MXPA97009202A - Derivatives of the 4-hidroxi-piperid - Google Patents

Abstract

The present invention relates to derivatives of the 4-hydroxy-piperidine of the general formula (I), wherein X means -O-, -NH-, -CH2-, -CH =, -CHOH-, -CO-, -S-, -SO-, or -SO2; R1-R4 are, independently with respect to each other, hydrogen, hydroxy, lower alkyl-sulfonylamino, 1-or 2-imidazoyl or acetamido; R5-R8 are, independently one with respect to the other, hydrogen, hydroxy, lower alkyl, halogen, lower alkoxy, trifluoromethyl or trifluoromethyloxy; and a and b may be a double bond, with the proviso that, when "a" is a double bond, "b" can not to be a double bond, n is 0-2, m is 1-3, p is 0 or 1, and salts are of this type, acceptable from the pharmaceutical point of view. The compounds of the present invention are selective blockers of the NMDA receptor subtype (N-methyl-D-aspartate), which can be used in mediating processes subordinated to the development of the CNS, including the function of learning and memory formation.

Description

DERIVATIVES OF 4-HIDrK) XI-PIPERIDI A Description of the invention The present invention relates to 4-hydroxy-piperidine derivatives of the general formula wherein X means -O-, -NH-, -CH2-, -CH =, -CHOH-, -CO-, -S-, -SO-, or -S02-: R1-R4 are, independently with respect to each other, hydrogen, hydroxy, lower alkyl-sulfonylamino, 1- or 2-imidazoyl or acetamido; R5-R8 are, independently with respect to each other, hydrogen, hydroxy, lower alkyl, halogen, also lower xi, trifluoromethyl or trifluoromethyloxy; a and b can be a double bond, with the proviso that, when "a" is a double bond, "b" can not be a double bond; REF: 26113 n is 0-2; m is 1-3; p is 0 or 1 and salts thereof, acceptable from the pharmaceutical point of view. The compounds of formula I and their salts are distinguished by therapeutically valuable properties. The compounds of the present invention are selective blockers of the NMDA receptor sub-type (N-methyl-D-aspartate), which can have a key function in the modulation of neuronal activity and plasticity that makes them a key player in mediation processes subordinated to the development of the CNS, including the function of learning and memory training.

Under pathological conditions of chronic acute forms of neurodegeneration, overactivation of NMDA receptors is a key event in triggering the death of neuronal cells. The NMDA receptors are composed of members of two subunits of families, namely, the NR-1 (8 different splice variants) and the NR-2 (A to D) that originate from different genes. The members of the two subunits of families show a distinct unmistakable distribution in different areas of the brain. Heteromeric combinations of NR-1 members with different subunits of NR-2 result in NMDA receptors having different pharmaceutical properties. Possible therapeutic indications for selective blockers of the NMDA receptor subtype include acute forms of neurodegeneration caused, for example, by stroke and brain trauma and chronic forms of neurodegeneration, such as Alzheimer's disease, Parkinson's disease, of Huntingston, ALS (amyotrophic lateral sclerosis) - and neurodegeneration associated with bacterial or viral infections. The subject of the invention are the compounds of formula I and the addition salts thereof, pharmaceutically acceptable, racemic mixtures and their corresponding enantiomers, the preparation of the aforementioned compounds, medicaments containing them and their manufacture, as well as the use of the aforementioned compounds, in the control or prevention of diseases, especially diseases and disorders of the type referred to above, or for the manufacture of the corresponding drugs.

The following definitions of the general terms used in the present description are applied interchangeably whether the terms in question appear alone or in combination. As used herein, the term "lower alkyl" means a linear or branched alkyl group containing from 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, -butyl and tert. -butyl. The term "halogen" means chlorine, iodine, fluorine and bromine. The term "lower alkyl" means a group wherein the alkyl residue is as defined above. The term "leaving group" has the meaning conventionally used and refers, for example, to halogen, alkylsulfonyloxy, arylsulfonyloxy and the like. The most preferred leaving group in the present case is a halogen. The term "pharmaceutically acceptable addition salts", covers salts with inorganic and organic acids and generates knowledge from people skilled in the art of this technique, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, acid citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane sulphonic acid, p-toluene sulphonic acid, and the like. The compounds of formula I are preferred, wherein is -O-, -NH-, -CHOH, or -CH2. Preferred compounds in which -X- means -OR-, are, by way of example: (RS) -1- (5-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl 4- (4-methyl-benzyl) -piperidin-4-ol, ( RS) -4-benzyl-1- (5-hydroxy-2,3-dihydro-benzofuran-ylmethyl) -piperidin-4-ol, (RS) -4- (4-fluoro-benzyl) -l- (5- hydroxy-2, 3-dihydr benzofuran-2-ylmethyl) -piperidin-4-ol, (RS) -4- (4-ethyl-bensyl) -l- (5-hydroxy-2,3-dihydr benzofuran-2- ilmethyl) -piperidin-4-ol, (s) -l- (5-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl) 4- (4-methyl-benzyl) -piperidin-4-ol, (s) -l- (5-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl 4- (4-chloro-benzyl) -piperidine- 4-ol, (RS) -N- [2-. {4-hydroxy-4- (4-methyl-benzyl) -piperidin-ylmethyl} -2, 3-dihydrobenzofuran-5-yl] methanesulfonamide ( RS) -N- [2-. {4-hydroxy-4- (4-methyl-benzyl) -piperidin-ylmethyl} -2, 3-dihydrobenzofuran-5-yl] methane sulfonamide Preferred compounds in which X means -CHOH, are, by way of example: (1RS, 2RS) and (lRS, 2RS) -2- [4-hydroxy-4- (4-methyl-ben -yl) -piperidin-1-ylmethyl] -indan -1, 5-diol, (1RS, 2RS) -1- (1, 6-dihydroxy-l, 2,3, 4-tetrahydro-naphtha-len-2-ylmethyl) -4- (4-methyl-benzyl) -piperidin-4-ol and (1RS, 2RS) -2- (4-benzyl-4-hydroxy-piperidin-1-ylmethyl) -6-hydroxy-l, 2,3,4-tetrahydronaphthalen-1-ol Other exemplary compounds in which X means -CH 2 - are: (RS) -l- (5-hydroxy-indan-2-ylmethyl) -4- (4-methyl-ben -yl) -piperidine- 4-ol and (RS) -1- (6-hydroxy-l, 