amine was dissolved in 5 ml of ether and 1 ml of 2.3 M hydrochloric acid in ether was added dropwise. The precipitate was filtered off, washed with ether and dried in vacuo, which gave 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) To a solution of 200 mg (0.64 mmol) of 2- (1-cyclodecyl-piperidin-4-yl) -phenol (example le) in 2 ml of anhydrous tetrahydrofuran at 0 ° C was added 152 mg (0.76 mmol). mmol) of potassium bis (trimethylsilyl) amide. Stirring was continued for 1 hour at this temperature and 92 mg (0.76 mmol) of allyl bromide was added. After stirring for 30 minutes at 0 ° C, 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, which gave 164 mg of an oil. The amine was dissolved in 10 ml of ether and 1 ml of 2.3 M hydrochloric acid in ether was added dropwise. The precipitate was filtered off, washed with ether and dried in vacuo, which gave 138 mg (55%) of the title compound as a white powder.

MS m / e (%): 356 (M + H +, 100).

Example 4 (3RS, 4RS) -l-cyclononyl-4- (2-hydroxy-phenyl) -piperidin-3-ol hydrochloride (1: 1) a) (3RS, 4RS) -l-benzyl-4- (2-benzyloxy-phenyl) -piperidin-3-ol hydrochloride (1: 1) The title compound was prepared in a comparable yield according to a literature procedure (Juan C. Jean and La Rence D. Wise, J. Heterocyclic Chem. 1987, 24, 1317-1319) in three steps from 2-benzyloxybromobenzene. instead of 2-bromoanisol. The product was obtained in the form of white crystals.

MS m / e (%): 374 (M + H +, 100). b) (3RS, 4RS) -4- (2-hydroxy-phenyl) piperidin-3-ol hydrochloride (1: 1) To a solution of 46.5 g (0.11 mol) of (3RS, 4RS) -l-benzyl-4- (2-benzyloxy-phenyl) -piperidin-3-ol hydrochloride (1: 1) in 1100 ml of methanol, 8.5 g of 10% palladium on activated charcoal were added. The reaction mixture was hydrogenated (room temperature, 5 bar) until the theoretical amount of hydrogen was collected (about 20 hours). The catalyst was filtered off and washed three times with 100 ml portions of methanol. The filtrate was evaporated in vacuo, which gave 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 To a solution of 3.17 g (1.38 mmol) of (3RS, 4 RS) -4 - (2-hydroxy-phenyl) -piperidin-3-ol (1: 1) hydrochloride in 30 ml of methanol, 1.5 g of sodium carbonate was added. After stirring for 1 hour at room temperature, the sodium salts were filtered off and washed with 10 ml of ethanol. The filtrate was concentrated, diluted with ethanol and filtered again. The filtrate was evaporated, which gave 2.7 g (quantitative) of the title compound as a white solid.

MS m / e (%): 194 (M + H +, 100). d) (3RS, 4RS) -l-cyclononyl-4- (2-hydroxy-phenyl) piperidin-3-ol To a suspension of 520 mg (2.69 mmol) of (3RS, 4RS) -4- (2-hydroxy-phenyl) -piperidin-3-ol in 380 mg (1.55 mmol) of cyclononanone was added 3, 80 g (13 mmol) of tetraisopropy 1 ortot itanat or. After stirring for 2 days at room temperature, a viscous oil was obtained. A solution of 120 mg (1.9 mmol) of sodium cyanoborohydride in 1 ml of ethanol was added dropwise within 3-4 minutes. Stirring was continued for 6 hours at room temperature and 2 ml of 2.5 M ammonia in ethanol was added. The precipitate was filtered off, and the filtrate was evaporated. The residue was purified by flash chromatography, which gave 435 mg (51%) of the title compound as a yellow foam.

MS m / e (%): 318 (M + H +, 100). e) Hydrochloride of (3RS, 4RS) -l-cyclononyl-4- (2-hydroxy-phenyl) -piperidin-3-ol (1: 1) To a solution of 100 mg (0.32 mmol) of (3RS, 4RS) -l-cyclononyl-4- (2-hydroxyphenyl) -piperidin-3-ol in 10 ml of ether was added 1 ml of hydrochloric acid 2 , 3 N in ether. After stirring for 30 minutes, the excess of hydrochloric acid and ether was removed in vacuo and the residue was resuspended in 10 ml of ether. Filtration of the precipitate and washing with ether gave 98 mg (88%) of the title compound as a white powder. MS m / e (%): 318 (M + H +, 100).

Example 5 (3RS, 4RS) -l-cyclononyl-4- (2-methoxy-phenyl) -piperidin-3-ol (1: 1) hydrochloride To a solution of 110 mg (0.35 mmol) of (3RS, 4RS) -l-cyclononyl-4- (2-hydroxyphenyl) -piperidin-3-ol (example 4d) in 1 ml of anhydrous tetrahydrofuran at 0 ° C, 85 mg (0.42 mmol) of potassium bis (trimethylsilyl) amide was added . Stirring was continued for 1 hour at this temperature and 59 mg (0.42 mmol) of methyl iodide was added. After stirring for 30 minutes at 0 ° C, 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, which gave 74 mg of an oil. The amine was dissolved in 5 ml of ether and 1 ml of 2.3 M hydrochloric acid in ether was added dropwise. The precipitate was filtered off, washed with ether and dried in vacuo, which gave 70 mg (54%) of the title compound as a white powder.

MS m / e (% 332 (M + H +, 100 Example 6 (3RS, 4RS) -l-cyclodecyl-4- (2-hydroxy-enyl) -piperidin-3-ol hydrochloride (1: 1) To a suspension of 2.50 g (12.9 mmol) of (3RS, 4RS) -4- (2-hydroxy-phenyl) -piperidin-3-ol (Example 4c) in 2.00 g (12.9 mmol) of cyclodecanone were added 4.58 g (16.1 mmol) of tetraisopropyl orthotitanate. After stirring overnight at room temperature a viscous oil was obtained. A solution of 570 mg (9 mmol) of sodium cyanoborohydride in 10 ml of ethanol was added dropwise within 1 minute. Stirring was continued at room temperature overnight and 50 ml of 1N hydrochloric acid solution was added. After 30 minutes, the precipitate was filtered off and washed with a 1N hydrochloric acid solution, which gave 2.81 g (59%) of the title compound as a light brown foam.

MS (m / e (%): 332 M + H +, 100 Example 7 (3RS, 4RS) -l-cyclodecyl-4- (2-ethoxy-phenyl) -piperidin-3-ol hydrochloride (1: 1) a) (3RS, 4RS) -l-cyclodecyl-4- (2-hydroxy-phenyl) -piperidin-3-ol To a solution of 570 mg (1.55 mmol) of (3RS, 4RS) -l-cyclodecyl-4- (2-hydroxyphenyl) -piperidin-3-ol (1: 1) hydrochloride (Example 6) in ml of ethanol, 1.5 g of sodium carbonate was added. After stirring for 1 hour at room temperature, the sodium salts were filtered off and washed with 10 ml of ethanol.

The filtrate was evaporated, which gave 510 mg (quantitative) of the title compound as a white solid.

MS m / e (%): 332 (M + H +, 100). b) (3RS, 4RS) -l-cyclodecyl-4- (2-ethoxy-phenyl) piperidin-3 -ol To a solution of 204 mg (0.62 mmol) of (3RS, 4RS) -l-cyclodecyl-4 - (2-hydroxyphenyl) -piperidin-3-ol in 1 ml of anhydrous tetrahydrofuran at 0 ° C, 147 mg (0.74 mmol) of potassium bis (trimethylsilyl) amide was added. Stirring was continued for 1 hour at this temperature and 74 mg (0.68 mmol) of ethyl bromide was added. After stirring for 30 minutes at 0 ° C, 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, which gave 51 mg (23%) of the title compound as a colorless oil.