2,3,4, tetrahydro-natalen-2-ylmethyl) -4- (4-methyl-benzyl) ) -piperidin-4-ol. In addition, another preferred compound in which X is -NH-, is (RS) -2- [4-hydroxy-4- (4-methyl-benzyl) -piperidin-1-ylmethyl] -2, 3-dihydro -lH-indol-5-ol. The present compounds of formula I, and their pharmaceutically acceptable salts, can be prepared by methods known in the art of this art, for example, by the methods described below, which comprise: a) the reaction of a compound of formula wherein R1-R4, X, a, b, n and m, have the given meaning, eg, halogen or -O-tosyl, with a compound of the formula wherein R5-R8 and p, have the meaning given above above, or b) the reaction of a compound of formula wherein the substituents have the meaning given above, with a compound of the formula in the presence of paraformaldehyde, to provide a compound of the formula wherein m is 1 and, the other substituents, have the meaning given above, or c) dehydration of a compound of the formula to provide a compound of formula wherein, m is 1 and the other substituents have the meanings given above or d) the reduction of a compound of formula IA, to provide a compound of formula IB, or e) the debenzylation of a compound of the formula f) the reaction of a compound of formula I, wherein one of R1-R4 is an amino group with lower alkyl-halogenosulfonyl, to provide a compound of formula I, wherein one of R1-R4, is a lower alkyl sulfonylamino group, or g) the hydrogenation of the double bond isolated in a compound of formula I, or the division or cleavage of (a) hydroxy or amino protecting group (s), present (s) as (a) ) substituent (s) R1 R4 or as X '= - N (protecting group), or i) oxidation of a compound of formula I, e wherein, X represents -S- or -SO-, to provide the corresponding group sulfonyl (-S02), and j) if desired, the conversion of the obtained formula I compound, into an acceptable addition salt from a pharmaceutical point of view. According to the process variant to a mixture of a compound of formula II and of formula III, wherein, the leaving group L in formula II is, for example, bromine, it was dissolved in an appropriate solvent, for example DMF, and heated to a temperature of about 80 90'c. This reaction is carried out in the presence of a basic base. mpues or emumu I, is then separated according to conventional methods or forms. When one of the R1-R4 in formula II is a hydroxy group, these groups are protected by conventionally used groups. Examples of these groups are described roughly in T. Protective Groups in Organis Synthesis, John Wiley and Sons, Inc. (1981), pp 218-287. Most preferred are the benzyloxy and alkyloxy groups. This reaction can be carried out by known methods, for example, by hydrogenation with Pd / C (10%) or boron-dichloromethane tribromide solution. Process variant b) describes a process for obtaining compounds of formula I, wherein X is a -C0- group. A compound of formula IV is heated in an appropriate solvent, for example in DMF, together with a compound of formula IIIA, in the presence of paraformaldehyde.

This reaction is carried out at a temperature of approximately 80 °, according to conventional methods or forms. In accordance with process variant c), a compound of formula IB can be dehydrated in the presence of ethanolic HCL according to conventional methods or forms. Compounds of formula I are obtained, in which "a" represents a double bond. Variant d), describes a process for the reduction of compounds of formula IA, to provide compounds of the formula IB. This reaction is carried out in a conventional manner, the presence of LIA1H4 and TFH and at a temperature of about 5-ioaC being preferred. In accordance with process variant e), a compound of formula I is obtained, wherein one of the Rl-R4 is hydroxy. This process is carried out by debenzylating a compound of formula V, with the proviso that none of the R5-R8 is halogen. The debenzylation is carried out in a conventional manner. For example, a compound of formula V is dissolved in an appropriate solvent or mixture of solvents, such as ethanol and ethyl acetate, and hydrogenated in the presence of Pd or C at room temperature and atmospheric pressure. In accordance with process variant f), a compound of formula I can be obtained, wherein one of the R 1 -R 4 is a lower alkyl-sulfonyl-amino group. This reaction is carried out by treating a compound of formula I wherein one of the R1-R4 is an amino group, with a lower alkyl-halogensulfonyl, such as the sulfonylchloride of methane, in an appropriate solvent, such as sodium chloride. methylene, in the presence of pyridine, at room temperature. The hydrogenation of a compound of formula I, wherein "a" or "b" is a double bond, according to process g), is carried out in a conventional manner for example, in the presence of Pd / C in acetate of ethyl, under nitrogen atmosphere, during a course of time of 2 hours, at room temperature. Protecting groups, for example the hydroxy group, can be divided or cleaved by the methods described above. The appropriate protection groups and procedures for their division or split will be familiar to any person skilled in the art of the art; in spite of this, of course, only those protective groups can be used that can be divided or cleaved by processes under conditions in which other ctural elements and compounds are not affected. The oxidation of the compounds of formula I where X is -S- or -SO-, is carried out in a conventional manner. In accordance with the process variant i), a compound of formula I, wherein X represents -S- or -SO-, is oxidized to provide the corresponding sulfonyl compound (S02 -) -. Oxidation can be carried out in the presence of Oxone® (triple salt of potassium monopersulfate) at room temperature, or in the presence of metachloroperbenzoic acid. The addition salts of the compounds of formula I are especially well suited for pharmaceutical use. The starting materials for the preparation of compounds of formula I are known or can be prepared by well known methods, for example, according to the following reaction schemes. These reactions are described in more detail in Examples 33-75.

Scheme 1 On the e ect of their listeners, they are as indicated above. Scheme 2 LDA / 'osilo -CI, E N 1, 3-DIBROMOPROPAN wherein, the meanings of the substituents are as indicated above.

O / NaOAc wherein, the meanings of the substituents are as indicated above. scheme 4 wherein, the meanings of the substituents are as indicated above. wherein, the meanings of the substituents are as indicated above. As mentioned above, the compounds of formula I and their pharmaceutically usable salts possess valuable pharmacodynamic properties. These selective blockers of the NMDA receptor subtype (N-methyl-aspartate), which have the key function of modulating neuronal activity and plasticity, which makes them key players in subordinated mediation processes of the CNS, as well as of the learning and memory formation function. The compounds were tested according to the test tests given below. Method 1 Binding 3H-RQ25-6981 (Ro 25-6981, is [R- (R *, S *)] -a (4-Hydroxy-phenyl) -b-methyl-4- (phenyl-methyl) -1- piperidinpropanol) Füllindorf male albino rats weighing 150-200 g were used. Membranes were prepared by homogenization of the whole brain minus cerebellum and medulla oblongata with Polytron (10,000 rpm, 30 seconds), in 25 volumes of a cold buffer solution of 50 mM tris-HCL, 10 mM EDTA, with a pH value equal to 7, 1. The homogenized product was centrifuged at 48,000 g for a period of 10 minutes at a temperature of 4 C. The pellet was resuspended using Polytron in the same volume of buffer solution and the homogenized product was incubated with a temperature of 37"c, during a course of time of 10 minutes After centrifugation, the" pellet "was homogenized in the same buffer solution and was frozen at a temperature of -80 ° C, during at least 16 hours, but no more than 10 days.For the binding test, the homogenized product was de-gellated at a temperature of 37 ° C, centrifuged, and the pellet was washed three times as above in a cold buffer solution of tris-HCl 5 mM, with a pH value equal to 7.4 The final pellet was resuspended in the same buffer solution and used in a final concentration of 200 μg protein / ml The 3H-Ro 25.6981 binding experiments were performed using a 50 mM tris-HCl buffer solution, with a pH value equal to 7.4 For the displacement experiments, 5nM of 3H-Ro 25-6981 were used and a non-specific binding was measured using 10 μM of tetrahydroisoquinoline and, usually, it accounts for 10% of the total . The incubation time was 2 hours at a temperature of 4 ° C and the test was stopped by filtration on Whatmann GF / B glass fiber filters (Unifilter-96, Packard, Zürich, Switzerland). washed 5 times with cold buffer solution. L radioactivity in the filter was counted in a cente meter filled with PasKard Top counter microplate, after the addition of 40 mL of Microscint 40 (Canberra Pacxkard S.A. Zürich Switzerland). The effects of the compounds were measured using a minimum of 8 concentrations and were repeated at least once. The extracted normalized values were analyzed using a non-linear regression calculation program provided by ICgo, with its upper and lower relative confidential limits of 95% (RSl, BBN, United States of America). Method 2 3 H-Prazosin binding Füllindorf male albino rats, weighing between 150 and 200 g, were used. Membrane was prepared by homogenization of the whole brain minus cerebellum medulla oblongata with Polytron (10,000 rpm, 30 seconds), and 25 volumes of a cold buffer solution of 50 mM tris-HCL EDTA 10 mM, with a pH value equal to 7.1. The homogenized product was centrifuged at 48,000 g, over a period of 10 minutes, at a temperature of 4 * C. The pellet resuspended using Polytron in the same volume of buffer solution and, the homogenized product, was incubated at a temperature of 37 ° C, for a period of 10 minutes. After centrifugation, the pellet was homogenized in the same buffer solution and frozen at a temperature of -80 ° C, for at least 16 hours, but not more than 10 days For the binding test, the homogenized product was thawed at a temperature of 37 ° C, centrifuged, and the pellet was washed three times as above in a cold buffer solution of 5 mM tris-HCl., with a pH value equal to 7.4. The final "peílet" was resuspended in the same buffer solution and used in a final concentration of 200 μg protein / ml. The 3H-Prazosin binding experiments were performed using a 50 mM tris-HCl buffer solution, with a pH value equal to 7.4. For the displacement experiments, 0.2 nM of 3 H-Prazosin was used and a non-specific binding was measured using 100 μM of Chloropromazine. The incubation time was 30 minutes at room temperature and the assay was stopped by filtration in Whatmann GF / B glass fiber filters (Unifilter-96, Packard, Zürich, Switzerland). The filters were washed 5 times with cold buffer solution. The radioactivity in the filter was counted in a PacKard Top counter microplate scintillation counter, after the addition of 40 L of Microscint 40 (Canberra Pacxkard S.A. Zürich, Switzerland). The effects of the compounds were measured using a minimum of 8 concentrations and repeated at least once. The extracted normalized values were analyzed using a non-linear regression calculation program that provides ICso, with its confidential upper and lower relative limits of 95% (RSlm BBN, United States of America). Method 3 Electrophysiology in recombinant NMDA receptors The cDNA clones encoding the NRIC and NR2A subunits of the NMDA receptor (see Hollmann and Heine ann, 1994, Annu, Rev. Neurosci, 17:31 for the nomenclature of recombinant NMDA subunits ) were isolated from a rat brain library of Agt ll cDNA, as published elsewhere (Sigel et al, 1994, J. Biol. Chem. 269: 8204). The clone for the rat brain NMDA receptor NR2B subunit was obtained from S. Nakanishi (Kyoto, Japan). The cDNAS encoding the rat NRIC, NR2A and NR2B were subcloned into the expression vector pBC / CMV (Ber-tocci and colleagues, 1991, Pros. Nati, Acad. Sci. USA 88: 1416), placing the transcription of the cDNA under the control of the human cytomegalovirus promoter. The expression plasmids purified with CsCl, were mixed in an NR1C: NR2A or NRIC: NR2B ratio of 1: 3, in an injection buffer solution ((88 mM NaCl, lmM KCl, 15 mM HEPES, at a pH value of 7.0) South African frog oocytes (Xenopus laevis) were used for the expression of either a combination of the NRIC and NR2A subunits, or of the NRIC and NR2B subunits, 12 to 120 pg of a 1: 3 mixture (NR1C: NR2B) of the respective cDNA species, in the nucleus of each oocyte In the following two days, the ion current through the NMDA receptor channels was measured in fixation experiments (retention) of voltage for the procedures of expression of cNDA in oocytes, and voltage setting (see for example in Methods in Neurosciences 4: 174, of the year 1991, by Bertrand and colleagues.) The membrane potential was set at - 80 mV and, the receptors, were activated by the application of a modified Ringer's solution, which It had NMDA receptor agonists, L-glutamate (Glu) and glycine (Gly). Different concentrations of agonists were chosen for both subunits to account for the different agonist sensitivities of the two receptor types (2.7 μM Glu plus 0.9 μM Gly for NRIC + NR2A and 1.3 μM Glu plus 0.07 μM Gly for NRIC + NR2B). The agonists were applied for intervals of 15 s, once every 2.5 minutes, by rapid superfusion of the oocyte with agonist containing the solution and the amplitude of the current