MS m / e (%): 360 (M + H +, 100). c) Hydrochloride of (3RS, 4RS) -l-cyclodecyl-4- (2-ethoxy-phenyl) -piperidin-3-ol (1: 1) To a solution of 7 mg (0.02 mmol) of (3RS, 4RS) -l-cyclodecyl-4- (2-ethoxy-phenyl) -piperidin-3-ol in 1 ml of ether was added 0.2 ml 2.5 N hydrochloric acid in ether. After stirring for 30 minutes, excess hydrochloric acid and ether were removed in vacuo and the residue resuspended in 2 ml of ether. Filtration of the precipitate and washing with ether gave 7 mg (quantitative) of the title compound as white crystals.

MS m / e (%): 360 (M + H +, 100).

Example 8 (3RS, 4RS) -l-cyclodecyl-3-ethoxy-4- (2-ethoxy-enyl) -piperidine hydrochloride (1: 1) a) (3RS, 4RS) -l-cyclodecyl-3-ethoxy-4- (2-ethoxy-phenyl) -piperidine The title compound was obtained as a by-product during the isolation and purification of (3RS, RS) -1-cyclodecyl-4- (2-ethoxy-phenyl) -piperidin-3-ol (example 7b). 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) -l-cyclodecyl-3-ethoxy-4- (2-ethoxy-phenyl) -piperidine hydrochloride (1: 1) To a solution of 10 mg (0.025 mmol) of (3RS, 4RS) -l-cyclodecyl-3-ethoxy-4- (2-ethoxy-phenyl) -piperidine in 1 ml of ether was added 0.2 ml of acid 2.5 N hydrochloric acid in ether. After stirring for 30 minutes, the excess of hydrochloric acid and ether was removed in vacuo, and the residue was resuspended in 2 ml of ether. Filtration of the precipitate and washing with ether gave 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 To a solution of 645 mg (1.96 mmol) (3RS, 4RS) -l-cyclodecyl-4 - (2-hydroxyphenyl) -piperidin-3-ol (example 7a) in 6 ml of anhydrous acetone, 298 mg (21.15 mmol) of potassium carbonate and 260 mg (2.15 mmol) of allyl bromide were added. After stirring at 60 ° C overnight, the product was extracted with three 10 ml portions of ethyl acetate, washed with brine, dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography, which gave 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) To a solution of 133 mg (0.36 mmol) of (3RS, 4RS) -4- (2-allyloxy-phenyl) -l-cyclodecyl-piperidin-3-ol in 2.5 ml of tetrahydrofuran was added 2 ml 2.5 N hydrochloric acid in ether. After stirring for 30 minutes, the excess of hydrochloric acid and ether was removed in vacuo, and the residue was resuspended in 10 ml of ether. Filtration of the precipitate and washing with ether gave 100 mg (68%) of the title compound as white crystals.

MS (m / e (%): 372 M + H +, 100).

Example 10 (3RS, 4RS) -4- (2-allyloxy-enyl) -1-cyclodecyl-3-methoxy-piperidine hydrochloride (1: 1) To a solution of 133 mg (0.36 mmol) of (3RS, 4RS) -4- (2-allyloxy-phenyl) -1-cyclodecyl-piperidin-3-ol (example 9a) in 1.5 ml of Anhydrous tetrahydrofuran at 0 ° C, 85 mg (0.43 mmol) of potassium bis (trimethylsilyl) amide was added. Stirring was continued for 1 hour at this temperature, and 61 mg (0.43 mmol) of methyl iodide was added. After stirring for 30 minutes at 0 ° C, the ice bath was removed and the reaction mixture was allowed to warm to room temperature overnight.

After the addition of 2 ml of water, the product was extracted with three 10 ml portions of ether, dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography, which gave 77 mg of an oil. The amine was dissolved in 10 ml of ether, and 1 ml of 2.3 M hydrochloric acid in ether was added dropwise. The precipitate was filtered off, washed with ether and dried under vacuum, which gave 67 mg (44%) of the title compound as a white powder.

MS (m / e (%) 386 M + H +, 100) Example 11 (3RS, 4RS) -l-cyclodecyl-3-methoxy-4- (2-propoxy-enyl) -piperidine hydrochloride (1: 1) To a solution of 30 mg (0.07 mmol) of (3RS, RS) -4 - (2-alioxy-phenyl-1) -1-cyclodecyl-3-methoxy-piperidine hydrochloride (1: 1) (Example 10) ) in 1.5 ml of methanol, 10 mg of 10% palladium on activated charcoal were added. The reaction mixture was hydrogenated (room temperature, 1 bar) overnight. The catalyst was filtered off and washed three times with 1 ml portions of methanol. The filtrate was evaporated in vacuo, which gave 23 mg (77%) of the title compound as a white powder.

MS (m / e (%) M + H +, 100).

Example 12 (3RS, 4RS) -4- (2-benzyloxy-phenyl) -1-cyclodecyl-piperidin-3-ol hydrochloride (1: 1) To a solution of 721 mg (1.96 mmol) of (3RS, 4RS) -1-cyclodecyl-4- (2-hydroxyphenyl) -piperidin-3-ol (1: 1) hydrochloride (Example 6) in 3 ml of anhydrous dimethylformamide were added 810 mg (5.88 mmol) of potassium carbonate and 370 mg (2.16 mmol) of benzyl bromide. After stirring at 60 ° C overnight, the product was extracted with three 10 ml portions of ethyl acetate, washed with brine, dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography, which gave 90 mg of a light yellow solid. The amine was dissolved in 10 ml of ether and 1 ml of 2.3 M hydrochloric acid was added dropwise. The precipitate was filtered off, washed with ether and dried under vacuum, which gave 63 mg (7%). ) of the title compound in the form of a solid powder.

MS m / e (%): 422 (M + H +, 100).

Example 13 (3RS, 4RS) -l-cycloundecyl-4- (2-hydroxy-enyl) -piperidin-3-ol hydrochloride (1: 1) a) (3RS, 4RS) -l-cycloundecyl-4- (2-hydroxy-phenyl) piperidin-3-ol To a suspension of 300 mg (1.55 mmol) of (3RS, 4RS) -4- (2-hydroxy-phenyl) -piperidin-3-ol (example 4c) in 260 mg (1.55 mmol) of cycloundecanone was added 2.20 g (7.8 mmol) of t et raisopropil ort ot i tanat o. After stirring for 6 days at room temperature, a viscous oil was obtained. A solution of 70 mg (1.1 mmol) of sodium cyanoborohydride in 1 ml of ethanol was added dropwise within 3-4 minutes. Stirring was continued for 6 hours at room temperature and 2 ml of 2.5 M ammonia in ethanol was added. The precipitate was filtered off and the filtrate was evaporated. The residue was purified by flash chromatography, which gave 138 mg (26%) of the title compound as a light yellow foam.

MS (m / e (%): 346 M + H +, 100). b) Hydrochloride of (3RS, 4RS) -l-cyclo ndecyl-4- (2-hydroxy-enyl) -piperidin-3-ol (1: 1) To a solution of 7 mg (0.02 mmol) of (3RS, 4RS) -l-cycloundecyl-4- (2-hydroxy-phenyl) -piperidin-3-ol in 1 ml of ether was added 0.2 ml of 2.3 N hydrochloric acid in ether. After stirring for 30 minutes, the excess of hydrochloric acid and ether was removed in vacuo, and the residue was resuspended in 1 ml of ether. Filtration of the precipitate and washing with ether gave 7 mg (quantitative) of the title compound as a white powder.

MS m / e (% 346 (M + H +, 100 Example 14 (3RS, 4RS) -l-cycloundecyl-4- (2-methoxy-enyl) -piperidin-3-ol hydrochloride (1: 1) To a solution of 110 mg (0.31 mmol) of (3RS, 4RS) -l-cycloundecyl-4- (2-hydroxyphenyl) -piperidin-3-ol (example 13a) in 1 ml of anhydrous tetrahydrofuran at 0 ° C , 65 mg (0.34 mmol) of potassium bis (trimethylsilyl) amide was added. Stirring was continued for 1 hour at this temperature, and 48 mg (0.34 mmol) of methyl iodide was added. After stirring for 30 minutes at 0 ° C, the ice bath was removed and the reaction mixture was allowed to warm to room temperature overnight.

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

MS m / e (%): 360 (M + H +, 100).

Example 15 Mixture of (3RS, 4RS) - and (3SR, 4SR) -4- (2-Hydrox-phenyl) -1 - [(RS) -1,2,3,4-tetrahydro-naphthalen-2-yl hydrochloride] -piperidin-3-ol a) Mixture of (3RS, 4RS) - and (3SR, 4SR) -4- (2-hydroxy-phenyl) -1 - [(RS) -1,2,3,4-tetrahydro-naphthalen-2-yl] - piperidin-3-ol To a mixture of 300 mg (1.55 mmol) of (3RS, 4RS) -4- (2-hydroxy-phenyl) -piperidin-3-ol (eg 4c) and 230 (2), 55 mmol) of beta-tetralone, 2.20 g (7.8 mmol) of tetraisopropyl orthotitanate were added. After stirring for 5 days at room temperature, a viscous oil was obtained. A solution of 70 mg (1.1 mmol) of sodium cyanoborohydride in 1 ml of ethanol was added dropwise within 3-4 minutes. Stirring was continued for 6 hours at room temperature and 2 ml of 2.5 M ammonia in ethanol was added. The precipitate was filtered off, and the filtrate was evaporated. The residue was purified by flash chromatography, which gave 100 mg (20%) of the title compound as a light brown foam.

MS m / e (%): 324 (M + H +, 100) b) Mixture of (3RS, 4RS) - and (3SR, 4SR) -4- (2-hydroxy-phenyl) -1- [(RS) -1,2,3,4-tetrahydro-naphthalene-2-hydrochloride. il] -piperidin-3-ol (1: 1) To a solution of 7 mg (0.02 mmol) of the mixture of (3RS, 4RS) - and (3SR, 4 SR) -4 - (2-hydroxyphenyl) -1- [(RS) -1, 2, 3 , 4-tetrahydro-naphthalen-2-yl] -piperidin-3-ol in 1 ml of ether, 0.2 ml of 2.3 N hydrochloric acid in ether was added. After stirring for 30 minutes, excess hydrochloric acid and ether were removed under vacuum and the residue was resuspended in 1 ml of ether. Filtration of the precipitate and washing with ether gave 7 mg (quantitative) of the title compound as a white powder.

MS m / e (%): 324 (M + H +, 100).

Example 16 Mixture of (3RS, 4RS) - and (3SR, 4SR) -4- (2-methoxy-phenyl) -1- [(RS) -1,2,3,4-tetrahydro-na talen-2-yl hydrochloride. ] -piperidin-3-ol (1: 1) To a solution of 78 mg (0.24 mmol) of the mixture of (3RS, 4RS) - and (3SR, 4SR) -4 - (2-hydroxyphenyl) -l- [(RS) -1.2, 3, 4- tetrahydro-naphthalen-2-yl] -piperidin-3-ol (example 15a) in 0.8 ml of anhydrous tetrahydrofuran at 0 ° C, 55 mg (0.27 mmol) of potassium bis (trimethylsilyl) amide was added. Stirring was continued for 1 hour at this temperature, and 38 mg (0.27 mmol) of methyl iodide was added. After stirring for 30 minutes at 0 ° C, the ice bath was removed and the reaction mixture was allowed to warm to room temperature overnight.

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

MS (m / e (%): 338 (M + H +, 100).

Example 17 Mixture of (3RS, 4RS) - and (3SR, 4SR) -4- (2-hydroxy-phenyl) -1 - [(RS) -1,2,3,4-tetrahydro-naphthalen-1-yl] hydrochloride] -piperidin-3-ol (1: 1) a) Mixture of (3RS, 4RS) - and (3SR, 4SR) -4- (2-hydroxy-phenyl) -1 - [(RS) -1,2,3, 4-tetrahydro-naphthalen-1-yl ] -piperidin-3-ol To a mixture of 300 mg (1.55 mmol) of (3RS, 4RS) -4- (2-hydroxy-phenyl) -piperidin-3-ol (eg 4 c) and 230 mg (2.55 mmol) of alfa-t et ralona, 2.20 g (7.8 mmol) of tet raisopropi 1 orthotinate were added. After stirring for 5 days at room temperature, a viscous oil was obtained. A solution of 70 mg (1.1 mmol) of sodium cyanoborohydride in 1 ml of ethanol was added dropwise within 3-4 minutes. Stirring was continued for 6 hours at room temperature, and 2 ml of 2.5 M ammonia in ethanol was added. The precipitate was filtered off, and the filtrate was evaporated. The residue was purified by flash chromatography, which gave 29 mg (6%) of the title compound as a light brown foam.

MS m / e (%): 324 (M + H +, 100 b) Mixture of (3RS, 4RS) - and (3SR, 4SR) -4- (2-hydroxy-phenyl) -1- [(RS) -1,2,3,4-tetrahydro-na talen-1 hydrochloride. -yl] -piperidin-3-ol (1: 1) To a solution of 4 mg (0.01 mmol) of the mixture of (3RS, 4RS) - and (3SR, 4SR) -4 - (2-hydroxy-phenyl) -1 - [(RS) -1.2, 3, 4 -hydrohydro-naphthalen-1-yl] -piperidin-3-ol in 1 ml of ether, 0.2 ml of 2.3 N hydrochloric acid in ether was added. After stirring for 30 minutes, the excess of hydrochloric acid and ether was removed in vacuo, and the residue was resuspended in 1 ml of ether. Filtration of the precipitate and washing with ether gave 4 mg (quantitative) of the title compound as a white powder.

MS m / e (%): 324 (M + H +, 100).

Example 18 Mixture of (3RS, 4RS) -4- (2-hydroxy-phenyl) -1- (cis- and - (trans-4-isopropyl-cyclohexyl) -piperidin-3-ol hydrochloride (1: 1) a) Mixture of (3RS, 4RS) -4- (2-hydroxy-phenyl) -1- (cis- and - (trans-4-isopropyl-cyclohexyl) -piperidin-3-ol To a suspension of 2.50 g (12.9 mmol) of (3RS, 4RS) -4- (2-hydroxy-phenyl) piperidin-3-ol (example 4c) in 1.88 g (12.9 mmol) of 4-isopropylcyclohexanone, 9.16 g (32.2 mmol) of tetraisopropyl orthotitanate were added. After stirring overnight at room temperature, a viscous oil was obtained. A solution of 570 mg (9 mmol) of sodium cyanoborohydride in 10 ml of ethanol was added dropwise within 1 minute. Stirring was continued at room temperature overnight and 50 ml of 1N hydrochloric acid solution was added. After 30 minutes, the precipitate was filtered off and washed with 2N hydrochloric acid solution, which gave 1.51 g of a white solid. The mother liquors were extracted with dichloromethane and the extract was combined with the first precipitate. Purification by flash chromatography gave 1.90 g (46%) of the title compound as a white solid.

MS m / e (%): 318 (M + H +, 100 b) Hydrochloride mixture of (3RS, 4RS) -4- (2-hydroxy-phenyl) -1- (cis- and - (trans-4-isopropyl-cyclohexyl) -piperidin-3-ol (1: 1) To a solution of 10 mg (0.03 mmol) of the mixture of (3RS, 4 RS) -4 - (2-hydroxyphenyl) -1- (cis- and - (trans-4 -i-sopropi-1-cyclohexyl) - piperidin-3-ol in 1 ml of ether, 0.2 ml of 2.5 N hydrochloric acid in ether was added in. After stirring for 30 minutes, the excess hydrochloric acid and ether was removed in vacuo and turned to suspend the residue in 1 ml of ether.

Filtration of the precipitate and washing with ether gave 10 mg (quantitative) of the title compound as a white powder.