evoked by the agonist, it was measured immediately before the end of each application. After a series of initial control applications, the antagonist to be tested was added to both solutions, the Ringer's basal and the one containing the agonist. The concentration of antagonist applied to the oocytes expressing the NR2A unit was 10 μmol / 1, while 0.1 μmol / 1 was applied to the expression oocytes of NR2B. They tested, that is, four to six oocytes were tested for each compound and NMDA receptor subtype. The oocytes were exposed to the compounds for 5 to 30 minutes, depending on the time needed to reach an equilibrium block of the NMDA receptor current. For each oocyte, the decrease in the amplitude of the current was expressed as a percentage of the control current measured before the application of the compound. The figures given in the table are values of arithmetic meaning of these percentage values. The activity determined in this way of some compounds, in accordance with the present invention, will be apparent from the following table. (continuation table) * 33% block at a concentration of 1 μM (01) 1- (6-hydroxy-3,4-dihydro-naphthalen-2-ylmethyl) -4 (4-methyl-bensyl) -piperidin-4-ol (02 ) (RS) -1- (5-Hydroxy-2,3-dihydro-benzofuran-2-ylmethyl) -4- (4-methyl-benzyl) -piperidin-4-ol) -hydrochloride (04) (RS) -4- benzyl-1- (5-hydroxy-2,3-dihydro-benzofu-ran-2-ylmethyl) -piperidin-4-ol hydrochloride (05) (RS) -4- (4-fluoro-benzyl) -l- (5 -hydroxy-2,3-dihi dro-benzofuran-2-ylmethyl) -piperidin-4-ol hydrochloride (07) (RS) -4- (4-ethyl-benzyl) -1- (5-hydroxy-2, 3 -dihi dro-benzofuran-2-ylmethyl) -piperidin-4-ol hydrochloride (13) (S) -1- (5-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl) -4- (4- methyl-benzyl) -piperidin-4-ol) hydroloride (1) (S) -1- (5-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl) -4- (4-chloro-benzyl) - piperidin-4-ol hydrosulphide - - (16) (1RS, 2RS) and (lRS, 2SR) -2- (4-hydroxy-4- (4-methyl-benzyl) -piperidin-1-ylmethyl} -indan -l, 5-diol fumarate, salt (19) (RS) -1- (5-hydroxy-indan-2-ylmethyl) -4- (4-methyl-benzyl) -piperidin-4-ol (21) (RS) ) -2- {4-hydroxy-4- (4-methyl-benzyl) -piperidin-1-ylmethyl} -2,3-dihydro-lH-indol-5-ol (22) (RS) -N- [2-. { 4-hydroxy-4- (4-methyl-benzyl) -piperi-din-1-ylmethyl} -2, 3-dihydrobenzofuran-5-yl] -methane sulfonamide hydrochloride (23) (RS) -N- (2- [4-hydroxy-4-. {4-methyl-benzyl.} - piperi-din- l-ylmethyl] -2, 3-dihydrobenzofuran-5-yl) -methane sulfonamide hydrochloride (27) (1RS, 2RS) -1- (1,6-dihydroxy-l, 2,3,4-tetrahydro-naphthalene-2 -ylmethyl) -4- (4-methy1-benzyl) -piperidin-4-ol fumarate, salt (29) (1RS, 2RS) -2- (4-benzyl-4-hydroxy-piperidine-1-ylmethyl) -6 -hydroxy-l, 2,3,4-tetrahydronaphthalen-1-ol (30) (RS) -1- (6-hydroxy-l, 2,3,4-tetrahydro-naphthalen-2-ylmethyl) -4- ( 4-methyl-benzyl) -piperidin-4-olhydroloride Conducting a screening investigation (filtering) of the compounds of formula I, these could be identified as selective blockers of the NMDA receptor subtype and -for selected compounds- the preference could be demonstrated for NMDAR-2B units, by electrophysiological characterization, using expressed oocytes of NMDA receptor subtypes cloned. The compounds of formula I and their salts, as described herein, can be incorporated into standard pharmaceutical dosage forms, for example, for oral or parenteral application, with the usual auxiliary pharmaceutical materials, for example, carrier materials. inert organic or inorganic, such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols and the like. The pharmaceutical preparations can be used in solid forms, for example, as tablets, suppositories, capsules, or in liquid forms, for example as solutions, suspensions or emulsions. Auxiliary pharmaceutical materials can be added and these include preservatives stabilizers, wetting or emulsifying agents, salts to change the osmotic pressure or for current as buffers. The pharmaceutical preparations may also contain other active substances from the pharmaceutical point of view. The daily dose of the compounds of formula I to be administered varies with the particular compound employed, the chosen route of administration, and the container. Representative of the method for administering the compounds of formula I are oral and parenteral routes of administration. An oral formulation of a compound of formula I is preferably administered to an adult at a dose ranging from 150 mg to 1.5 g per day. A parenteral formulation of a compound of formula I is preferably administered to an adult at a dose ranging from 5 to 500 mg per day. The examples given below illustrate the present invention in greater detail. All temperatures are given in degrees Celsius. Example 1 1-f 6-hydroxy-3,4-dihydro-naphthalen-2-ylmethyl '> -4-f 4-methyl-benzyl-1-piperidin-4-ol was dissolved (1RS, 2RS) (1-1,6-dihydroxy-1,2,4,4-tetrahydro-naphthalen-2-ylmethyl) -4- (4-methyl-benzyl) -piperidin-4-ol (8286 mg, 0.75 mmol) in EtOAc (25 mL), and treated with a 6.4 N solution of C1H in EtOH, at room temperature. The mixture was then heated over a period of 1 hour. After cooling, H20 (25 ml) was added and the mixture was neutralized with a 10% solution of NaHCO3.

The reaction mixture was then extracted with EtOAC (2x50 ml), washed with saturated NaCl solution (25 ml), dried with NaS04, filtered, and evaporated, to give the title compound, as a pink colored solid compound (238.8 mg, 0.657 mg). mmol, 87%); MS: m / e = 363.2 (M + H *). Example 2 fRS -1-f 5-hydroxy-2, 3-dihydro-benzofuran-2-ylmethyl-4-f 4-methyl-benzyl) -piperidin-4-ol) hydrochloride Hydrogenated (RS) -l- (5 -benzyloxy-2,3-dihydro-benzo-furan-2-ylmethyl) -4- (4-methyl-benzyl) -piperidin-4-ol (1.0 g, 2.2 mmol) in MeOH (100 mL) , it was hydrogenated with Pd / C (10%) (200mg) for a period of 17 hours at room temperature. Removal of the catalyst and evaporation gave a yellow foam (720 mg, 2.0 mmol, 92%). This material (618 mg), 1.75 mmol), was then dissolved in EtOH (20 ml) and treated with a 1.45 N HCl / EtOH solution (1.1 equivalents) at a temperature of 0-5 °. C, pair provide (RS) -1- (5-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl) -4- (4-methyl-benzyl) -piperidin-4-ol) hydrochloride, as a foam white / beige, mixture of E / Z isomers (679 mg cant.), M / S: m / e = 354.2 (M + H +). Following the procedure of Example 2, the compounds of Examples 3 to 12 Example 3 fRS) -1- 5-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl-4-f4-methoxy-benzyl were prepared. -piperidin-4-ol) hydrochloride The compound of the MS heading: m / e = 370.2 (M + H *) was prepared from (RS) -l- (5-benzyloxy-2,3-dihydro-benzo furan-2-ylmethyl) -4- (4-methoxy-benzyl) -piperidin-4-ol. Example 4 (RS) -4-benzyl-l-5-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl) -piperidin-4-ol hydrochloride The title compound MS: m / e = 340.2 (M + H *) was prepared from (RS) -4-benzyl-1- (5-benzyloxy-2,3-dihydro-benzofuran-2-ylmethyl) -piperidin-4-ol. Example 5 fRS -4-f 4- luoro-benzyl) -1-f 5-hydroxy-2 f3-dihydro-benzo-uran-2-ylmethyl-1-piperidin-4-ol hydrochloride The compound of the heading MS: m / e = 358, 2 (M + H *) was prepared from (RS) -4- (fluoro-benzyl) -l- (5-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl) -piperidin-4-ol.

Example 6 f RSl -4- 3, 4-dimethyl-benzyl) -l-fF-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl-piperidin-4-ol hydrochloride The title compound MS: m / e = 368.2 (M + H *), was prepared from (RS) -4- (3, 4-dimethyl-benzyl) -l- (5-benzyloxy-2,3-dihydro-benzofuran-2) -ylmethyl) -piperidin-4-ol Example 7 fRS) -4-f 4-ethyl-benzyl) -1-f5-hydroxy-2,3-dihydro-ben-zofuran-2-ylmethyl-1-piperidin-4-ol hydrochloride The compound of the heading MS: m / e = 368.2 (M + H *), was prepared from (RS) -4- (4-ethyl-benzyl) -l- (5-benzyloxy-2, 3- dihydro-benzofuran-2-ylmethyl) -piperidin-4-ol. Example 8 fRS1 -4- f 4-isopropy1-benzyl 1 -1-f 5-hydroxy-2,3-dihydro-benzo-uran-2-ylmethyl-1-piperidin-4-ol hydrochloride The title compound MS: m / e = 382.2 (M + H *), was prepared from (RS) -4- (4-isopropyl-benzyl) -l- (5-benzyloxy-2,3-dihydro-benzofuran-2-ylmethyl) -piperidin-4-ol. Example 9 (RS) -4- 2-methy1-benzyl) -1- f 5-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl) -piperidin-4-ol hydrochloride The compound of the heading MS: ra / e = 354.2 (M + H *), was prepared from (RS) -4- (2-methyl-benzyl) -l- (5-benzyloxy-2,3-dihydro-benzofuran-2-ylmethyl) - piperidin-4-ol. Example 10 RS) -4-f 2.4-Diluoro-benzyl) -l-5-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl) -piperidin-4-ol hydrochloride The title compound MS: m / e = 376.2 (M + H *), -. was prepared from (RS) -4- (2,4-difluoro-benzyl) -l- (5-benzyloxy-2,3-dihydro-benzofuran-2-ylmethyl) -piperidin-4-ol. Example 11 fRS) -4-f 4-trifluoromethoxy-benzyl-l-f 5-hydroxy-2,3-dihydro-benzof ran-2-ylmethyl) -piperidin-4-ol hydrochloride The compound of the heading MS: m / e = 424, 2 (M + H *), was prepared from (RS) -4- (4-trifluoro-methoxy-benzyl) -l- (5-benzyloxy-2,3-dihydro-benzofuran-2-ylmethyl) - piperidin-4-ol. Example 12 fRS1-4-f 3-trifluoromethoxy-benzyl) -1- f 5-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl) -piperidin-4-ol hydrochloride The title compound MS: m / e = 408, 2 (M + H *), was prepared from (RS) -4- (3-trifluoro-methoxy-benzyl) -l- (5-benzyloxy-2,3-dihydro-benzofuran-2-ylmethyl) -piperidine. -4-ol. Example 13 fSI-1-f5-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl-1-4-f-4-methyl-benzyl) -piperidin-4-ol hydrochloride (S) -1- (5-methoxy-2, 3 -dihydro-benzofuran-2-ylmethyl) -4- (methyl-benzyl) -piperidin-4-ol (2.10 g, 5.71 mol) dissolved in 50 ml of CH2C12, cooled to a temperature of -78" C and an ICM solution of BBr3-CH2C12 (12.5 ml, 2.2 eq.) Was added dropwise under argon, the beige suspension was allowed to warm to room temperature for 30 minutes and then stirred for an additional 1 hour, during which time a yellow resinous solid was deposited.To quench the reaction, then MeOH (10 ml) was added, followed by H20 (100 ml). and a saturated solution of NaHCO3 (25 ml); The mixture was then agitated in an intense manner for a period of 15 minutes. The organic phase was separated, a saturated solution of NaCl (100 ml) was then added to the aqueous phase and extracted with CH2C12 (2x50 ml). The combined organic extracts were dried with Na 2 SO 4, then filtered and evaporated. The resulting yellow foam was chromatographed on Si02 (Merck 230-400 raesh) eluting with CH2C12, followed by Me0H-CH2C12 (3:97), followed by MeOH-CH2C12 (7:93) (1.7 g, 4%). 81 mmol, 84% yield). Suspended (S) -l- (5-hydroxy-2,3-dihydro-benzofu-ran-2-ylmethyl) -4- (methyl-benzyl) -piperidin-4-ol (1.62 g, 4.58 mmol) in EtOH and treated with 1.1 equivalents of ethanolic HCl at a temperature of 0-5 ° C, providing (S) -l- (d-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl) -4- (4 -methyl-benzyl) -piperi-din-4-ol hydrochloride as white foam and mixture of E / Z isomers (1.74 g, 4.46 mmol, 97%) MS: m / e = 354.2 (M + H *) [a] 20 D + 57.8 ° (s = 1.0, EtOH). Following the general procedure of example 8, the compounds of examples 14 and 15 were prepared. Example 14 fS) -1-f5-hydroxy-2 r 3-dihydro-benzofuran-2-ylmethyl) -4- 4-chloro-benzyl ) -piperidin-4-ol hydrochloride The compound of the MS heading: m / e = 374.2 (M + H *), [a] 2 ° D = + 32.4 ° (c = 1.0, DMF) > 99% e.e. by HPLC (liquid chromatography, high efficiency) chiral phase, was prepared from (S) -l- (5-methoxy-2,3-dihydro-benzofuran-2-ylmethyl) -4- (chloro -benzyl) -piperidin-4-ol.