MS m / e (%): 318 (M + H +, 100) Example 19 Mixture of (3RS, 4RS) -4- (2-methoxy-phenyl) -1- (cis- and - (trans-4-isopropyl-cyclohexyl) • piperidin-3-ol hydrochloride (1: 1) To a solution of 75 mg (0.24 mmol) of the mixture of (3RS, RS) -4 - (2-hydroxyphenyl) -1- (cis- and - (trans -4 -isopropyl-cyclohexyl) -piperidine- 3-ol (example 18a) in 1 ml of anhydrous tetrahydrofuran at 0 ° C, 103 mg (0.52 mmol) of potassium bis (trimethylsilyl) amide was added, stirring was continued for 1 hour at this temperature and 70 mg (0.49 mmol) of methyl iodide After stirring for 30 minutes at 0 ° C, 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, which gave 7 mg of an oil. The amine was dissolved in 1 ml of ether and 0.2 ml of 2.3 M hydrochloric acid was added dropwise. The precipitate was filtered off, washed with ether and dried in vacuo, which gave 7 mg ( 8%) of the title compound in the form of a white powder.

MS m / e (%): 332 (M + H +, 100; Example 20 Mixture of (3RS, 4RS) -4- (2-allyloxy-enyl) -1- (cis- and - (trans-4-isopropyl-cyclohexyl) • piperidin-3-ol (1: 1) hydrochloride a) Mixture of (3RS, 4RS) -4- (2-allyloxy-phenyl) -1- (cis- and - (trans-4-isopropyl-cyclohexyl) -piperidin-3-ol To a solution of 700 mg (2 , 2 mmol) of the mixture of (3RS, 4RS) -4 - (2-hydroxyphenyl) -1- (cis- and - (trans-4-isopropyl-cyclohexyl) -piperidin-3-ol (example 18a) in 3 ml of dimethyl il-formamide anhydrous, 610 mg (4.4 mmol) of potassium carbonate and 320 mg (2.64 mmol) of allyl bromide were added in. After stirring at 60 ° C overnight, the solvent and the residue was purified by flash chromatography, which gave 125 mg (16%) of the title compound as a colorless foam.

MS m / e (%): 358 (M + H +, 100) b) Hydrochloride mixture of (3RS, 4RS) -4- (2-allyloxy-phenyl) -1- (cis- and - (trans-4-isopropyl-cyclohexyl) -piperidin-3-ol (1: 1) To a solution of 5 mg (0.014 mmol) of the mixture of (3RS, 4RS) -4 - (2-allyloxyphenyl) -1- (cis- and - (trans -4 -isopropy1-cyclohexyl) -piperidine- 3 - In 1 ml of ether, 0.2 ml of 2.3 N hydrochloric acid in ether were added in. After stirring for 30 minutes, excess hydrochloric acid and ether were removed in vacuo, and the residue was resuspended. in 1 ml of ether, filtration of the precipitate and washing with ether gave 5 mg (quantitative) of the title compound as a white powder.

MS m / e (%): 358 (M + H +, 100).

Example 21 Mixture of (3RS, 4RS) -4- (2-allyloxy-phenyl) -1- (cis- and trans-4-isopropyl-cyclohexyl) -3-ethoxy-piperidine hydrochloride (1: 1) To a solution of 50 mg (0.14 mmol) of the mixture of (3RS, 4 RS) -4 - (2-allyloxy-phenyl) -1- (cis- and trans -4 -isopropyl-cyclohexyl) 3-methoxy-piperidin-3-ol (example 20a) in 0.5 ml of anhydrous tetrahydrofuran at 0 ° C, 33 mg (0.17 mmol) of potassium bis (trimethylsilyl) amide was added. Stirring was continued for 1 hour at this temperature and 24 mg (0.17 mmol) of methyl iodide was added. After stirring for 30 minutes at 0 ° C, the ice bath was removed and the reaction mixture was allowed to warm to room temperature overnight.

After the addition of 2 ml of water, the product was extracted with three 10 ml portions of ether, dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography, which gave 30 mg of an oil. The amine was dissolved in 2 ml of ether, and 0.5 ml of 2.3 M hydrochloric acid was added dropwise. The precipitate was filtered off, washed with ether and dried in vacuo, which gave 32 mg (56%) of the title compound as a white powder. MS m / e (%): (M + H +, 100). 22 Mixture of (3RS, 4RS) -4- (2-benzyloxy-phenyl) -1- (cis- and trans-4-isopropyl-cyclohexyl) -piperidin-3-ol hydrochloride (1: 1) a) Mixture of (3RS, 4RS) -4- (2-benzyloxy-phenyl) -1- (cis- and trans-4-isopropyl-cyclohexyl) -piperidin-3-ol To a solution of 397 mg (1.25 mmol) of the mixture of (3RS, 4RS) -4 - (2-hydroxyphenyl) -1- (cis- and - (trans -4 -i-sopropi-1-cyclohexyl) -piperidine) -3-ol (example 18a) in 3 ml of anhydrous dimethyl-formamide was added 912 mg (6.6 mmol) of potassium carbonate and 450 mg (2.64 mmol) of benzyl bromide. C during the night, the solvent was removed, and the residue was purified by flash chromatography, which gave 228 mg (45%) of the title compound as a colorless foam.

MS m / e (%): 408 (M + H +, 100). b) Mixture of (3RS, 4RS) -4- (2-benzyloxy-phenyl) -1- (cis- and trans-4-isopropyl-cyclohexyl) -piperidin-3-ol hydrochloride (1: 1) To a solution of 7 mg (0.017 mmol) of the mixture of (3RS, 4 RS) -4- (2-benzyloxy-phenyl) -1- (cis- and trans-4-isopropyl-cyclohexyl) -piperidin-3- In 1 ml of ether, 0.2 ml of 2.3 N hydrochloric acid in ether was added. After stirring for 30 minutes, the excess of hydrochloric acid and ether was removed in vacuo, and the residue was resuspended in 1 ml of ether. Filtration of the precipitate and washing with ether gave 7 mg (quantitative) of the title compound as a white powder.

MS m / e (%): 408 (M + H +, 100).

Example 23 (3RS, 4RS) -l-benzyl-3-methoxy-4- (2-methoxy-phenyl) -piperidine hydrochloride (1: 1) a) (3RS, 4RS) -1-benzyl-4- (2-methoxy-phenyl) -piperidin-3-ol The title compound was prepared in a comparable yield according to a literature procedure (Juan C. Jean and La Rence D. Wise, J. Heterocyclic Chem. 1987, 24, 1317-1319) in three steps from 2 -bromoanisol. The product was obtained in the form of a white powder.

MS m / e (%): 298 (M + H +, 100) b) (3RS, 4RS) -l-benzyl-3-methoxy-4- (2-methoxy-enyl) -piperidine hydrochloride (1: 1) To a solution of 149 mg (0.5 mmol) of (3RS, 4RS) -l-benzyl-4- (2-methoxy-phenyl) -piperidin-3-ol in 1.5 ml of anhydrous tetrahydrofuran at 0 ° C, 126 mg (0.6 mmol) of bis ( trimethylsilyl) amide. Stirring was continued for 1 hour at this temperature, and 85 mg (0.6 mmol) of methyl iodide was added. After stirring for 30 minutes at 0 ° C, the ice bath was removed and the reaction mixture was allowed to warm to room temperature overnight.

After the addition of 2 ml of water, the product was extracted with three 10 ml portions of ether, dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography, which gave 128 mg of an oil. The amine was dissolved in 10 ml of ether and 1 ml of 2.3 M hydrochloric acid was added dropwise. The precipitate was filtered off, washed with ether and dried in vacuo, which gave 130 mg (75 mL). %) of the title compound in the form of a white powder.

MS m / e (I): 312 (M + H +, 100) Example 24 (3RS, 4RS) -3-methoxy-l- (2-methoxy-benzyl) -4- (2-methoxy-phenyl) -piperidine hydrochloride (1: 1) a) (3RS, 4RS) -3-methoxy-4- (2-methoxy-phenyl) -piperidine To a solution of 4.03 g (11.6 mol) of (3RS, 4RS) -l-benzyl-3-methoxy-4 - (2-methoxyphenyl) -piperidine (1: 1) hydrochloride (example 23b) in 100 ml of methanol, 1.0 g of 10% palladium on activated charcoal was added. The reaction mixture was hydrogenated (room temperature, 1 bar) for 20 hours. The catalyst was filtered off and washed three times with 10 ml portions of methanol. The filtrate was concentrated to a total volume of about 50 ml and 1.3 g of sodium carbonate was added. After stirring the suspension for a further 2 hours, the solvent was removed under reduced pressure and the residue was resuspended in 50 ml of dichloromethane. The inorganic salts were filtered off and the filtrate was evaporated, which gave 2.20 g (74%) of the title compound as a light yellow oil.