- -. Example 15 (Rl-1- 5 -hydroxy-2,3-dihydro-benzofuran-2-ylmethyl-1-4-f4-methyl-benzyl) -piperidin-4-ol hydrochloride The title compound, as a white foam and mixture of E-isomers / Z (1.64 g, 4.20 mmol, 100%) MS: m / e = 344.2 (M + H *), [a] 2 D = -58.0 ° (c = 1.0 , EtOH), was prepared from (R) -l- (5-methoxy-2,3-dihydro-benzofuran-2-ylmethyl) -4- (methyl-benzyl) -piperidin-4-ol. Example 16 (1RS.2RS) v LRS.2SR) -2-f4-hydroxy-4-f4-methyl-benzyl) -piperidin-1-ylmethyl-indan-1,5-diol fumarate. salt was prepared (collected) (1RS, 2RS) and (lRS, 2SR) -2-. { 4-benzyloxy-4- (4-methyl-bensyl) -piperidin-1-ylmethyl} Indan-1,5-diol (674 mg, 1.84 mmol) in EtOH (20 ml), and fumaric acid (106 mg, 0.92 mmol) was added and the mixture was stirred over a period of time 2 hours at room temperature; after evaporation of the solvent, (1RS, 2RS) and (1RS, 2SR) -2- (4-hydroxy-4- (4-methyl-1-benzyl) -piperidin-1-ylmethyl} -indan-1 was obtained. , 5-diol salt, of fumaric acid, as a white foam (0.78 g, quantity.), MS m / e = 368.2 (M + H *) Example 17 flRS.2RS1 and flRS.2SR) -2- (4-hydroxy-4-4-methyl-ben -yl) -piperidin-1-ylmethyl-indan-1, 5-diol A solution of (1RS, 2RS) and (1RS, 2SR) -2-. { 4-Benzyl-xi-4- (4-methyl-benzyl) -piperidin-1-ylmethyl} -indan-l, 5-diol (0.83 g, 1.82 mmol) in MeOH (100 mL) and 10% Pd / C (100 mg) was stirred vigorously under nitrogen atmosphere for 1 hour at room temperature. After removal of the catalyst and evaporation of the solvent, the title compound (1RS, 2RS) and (1RS, 2SR) -2- was obtained. { 4-hydroxy-4- (4-methyl-1-benzyl) -piperidin-1-ylmethyl} -indan-l, 5-diol (664 mg, 1.81 mmol, 99%), as a white amorphous foam, mixture (1:19) of diastereoisomers, MS me = 368.2 (M + H *) . Example 18 (RS) -1-f 5-hydroxy-indan-2-ylmethyl-4-methyl-4-methyl-benzyl) -piperidin-4-ol hydrosulphide (RS) -l- (5-hydroxy) indan-2-ylmethyl) -4- (4-methyl-benzyl) -piperidin-4-ol (177 mg, 0.503 mmol) in EtOH and ethanolic HCl (1.7 equivalents) was added; the product was precipitated after a lapse of 15 minutes by the addition of diethyl ether, while cooling to a temperature of 4 ° C. The product was obtained, as a white solid foam, (RS) -l- (5-hydroxy-indan-2-ylmethyl) -4- (4-methyl-benzyl) -piperidin-4-ol hydrochloride (95, 7 mg, 0.246 mmol, 49%), from a melting point of 88-90 ° C, MS m / e = 352.2 (M + H *). Example 19 fRS) -1-f 5-hydroxy-indan-2-ylmethyl) -4-f4-methy1-ben -yl) -piperidin-4-ol was stirred vigorously and under a hydrogen atmosphere, at room temperature and a course of 2 hours, a mixture of l- (6-hydroxy-lH-inden-2-ylmethyl) -4- (4-methyl-benzyl) -piperidin-4-ol (256 mg, 0.732 mmol) and 10% Pd / C (50 mg) in EtOAc (15 ml). Removal of the catalyst and evaporation of the solvent afforded (RS) -l- (5-hydroxy-indan-2-ylmethyl) -4- (4-methyl-benzyl) -piperidin-4-ol, as a colorless oil ( 235 mg, 0.667 mmol, 91%), MS m / e = 352.2 (M + H *). Example 20 1-f 6-hydroxy-lH-inden-2-ylmethyl-4-f 4-methyl-benzyl) -piperidin-4-ol A mixture of (1RS, 2RS) and (lRS, 2SR) -2 was heated -. { 4-hydroxy-4- (4-methyl-benzyl) -piperidin-1-ylmethyl} -indan-1, 5-diol (310 mg, 0.84 mmol) and ethanolic HCl (5 equivalents) in EtOAc (30 ml), at a temperature of 65 ° C, for a time of 1.5 hours. Distilled H20 (30 ml) and 10% NaHCO3 (30 ml) were added and the mixture was stirred; The aqueous phase was further extracted with EtOAc (2x20 ml) and the combined organic extracts were washed with a saturated solution of NaCl (30 ml), dried (Na2SO4) and filtered. Evaporation of the solvent gave l- (6-hydroxy-lH-inden-2-ylmethyl) -4- (4-methyl-benzyl) -piperidin-4-ol, as a beige solid (308 mg, 0.84 mmol, 100%) of a melting point of 154-157 ° C, MS m / e = 350.2 (M + H *). Example 21 fRS) -2- r 4-hydroxy-4-f 4-methyl-benzyl) -piperidin-1-ylmethyl1-2.3-dihydro-lH-indol-5-ol To the product (RS) -l- (5- methoxy-2,3-dihydro-lH-indol-2-ylmethyl) -4- (4-methyl-benzyl) -piperidin-4-ol (131 mg, 0.357 mol) in CH2C12 (10 ml), was added a solution BBr3-CH2C12 MM (2.14 ml, 2.74 mmol, 6 equivalents) at a temperature of -78 ° C, over a time course of 5 hours. minutes The reaction was stirred at room temperature for 48 hours and then MeOH (20 ml) was added, followed by 10% NaHC03 (20 ml) and the aqueous phase was extracted with water. CH2C12 (2x50 ml) and the combined extracts were washed with a saturated solution of NaCl (50 ml), dried over (Na2SO4), filtered and evaporated. Purification of the crude product with Si02 (Merck 230-400 mesh), eluting with CH2Cl2-MeOH (9: 1), provided (RS) -2- [4-hydroxy-4- (4-methyl-benzyl) -piperidin-1-ylmethyl] -2, 3-dihydro-lH-indole-5- ol, as a brown solid (64.6 mg), 0.183 mmol, 51%), from one to 10 melting point of 90-94 ° C, MS: m / e = 353.3 (M + H * ). EXAMPLE 22 fRS 1 -N- f 2- r 4-chloro-4-f 4-methy1-benzyl) -piperidin-1-ylmethyl-2,3-dihydrobenzofuran-5-yl-1-methanesulfonamide hydrochloride 15 (RS) - N- (2-bromomethyl-2,3-dihydro-benzofuran-5-yl) -methanesulfonamide (600 mg, 1.96 mmol), 4- (4-chloro-benyl) -piperidin-4-ol (514 mg, 1.96 mmol), Et3N (400 mg, *? 