MS m / e (%): 221 (M +, 17), 189 (100), 178 (62). b) (3RS, 4RS) -3-methoxy-l- (2-methoxy-benzyl) -4- (2-methoxy-phenyl) -piperidine hydrochloride (1: 1) To a solution of 111 mg (0.5 mmol) of (3RS, 4RS) -3-methoxy-4- (2-methoxy phenyl) -piperidine in 1.5 ml of methanol, 75 mg (0.55 mmol) was added. ) of 2-methoxybenzaldehyde. The reaction mixture was stirred for 5 minutes at room temperature and 63 mg (1.0 mmol) of sodium cyanoborohydride was added.

After overnight reaction, 1 ml of 2.3 M hydrochloric acid in methanol was added. The reaction mixture was evaporated, redissolved in 5 ml of water and washed with ether. The aqueous solution was adjusted to a pH of 10 by the addition of solid potassium hydroxide, and extracted with dichloromethane, dried (magnesium sulfate), evaporated and purified by flash chromatography, which gave 100 mg of an oil. The amine was dissolved in 10 ml of ether and 1 ml of 2.3 M hydrochloric acid in ether was added dropwise. The precipitate was filtered off, washed with ether and dried under vacuum, which gave 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) To a solution of 111 mg (0.5 mmol) of (3RS, 4RS) -3-methoxy-4- (2-methoxyphenyl) -piperidine (example 24a) in 1.5 ml of methanol was added 74 mg (0.degree. , 55 mmol) of 3-phenyl-propianaldehyde. The reaction mixture was stirred for 5 minutes at room temperature, and 63 (1.0 mmol) of sodium cyanoborohydride was added. After the reaction overnight, 1 ml of 2.3 M hydrochloric acid in methanol was added. The reaction mixture was evaporated, redissolved in 5 ml of water and washed with ether. The aqueous solution was adjusted to a pH of 10 by the addition of potassium hydroxide and extracted with dichloromethane, dried (magnesium sulfate) and evaporated, which gave 155 mg of an oil. The amine was dissolved in 10 ml of ether and 1 ml of 2.3 M hydrochloric acid in ether was added dropwise. The precipitate was filtered off, washed with ether and dried in vacuo, which gave 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) To a solution of 111 mg (0.5 mmol) of (3RS, 4RS) -3-methoxy-4- (2-methoxyphenyl) -piperidine (example 24a) in 1.5 ml of methanol, 89 mg were added ( 0.55 mmol) of 4-tert-butylbenzedehyde. The reaction mixture was stirred for 5 minutes at room temperature and 63 mg (1.0 mmol) of sodium cyanoborohydride was added. After the reaction overnight, 1 ml of 2.3 M 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 a pH of 10 with the addition of solid potassium hydroxide and extracted with dichloromethane, dried (magnesium sulfate), evaporated and purified by flash chromatography, which gave 100 mg of an oil. The amine was dissolved in 10 ml of ether and 1 ml of 2.3 M hydrochloric acid in ether was added dropwise. The precipitate was filtered off, washed with ether and dried under vacuum, which gave 110 mg (55%) of the title compound as a white powder.

MS m / e (%): 368 (M + H +, 100).

Example 27 (3RS, 4RS) -3-allyloxy-l-benzyl-4- (2-methoxy-phenyl) -piperidine hydrochloride (1: 1) To a solution of 149 mg (0.5 mmol) of (3RS, 4RS) -1-benzyl 1-4- (2-methoxy-phenyl) piperidin-3-ol (example 23a) in 1.5 ml of anhydrous tetrahydrofuran at 0 ° C, 126 mg (0.6 mmol) of potassium bis (trimethylsilyl) amide was added. Stirring was continued for 1 hour at this temperature and 73 mg (0.6 mmol) of allyl bromide was added. After stirring for 30 minutes at 0 ° C, the ice bath was removed and the reaction mixture was allowed to warm to room temperature overnight.

After the addition of 2 ml of water, the product was extracted with three 10 ml portions of ether, dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography, which gave 149 mg of an oil. The amine was dissolved in 10 ml of ether and 1 ml of 2,3-hydrochloric acid was added dropwise. The precipitate was filtered off, washed with ether and dried under vacuum, which gave 150 mg (80%) of the title compound as a white powder.

MS m / e (338 (M + H +, 100) Example 28 (3RS, 4RS) -l-cyclodecyl-4- (2-methoxy-phenyl) -piperidin-3-ol hydrochloride (1: 1) a) Hydrochloride of (3RS, 4RS) -4- (2-methoxy-phenyl) -piperidin-3-ol (1: 1) A solution of 5.95 g (20 mmol) of (3RS, 4RS) -l-benzyl-4- (2-methoxy-phenyl) -piperidin-3-ol (example 23a) in 100 ml of 1 N hydrochloric acid in Ethanol was stirred for 30 minutes. The solvent and excess hydrochloric acid were removed in vacuo. The residue was dissolved in 100 ml of methanol, and 1.5 g of 10% palladium on activated carbon was added. The reaction mixture was hydrogenated (room temperature, 1 bar) for 20 hours. The catalyst was filtered and washed three times with 10 ml portions of methanol. The filtrate was evaporated in vacuo, which gave 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 A __ a suspension of 4.7 g (20 mmol) of hydrochloride of (3RS, 4RS) -4 - (2- methoxy-phenyl) -piperidin-3-ol (1: 1) in 40 ml of methanol, 2.1 g of sodium carbonate was added. After stirring for 1 hour at room temperature, the sodium salts were filtered off and washed with 10 ml of methanol. The filtrate was concentrated, diluted with 2-propanol and filtered again. The filtrate was evaporated, which gave 4.10 g (quantitative) of the title compound as a white solid.

MS m / e (% 208 (M + H "100) c) (3RS, 4RS) -l-cyclodecyl-4- (2-methoxy-phenyl) piperidin-3 -ol To a suspension of 4.14 g (20 mmol) of (3RS, 4RS) -4- (2-methoxy-phenyl) -piperidin-3-ol in 3.09 g (20 mmol) of cyclodecanone were added 7, 12 g (25 mmol) of tet raisopropyl orthotitanate. After stirring overnight at room temperature, a viscous oil was obtained. A solution of 880 mg (14 mmol) of sodium cyanoborohydride in 20 ml of ethanol was added dropwise within 3-4 minutes. Stirring was continued for 48 hours at room temperature and 10 ml of 25% hydrochloric acid was added. After 30 minutes, the precipitate was filtered off and 200 ml of 2.5 M ammonia were added. The precipitate was filtered again and the filtrate was evaporated. The residue was purified by flash chromatography, which gave 5.40 g (78%) of a light yellow oil which crystallized on standing at room temperature.

MS m / e (%): 346 (M + H +, 100) d) Hydrochloride of (3RS, 4RS) -l-cyclodecyl-4- (2-methoxy-phenyl) -piperidin-3-ol (1: 1) To a solution of 270 mg (0.78 mmol) of (3RS, 4RS) -l-cyclodecyl-4- (2-methoxyphenyl) -piperidin-3-ol in 10 ml of ether, 2 ml of hydrochloric acid 2 were added. , 5 N in ether. After stirring for 30 minutes, the excess of hydrochloric acid and ether was removed in vacuo and the residue was resuspended in 20 ml of ether. Filtration of the precipitate and washing with ether gave 298 mg (quantitative) of the title compound as a white powder.

MS m / e (%): 346 (M + H +, 100).

Example 29 (3RS, 4RS) -3-methoxy-l-cyclodecyl-4- (2-methoxy-phenyl) -piperidine hydrochloride (1: 1) To a solution of 173 mg (0.5 mmol) of (3RS, 4RS) -l-cyclodecyl-4- (2-methoxy-phenyl) -piperidin-3-ol (example 28c) in 1.5 ml of anhydrous tetrahydrofuran at 0 ° C, 126 mg (0.6 mmol) of potassium bis (trimethylsilyl) amide was added. Stirring was continued for 1 hour at this temperature, and 85 mg (0.6 mmol) of methyl iodide was added. After stirring for 30 minutes at 0 ° C, the ice bath was removed and the reaction mixture was allowed to warm to room temperature overnight.

After the addition of 2 ml of water, the product was extracted with three 10 ml portions of ether, dried (magnesium sulfate) and evaporated.

The residue was purified by flash chromatography, which gave 120 mg of an oil. The amine was dissolved in 20 ml of ether and 1 ml of 2.3 M hydrochloric acid in ether was added dropwise.

MS m / e (%): 360 (M + H +, 100).

Example 30 (3RS, 4RS) -3-allyloxy-l-cyclodecyl-4- (2-methoxy-phenyl) -piperidine hydrochloride (1: 1) a) (3RS, 4RS) -3-allyloxy-l-cyclodecyl-4- (2-methoxy-phenyl) -piperidine To a solution of 146 mg (1.0 mmol) of (3RS, 4RS) -l-cyclodecyl-4- (2-methoxy phenyl) -piperidin-3-ol (example 28c) in 3.0 ml of anhydrous tetrahydrofuran a 0 ° C, 256 mg (1.2 mmol) of potassium bis (trimethylsilyl) amide was added. Stirring was continued for 1 hour at this temperature, and 145 mg (12.2 mmol) of allyl bromide was added. After stirring for 30 minutes at 0 ° C, the ice bath was removed and the reaction mixture was allowed to warm to room temperature overnight.

After the addition of 4 ml of water, the product was extracted with three 20 ml portions of ether, dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography, which gave 280 mg (73%) of the title compound as a colorless oil.

MS m / e (%) 386 (M + H 100) b) (3RS, 4RS) -3-allyloxy-l-cyclodecyl-4- (2-methoxy-phenyl) -piperidine hydrochloride (1: 1) To a solution of 100 mg (0.26 mmol) of (3RS, 4RS) -3-allyloxy-1-cyclodecyl-4- (2-methoxy-phenyl) -piperidine in 10 ml of ether was added dropwise. 2.3 M hydrochloric acid in ether. The precipitate was filtered off, washed with ether and dried in vacuo, which gave 109 mg (quantitative) of the title compound as a white powder.

MS m / e (%): 386 (M + H +, 100).

Example 31 (3RS, 4RS) -l-cyclodecyl-4- (2-methoxy-phenyl) -3-propoxy-piperidine hydrochloride (1: 1) To a solution of 77 mg (0.2 mmol) of (3RS, 4RS) -3-allyloxy-l-cyclodecyl-4- (2-methoxy-phenyl) -piperidine (example 30a) in 10 ml of ethyl acetate , 40 mg of 10% palladium on active carbon was added. The reaction mixture was hydrogenated (room temperature, 1 bar) for 20 hours. The catalyst was filtered and washed three times with 1 ml portions of ethyl acetate. The filtrate was evaporated in vacuo, which gave 78 mg of oil. The amine was dissolved in 10 ml of ether and 1 ml of 2.3 M hydrochloric acid in ether was added dropwise. The precipitate was filtered off, washed with ether and dried in vacuo, which gave 85 mg (quantitative) of the title compound as a white powder.

MS m / e (%): 388 (M + H +, 100).

Example 32 (3RS, 4RS) -l-cyclodecyl-4- (2-isopropyl-enyl) -piperidin-3-ol hydrochloride (1: 1) a) (3RS, 4RS) -l-benzyl-4- (2-isopropyl-enyl) -piperidin-3-ol The title compound was prepared in a comparable yield according to a literature procedure (Juan C. Jean and Lawrence D. Wise, J. Hetrecyclic Chem. 1987, 24, 1317-1319) in three steps from 2- bromoisopropylbenzene instead of 2-bromoanisol. 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 109 g (32 mmol) of (3RS, 4RS) -l-benzyl-4- (2-isopropyl-phenyl) -piperidin-3-ol in 100 ml of 1 N hydrochloric acid solution in ethanol was stirred for 30 minutes. minutes The solvent and excess hydrochloric acid were removed in vacuo. The residue was dissolved in 300 ml of methanol and 2.4 g of 10% palladium on activated carbon was added. The reaction mixture was hydrogenated (room temperature, 5 bar) for 20 hours. The catalyst was filtered off and washed three times with 50 ml portions of methanol. The filtrate was evaporated in vacuo, which gave 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 To a suspension of 5.75 g (22.6 mmol) of (3RS, 4 RS) -4 - (2-isopropyl-phenyl) -piperidin-3-ol (1: 1) hydrochloride in 150 ml of ethanol, 3.6 g of sodium carbonate were added. After stirring for 2 hours at room temperature, the sodium salts were filtered off and washed with 10 ml of ethanol. The filtrate was concentrated, diluted with 2-propanol and filtered again. The filtrate was evaporated, which gave 4.93 g (quantitative) of the title compound as a white solid.

MS m / e (% 220 (M + H 100) d) (3RS, 4RS) -l-cyclodecyl-4- (2-isopropyl-phenyl) -piperidin-3 -ol To a suspension of 500 mg (2.28 mmol) of (3RS, 4RS) -4- (2-isopropyl-phenyl) -piperidin-3-ol in 350 mg (2.28 mmol) of cyclodecanone, 3 were added, 24 g (11.4 mmol) of tetraisopropyl orthotinate. After stirring for 5 days at room temperature, a viscous oil was obtained. A solution of 100 mg (1.59 mmol) of sodium cyanoborohydride in 2 ml of ethanol was added dropwise within 3-4 minutes. Stirring was continued for 4 hours at room temperature and 25 ml of 2.3 N hydrochloric acid in ethanol was added. After heating for 3 hours at 60 ° C, the solution was adjusted to a pH of 8 with the addition of a 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, which gave 415 mg (51%) of the title compound as a white solid.

MS m / e (%): (M + H +, 100). e) Hydrochloride of (3RS, 4RS) -l-cyclodecyl-4- (2-isopropyl-phenyl) -piperidin-3-ol (1: 1) To a solution of 30 mg (0.08 mmol) of (3RS, 4RS) -l-cyclodecyl-4- (2-i-sopropi-1-phenyl) -piperidin-3-ol in 3 ml of ethanol was added dropwise 0.3 ml of 2.3 M hydrochloric acid in ethanol. The solution was stirred for 30 minutes at room temperature and evaporated. The residue was suspended in ether, and stirred for 1 hour. The precipitate was filtered off, washed with ether and dried under vacuum, which gave 23 mg (70%) of the title compound as a white powder.

MS m / e (%): 358 (M + H +, 100).

Example 33 (3RS, 4RS) -l-cyclodecyl-4- (2-isopropyl-phenyl) -3-methoxy-piperidine hydrochloride (1: 1) To a solution of 200 mg (0.56 mmol) of (3RS, 4RS) -l-cyclodecyl-4- (2-isopropylphenyl) -piperidin-3-ol (example 32 d) in 2 ml of anhydrous tetrahydrofuran at 0 ° C, 134 mg (0.67 mmol) of potassium bis (trimethylsilyl) amide was added. Stirring was continued for 1 hour at this temperature, and 80 mg (0.56 mmol) of methyl iodide was added. After stirring for 30 minutes at 0 ° C, the ice bath was removed and the reaction mixture was allowed to warm to room temperature overnight.

After the addition of 2 ml of water, the product was extracted with three 10 ml portions of ether, dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography, which gave 50 mg of an oil. The amine was dissolved in 10 ml of ether and 1 ml of 2.3 M hydrochloric acid was added dropwise. The precipitate was filtered off, washed with ether and dried in vacuo, which gave 34 mg. %) of the title compound in the form of a white powder.

MS m / e (%): 372 (M + H +, 100).