3.96 mmol) in DMF (50 ml) and heated to a temperature of 60 ° C, over a period of 90 hours. The DMF was then evaporated, the residue was dissolved in CH2C12 and washed with H2O. The organic phase was dried over Ma 2 S 4, and concentrated. The residue was chromatographed on Si2 (Merck 230-400 mesh), eluting with CH2C12-MeOH-NH40H (65: 10: 1), to give a beige foam, which was dissolved in 25 TFHF (50 ml) and treated with 1.2 N HCl (1 ml), to give (RS) -N- (2- [4-chloro-4- (4-methyl-benzyl) -piperidin-1-ylmethyl] -2 , 3-dihydrobenzofuran-5-yl) -methane sulfonamide hydrochloride, as a white foam and mixture of the E / Z isomers. MS: m / e = 451.3 (M + H *). Following the procedure of example 22, example 23 was prepared. Example 23 fRS) -Nf 2-f 4-hydroxy-4-f 4-methyl-benzyl) -piperidin-1-ylmethyl-2,3-dihydrobenzofuran-5-yl) -methane sulfonamide hydrochloride The title compound, MS: m / e = 431.5 (M + H *), was prepared from (RS) -N- (2-bromomethyl-2,3-dihydrobenzo-furan-5) -yl) -metanesulfonamide and 4- (4-methyl-benzyl) -piperidin-4-ol. Example 24 fRS) -1-f6-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl) -4-f 4-methyl-benzyl) -piperidin-4-ol hydrochloride (RS) -l- (6-methoxy-2 , 3-dihydro-benzofuran-2-ylmethyl) -4- (4-methyl-benzyl) -piperidin-4-ol (1.24 g, 3.37 mmol) dissolved in 35 ml of CH2C12, cooled to a temperature from -8 ° C and a solution of BBr3-CH2C12 (6.8 ml, 2 equivalents) was added dropwise under an argon atmosphere. The violet suspension was allowed to warm to room temperature and then stirred for 30 minutes. The reaction was then cooled to a temperature of 0 ° C and MeOH (9 ml) was added to quench the reaction, followed by saturated NaHCO 3 (50 ml). The organic phase was separated and the aqueous phase was extracted with CH2C12 (2x50 ml). The combined organic extracts were dried with NA2SO4 and then filtered and evaporated. The resulting yellow foam was chromatographed on Si02 (Merck 230-400 mesh), eluting with MeOH-CH2C12 (1:19), followed by MeOH-CH2C12 (1: 9), to give a yellow foam, which was dissolved in MeOH (5 ml) and treated with IN HCl (3.4 ml), to give (RS) -l- (6-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl) -4- (4-methyl-benzyl) -piperidin-4-ol hydrochloride (0.92 g, 70%), as a white solid and mixture of the E / Z isomers, of a melting point of 203-205 ° C MS: m / e = 354.3 (M + H *). Following the procedure of Example 24, the compound of Example 25 was prepared. Example 25 1-f 6-hydroxy-benzofuran-2-ylmethyl 1 -4-f 4-methy1-ben -yl) -piperidin-4-ol hydrochloride The title compound, with a melting point of 214 ° C and MS: m / e = 352.2 (M + H *), was prepared from l- (6-methoxy-benzofuran-2-ylmethyl) -4- (4-methyl-benzyl) -piperidin-4-ol. Example 26 fRS) -4-benzyl-l- f 6-hydroxy-chroman-2-ylmethyl) -pipe-ridin-4-ol hydrochloride (RS) -4-benzyl-1- (6-benzyloxy-chroman- 2-ylmethyl) -piperidin-4-ol (0.58 g, 1.31 mol) in EtOAc (30 ml) and 10% Pd / C (135 mg) was added; The mixture was placed under a hydrogen atmosphere and stirred vigorously for 17 hours at room temperature. Removal of the catalyst and chromatography on Si02 (Merck 230-400 mesh) CH2C12-Me0H-NH40H (100-5: 0, 25), gave a white foam (0.37 g, 1.04 mraol, 80%), which was taken up in EtOH (10 ml) and HCl / EtOH (1.1 equivalents) was added to a temperature of 0-5 ° C. Removal of the solvent gave (RS) -4-benzyl-1- (6-hydroxy-chroman-2-ylmethyl) -piperidin-4-ol hydrochloride (0.38 g, 0.98 mmol, 95%) , as a white foam, MS: m / e = 354.4 (M + H *). Example 27 f 1RS, 2RS) -! - (!, 6-dihydroxy-1,2,3,4-tetrahydro-naphtha-len-2-ylmethyl) -4- 4-methyl-benzyl) -piperidin-4-ol fumarate. salt was stirred (lRS, 2RS) -l- (1,6-dihydroxy-l, 2,3,4-tetrahydro-naphthalen-2-ylmethyl) -4- (4-methyl-benzyl) -piperidin-4 -ol (0.581 g, 1.53 mmol) in EtOH (20 ml) with fumaric acid (88 mg, 0.765 mmol, 0.5 equivalents) over a period of 2 hours, at room temperature. The mixture was then completely evaporated and evaporated and dried under high vacuum to give the title compound as an amorphous, white foam (0.66 g, qt) MS: m / e = 382.3 (M + H *). Example 28 f 1RS, 2RS) -1-f1.6-dihydroxy-l, 2,3,4-tetrahydro-naphtha-len-2-ylmethyl-1-4-f4-methyl-benzyl) -piperidin-4-ol was treated l- (1, 6-benzyloxy-l-dihydroxy-l, 2,3, 4-te-trahydro-naphthalen-2-ylmethyl) -4- (4-methyl-benzyl) -piperidin-4-ol (0.22 g , 0.46 mmol) in EtOAc (60 ml) with Pd / C (50 mg), and stirred for 6 hours, at room temperature, under nitrogen atmosphere. Removal of the catalyst and evaporation of the solvent afforded the title compound as a white foam (175 mg, qm) MS: m / e = 382.3 (M + H *).