Example 34 (3RS, 4RS) -l-cyclononyl-4- (2-isopropyl-phenyl) -piperidin-3-ol hydrochloride (1: 1) To a suspension of 200 mg (0.91 mmol) of (3RS, 4RS) -4- (2-isopropyl-phenyl) -piperidin-3-ol (example 32c) in 160 mg (1.14 mmol) of cyclononanone, 1.29 g (4.56 mmol) of tetraisopropyl orthotitanate were added. After stirring for 6 days at room temperature, a viscous oil was obtained. A solution of 24 mg (0.64 mmol) of sodium borohydride in 2 ml of ethanol was added dropwise within 3-4 minutes. Stirring was continued for 1 hour at room temperature, and 10 ml of 2.3 N hydrochloric acid in ethanol were added. After heating for 4 hours at 60 ° C, the solution was adjusted to a pH of 8 with the addition of a 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, which gave 160 mg of a light yellow oil. The amine was dissolved in 10 ml of ethanol and 1 ml of 2.3 M hydrochloric acid in ethanol was added dropwise. The solution was stirred for 30 minutes at room temperature and evaporated. The residue was suspended in ether and stirred for 1 hour. The precipitate was filtered off, washed with ether and dried under vacuum, which gave 175 mg (51%) of the title compound as a white powder.

MS m / e (% 344 (M + H +, 100) Example 35 2-Cyclodecyl-4- (2,6-dimethoxy-phenyl) -piperidine hydrochloride (1: 1) a) l-Benzyl-4- (2,6-dimethoxy-phenyl) -1,2,3,6-tetrahydro-pyridine The title compound was separated in a comparable yield according to a literature procedure (John C Jean and La rence D. Wise, J- Heterocyclic Chem. 1987, 24, 1317-1319) in two steps from 1,2-dimethoxyphen-2-yl-magnesium, instead of 2-methoxyphenylmagnesium bromide. The product was obtained in the form of white needles.

MS m / e (%): 310 (M + H +, 100). b) 4- (2,6-dimethoxy-phenyl) -piperidine A solution of 3.4 g (11 mmol) of l-benzyl-4- (2,6-dimethoxy-phenyl) -1,2,3,6-tetrahydro-pyridine in 100 ml of 1 N hydrochloric acid solution in Ethanol 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 hours. The catalyst was filtered off and washed three times with 50 ml pons of methanol. The filtrate was evaporated in vacuo, and the product was purified by flash chromatography, which gave 1.34 g (57%) of the title compound as a white powder.

MS m / e (%): 222 (M + H +, 100). c) L-cyclodecyl-4- (2,6-dimethoxy-phenyl) -piperidine hydrochloride (1: 1) To a suspension of 200 mg (0.9 mmol) of 4- (2,6-dimethoxy-phenyl) -piperidine in 140 mg (0.9 mmol) of cyclodecanone was added 1.28 g (4.52 mmol). of tetraisopropyl otitanate. After stirring for 4 days at room temperature, a viscous oil was obtained. A solution of 40 mg (0.63 mmol) of sodium cyanoborohydride in 1 ml of ethanol was added dropwise within 3-4 minutes. Stirring was continued for 5 hours at room temperature and 10 ml of 2.3 N hydrochloric acid in ethanol was added. After heating for 3 hours at 60 ° C, the solution was adjusted to a pH of 8 with the addition of 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, which gave 18 mg of white crystals. The amine was dissolved in 10 ml of ether and 1 ml of 2.3 M hydrochloric acid in ether was added dropwise. The solution was stirred for 30 minutes at room temperature 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, which gave 20 mg (6%) of the title compound as a white powder.

MS m / e (%) 360 (M + H '100) Example 36 (3RS, 4RS) -l-cyclodecyl-4- (2,6-dimethoxy-phenyl) -piperidin-3-ol hydrochloride (1: 1) a) Hydrochloride of (3RS, 4RS) -l-benzyl-4- (2,6-dimethoxy-phenyl) -piperidin-3-ol (1: 1) The title compound was separated in a comparable yield according to a literature procedure (Juan C. Jean and La Rence D. Wise, J. Heterocyclic Chem. 1987, 24, 1317-1319) in three steps from 1, 3-dimethoxyphen-2-ylmagnesium bromide in place of 2-methoxyphenylmagnesium bromide. The product was obtained in the form of white crystals.

MS m / e (%): 328 (M + H +, 100). b) Hydrochloride of (3RS, 4RS) -4- (2,6-dimethoxy-phenyl) -piperidin-3-ol (1: 1) To a solution of 2.9 g (8 mmol) of (3RS, 4RS) -1-benzyl-4- (2,6-dimethoxy phenyl) -piperidin-3-ol hydrochloride (1: 1) in 80 ml of methanol, 600 mg of 10% palladium on activated charcoal was added. The reaction mixture was hydrogenated (room temperature, 5 bar) until the theoretical amount of hydrogen was collected (around 20 hours). The catalyst was filtered off and washed three times with 20 ml pons of methanol. The filtrate was evaporated in vacuo, which gave 1.88 g (87%) of the title compound as a light yellow powder.

MS m / e (%): 237 (M +, 27), 208 (100). c) (3RS, 4RS) -4- (2,6-dimethoxy-phenyl) -piperidin-3-ol To a suspension of 1.78 g (6.53 mmol) of methyl (3RS, 4RS) -4 - (2, 6-dimethoxyphenyl) -piperidin-3-ol (1: 1) in 25 ml of ethanol , 1.0 g of sodium carbonate was added. After stirring for 2 hours at room temperature, the sodium salts were filtered off and washed with 10 ml of ethanol. The filtrate was concentrated, diluted with 2-propanol and filtered again. The filtrate was evaporated and gave 1.46 g (quantitative) of the title compound as a light yellow solid.

MS m / e (%): 238 (M + H +, 100). d) (3RS, 4RS) -l-cyclodecyl-4- (2,6-dimethoxy-phenyl) -piperidin-3-ol To a suspension of 500 mg (2.1 mmol) of (3RS, 4RS) -4- (2, 6-dimethoxyphenyl) -piperidin-3-ol in 325 mg (2.1 mmol) of cyclododecanone, was added '3.0 g (10.5 mmol) of tetraisopropyl orthotitanate. After stirring for 4 days at room temperature, a viscous oil was obtained. A solution of 93 mg (1.5 mmol) of sodium cyanoborohydride in 1.5 ml of ethanol was added dropwise within 3-4 minutes. Stirring was continued for 2 hours at room temperature and 25 ml of 2.3 N hydrochloric acid in ethanol was added. After heating for 2 hours at 60 ° C, the solution was adjusted to a pH of 8 with the addition of a 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, which gave 218 mg (27%) of the title compound as a yellow oil.

MS m / e (%): 376 (M + H +, 100 e) Methyl (3RS, 4RS) -1 -ciclodecil-4- (2, 6-dimethoxyphenyl) -piperidin-3-ol (1: 1) To a solution of 30 mg (0.08 mmol) of ( 3RS, 4RS) -l-cyclodecyl-4- (2, 6-dimethoxy phenyl) -piperidin-3-ol in 3 ml of ethanol was added drop by drop 0.3 ml of 2.3M hydrochloric acid in ethanol. The solution was stirred for 30 minutes at room temperature 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, which gave 20 mg (61%) of the title compound as a white powder.

MS m / e 376 (M + H +, 100 Example 37 1-cyclodecyl-4-phenylpiperidine hydrochloride (1: 1) To a suspension of 200 mg (1.24 mmol) of 4-phenylpiperidine in 230 mg (1.49 mmol) of cyclodecanone was added 1.76 g (6.2 mmol) of tetraisopropylortotitanate. After stirring for 5 days at room temperature, a viscous oil was obtained. A solution of 235 mg (6.2 mmol) of sodium borohydride in 10 ml of ethanol was added dropwise within 3-4 minutes. Stirring was continued for 2 hours at room temperature and 10 ml of concentrated ammonia solution was added. The inorganic precipitate was filtered off 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, which gave 270 mg of a yellow solid. The amine was dissolved in 10 ml of ethanol and 1 ml of 2.3 M hydrochloric acid in ethanol was added dropwise. The solution was stirred for 30 minutes at room temperature 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, which gave 200 mg (48%) of the title compound as a white powder.

MS m / e (%) 300 (M + H 100) Example 38 L-cyclodecyl-4-cyclohexyl-piperidine hydrochloride (1: 1) To a suspension of 200 mg (1.12 mmol) of 4-ciclohexilpiperidina 220 mg (1.43 mmol) of cyclododecanone, 1.67 g (6.0 mmol) of tetraisopropyl ortot itanato was added. After stirring for 5 days at room temperature, a viscous oil was obtained. A solution of 225 mg (6 mg) was added dropwise within 3-4 minutes., 0 mmol) of sodium borohydride in 10 ml of ethanol. Stirring was continued for 2 hours at room temperature and 10 ml of concentrated ammonia solution was added. The inorganic precipitate was filtered off and washed with dichloromethane. The filter was extracted with dichloromethane, the organic phase was washed with brine, dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography, which gave 80 mg of a light yellow solid. The amine was dissolved in 10 ml of ethanol and 1 ml of 2.3 M hydrochloric acid in ethanol was added dropwise. The solution was stirred for 30 minutes at room temperature 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, which gave 78 mg (19%) of the title compound as a white powder.

MS m / e (%) 305) M \ 1¡ 206 (100) It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (12)

Claims

1. The use of the compounds of the general formula where R1 is tetrahydronaphthyl; or - (CH2) nC6H5-R4 wherein n is 0-4 and R4 is H, alkyl (C? -C6), or alkoxy (C? -C6); or C5-C12 cycloalkyl, optionally substituted by alkyl (C? -C6); R is H, OH, (C? -C6) alkoxy, (C? -C6) alkenyloxy or (C? -C6) alkyl; R is C5-C7 cycloalkyl or phenyl, optionally substituted by OH, halogen, alkoxy (d-C6), alkenyloxy (C? -C6), alkyl (C? -C6) or -O- (CH2) n-C6H5 in where n is 0-3; and its pharmaceutically acceptable acid addition salts, for the manufacture of medicaments for treating diseases related to the orphanin receptor (OFQ).

2. The use according to claim 1, wherein R1 is cycloalkyl of 5-12, optionally substituted by alkyl (Ci-C6) •

3. The use according to claim 2, wherein the compounds are: (3RS, 4RS) -l-cyclononyl-4- (2-hydroxy-phenyl) piperidin-3-ol; l-cyclodecyl-4 - (2-methoxy-phenyl) -piperidine; (3RS, 4RS) -l-cyclodecyl-4- (2 -i-sopropi-1-phenyl) piperidin-3-ol); (3RS, 4RS) -l-cyclodecyl-4- (2-isopropyl-phenyl) piperidin-3-ol; (3RS, 4RS) -4- (2-hydroxy-phenyl) -1- (cis-y- (trans-4 'isopropylcyclohexyl) -piperidin-3-ol; 2- (l-cyclodecyl-piperidin-4-yl) phenol; (3RS, 4RS) -l-cyclodecyl-4- (2-methoxy-phenyl) -piperidin-3-ol; l-cyclodecyl-4-cyclohexyl-piperidine; (3RS, 4RS) -l-cyclononyl-4- (2-methoxy-phenyl) -piperidin-3-ol; (3RS, 4RS) -4- (2-allyloxy-phenyl) -l-cyclodecyl 'piperidin-3-ol; l-cyclodecyl-4-phenyl-piperidine; (3RS, 4RS) -l-cyclononyl-4- (2-isopropyl-phenyl piperidin-3-ol and (3RS, 4RS) -l-cyclodecyl-4- (2-hydroxy-phenyl) piperidin-3-ol.

4. The use according to any of claims 1-3, wherein the diseases related to the orphanin FQ receptor (OFQ) are memory and attention deficit, psychiatric, neurological and physiological disorders, such as anxiety and tension 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 seizures, acute and / or chronic pain conditions, withdrawal symptoms of addictive drugs and reduction of their abuse / desire, water balance control, Na + excretion and blood pressure disorders and metabolic disorders such as obesity.

5. Compounds of the general formula characterized because R1 is tetrahydronaphthyl; or - (CH2) nC6H5-R4 wherein n is 0-4 and R4 is H, alkyl (C? -C6), or alkoxy (Ci-C?); or C5-C? 2 cycloalkyl, optionally substituted by alkyl (Ci-C?); R2 is OH, (C? -C6) alkoxy, (C? -C6) alkenyloxy or (Ci-Ce) alkyl; R3 is C5-C7 cycloalkyl or phenyl, optionally substituted by OH, halogen, alkoxy (Ci-Ce), alkenyloxy (Ci-Ce), alkyl (C? -C6) or -O- (CH2) n-C6H5 wherein n is 0-3; and to its pharmaceutically acceptable acid addition salts, with the condition of: if R1 is - (CH2) nPh (n = l-2) and R2 is methyl, R3 can not be an unsubstituted phenyl group; if R1 is - (CH2) nPh (n = l-4) and R2 is OH, R3 can not be phenyl, optionally substituted by halogen or lower alkyl.

6. The compounds according to claim 5, characterized in that R1 is C5-C3.2 cycloalkyl, optionally substituted by alkyl (Ci-Cß) •

7. The compounds according to claim 6, characterized in that they are: (3RS, 4RS) -l-cyclononyl-4- (2-hydroxy-phenyl) piperidin-3-ol; (3RS, 4RS) -l-cyclodecyl-4- (2-isopropyl-phenyl) piperidin-3-ol); (3RS, 4RS) -4- (2-Hydroxy-phenyl) -1- (cis-y- (trans-4-isopropyl-1-cyclohexyl) -piperidin-3-ol; (3RS, 4RS) -l-cyclodecyl-4- (2-methoxy-phenylpiperidin-3-ol; (3RS, 4RS) -l-cyclononyl-4- (2-methoxy-phenyl) piperidin-3-ol; (3RS, 4RS) -4- (2-allyloxy-phenyl) -1-cyclodecyl-piperidin-3-ol; (3RS, 4RS) -l-cyclononyl-4- (2-isopropyl-phenyl) piperidin-3-ol; Y (3RS, 4RS) -l-cyclodecyl-4- (2-hydroxy-phenyl) piperidin-3-ol.

8. A medicament, characterized in that it contains one or more compounds of any of claims 1 to 3, or a respective pharmaceutically acceptable salt.

9. The medicament, according to claim 8, characterized in that it is for the treatment of memory and attention deficits, psychiatric, neurological and physiological disorders, such as anxiety and tension 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 seizures, acute and / or chronic pain conditions, withdrawal symptoms of addictive drugs and reduction of their abuse / desire, water balance control, Na + excretion and blood pressure disorders and metabolic disorders such as obesity.

10. The compounds according to any of claims 5 to 7, characterized in that they are used as a medicament.

11. A process for preparing a compound of formula la, as defined in claim 5, characterized in that the process comprises the reductive amination of a compound of formula II with a compound of formula wherein R1, R2 and R3 are as claimed in claim 5.

12. The compounds of the general formula la, obtained by the processes of claim 11 or by equivalent processes. Summary of the Invention The present invention relates to compounds of the general formula R is tetrahydronaphthyl; or - (CH2) nC6H5-R4 wherein n is 0-4 and R4 is H, lower alkyl or lower alkoxy; or C5-C12 cycloalkyl, optionally substituted by lower alkyl; R is H, OH, lower alkoxy, lower alkenyloxy or lower alkyl; R is C5-C7 cycloalkyl or phenyl, optionally substituted by OH, halogen, lower alkoxy, lower alkenyloxy, lower alkyl or -0- (CH2) n-C6H5 wherein n is 0-3; and its pharmaceutically acceptable acid addition salts. The compounds of the general formula (I) are suitable for the treatment of memory and attention deficits, psychiatric, neurological and physiological disorders, such as anxiety and tension 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 seizures, acute and / or chronic pain conditions, withdrawal symptoms of addictive drugs and reduction of their abuse / desire, water balance control, excretion of Na + and blood pressure disorders and metabolic disorders such as obesity.