EXAMPLE 29 Following the procedure of Example 28, the compound of Example 29 (1RS, 2RS) -2- (4-benzyl-4-hydroxy-piperidin-1-yl-methyl) -6-hydroxy-1 was prepared. , 2, 3.4-tetrahydro-naphthalene-1-ol The title compound was obtained as a white solid with a melting point of 94-98 ° C, MS: m / e = 368.4 (M + H *) , prepared from (lRS, 2RS) -2- (4-benzyl-4-hydroxy-piperidin-1-yl-methyl) -6-benzyloxy-l, 2,3,4-tetrahydro-naphthyl-ol. Example 30 fRS) -lf 6-hydroxy-l, 2,3,4-tetrahydro-naphthalen-2-ylmethyl) -4-f4-methyl-1-benzyl) -piperidin-4-ol hydrochloride To the product (RS) -l- (6-hydroxy-l, 2,3,4-tetrahydro-naphthalen-2-ylmethyl) -4- (4-methyl-benzyl) -piperidin-4-ol (500 mg, 1.36 mmol) in EtOH (4 ml), at a temperature of 4 ° C, ethanolic HCl (1.1 equivalents) was added. Evaporation of EtOH afforded the title compound as a white foam (530 mg, 1.32 mmol, 97%) MS: m / e = 366.2 (M + H *). EXAMPLE 31 fRSl -1-f 6-hydroxy-l .2.3.4-tetrahydro-naphthalen-2-ylmethyl-1-4-4-methyl-1-benzyl-1-piperidin-4-ol To the product (RS) -l- (6-methoxy -l, 2,3,4-tetrahydro-naphthalen-2-ylmethyl) -4- (4-methyl-benzyl) -piperidin-4-ol (843 mg, 2.22 mmol) in CH2C12 (20 mL), He added BBr3 / CH2C12 MM (488 ml, 4.88 mmol), 2.2 equivalents), over a period of 15 minutes, at a temperature of -78 ° C, then the mixture was allowed to warm to room temperature. u time course of 40 minutes. MeOH (3 ml), H20 (20 ml) and MaHC03 (20 ml) were added and the mixture was extracted with CH2C12 (4X50 ml). The extracts were washed with saturated NaCl solution (30 ml), dried (NaS04), filtered, and evaporated, to give the crude product as a yellow foam. Chromatography on Si02 (Merck 230-400 mesh), eluting with CH2C12-MeOH (97: 3), provided (RS) -1- (6-hydroxy-l, 2,3,4-tetrahydro-naphthalen-2-ylmethyl) ) -4- (-methyl-benzyl) -piperidin-4-ol, as a white foam (500 mg, 13.68 mmol, 61%) MS: m / e = 366.2 (M + H *) Example 32 fRS) -N-r6- 4-benzyl-4-hydroxy-piperidin-1-ylmethyl) -5-OXO-5 r6 f7.8-tetrahydronaphthalen-2-y1] -acetamide hydrochloride N- (5,6, 7,8-tetrahydro-5-oxo-2-naphthyl) acetamide (1.0 g, 4.92 mmol), 4- (encyl) -piperidin-4-ol hydrochloride (1.12 g, 4.92 mmol) , and parafomaldehyde (148 mg, 4.92 mmol), were heated together in DMF (50 ml), over a period of 4 hours, at a temperature of 80 ° C. The DMF was then evaporated and the residue was taken up in CH2C12 (50 ml) and washed with 10% NaHCO3 (25 ml); the aqueous phase was further extracted with CH2C12 (50 ml) and the combined extracts of CH2C12, dried (Na2SO4), filtered, and evaporated. The crude product was chromatographed on Si2 (Merck 230-400 mesh), eluting with CH2C12-MeOH-NH40H (110: 10: 1), affording 0.79 g of a yellow foam. This material was dissolved in EtOH, cooled to a temperature of 0-4 ° C, and ethanolic HCl (1.1 equivalents) was added, collecting and drying the precipitated solid color bank which was precipitated, to provide (RS) - N- [6- (benzyl-4-hydroxy-piperidin-1-ylmethyl) -5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl] -acetamide hydrochloride (639 mg, 1.44 mmol, 29%), from a melting point of 123-126 ° C, MS: m / e = 407.5 (M + H *). The N- (5,6,7,8-tetrahydro-2-naphthyl) acetamide was prepared according to the following literature: Biggs, D.F. and colleagues, J. Med. Chem, 19, 1976, 472-475; Allinger, N.L .; Jones, E.S., J, Org. Chem. 27, 1962, 70-76. Preparation of intermediates General preparation of the benzylpiperidine intermediates Example 33 f RS) -1- f 5-benzyloxy-2,3-dihydro-benzofuran-2-ylmethyl) -4-f4-methyl-benzyl) -piperidine- 4-ol (RS) -5-benzyloxy-2-bromomethyl-2,3-dihydro-benzofuran (840 mg, 2.63 mmol) and 4- (4-methyl-benzyl) -piperidin-4-ol (1, 08 g, 5.26 mmol), were suspended in toluene (20 ml) and heated to a temperature of 110 ° C for a period of 17 hours. The mixture was filtered and evaporated to give an orange oil, which was chromatographed on Si02 (Merck 230-400 mesh) with MeOH-CH2Cl2 (3:97) to give (RS) -1- (5- benzyloxy-2, 3-dihydro-benzofuran-2-ylmethyl) -4- (4-phenyl-benzyl) -piperidin-4-ol, as a yellow oil (1.03 g, 2.32 mmol), MS : m / e = 444.5 (M + H *). Preparation of intermediaries for examples 2-12 Following the general procedure of example 33, examples 34 to 43 were prepared. Example 34 1-f 5-benzyloxy-2,3-dihydro-benzofuran-2-ylmethyl-4-f 4-methoxy-benzyl) -piperidine- 4-ol The compound of the MS heading: m / e = 460.2 (M + H *), was prepared from 4- (4-methoxy-benzyl) -piperidin-4-ol and 5-benzyloxy-2- (RS) -bromomethyl-2, 3-dihydro-benzofuran. Example 35 (RS) 4-benzyl-lf 5-benzyloxy-2,3-dihydro-benzofuran-2-ylmethyl) -piperidin-4-ol The compound of the heading MS: m / e = 430.6 (M + H *), was prepared from 4- (encyl) -piperidin-4-ol and 5-benzyloxy-2- (RS) -bromomethyl-2,3-dihydro-benzofuran. Example 36 fRS) -4- 4-fluoro-benzyl) -1- 5-benzyloxy-2,3-dihydro-benzofuran-2-ylmethyl) -piperidin-4-ol The compound of the heading MS: m / e = 448.6 ( M + H *), was prepared from 4- (4-fluoro-benzyl) -piperidin-4-ol and 5-benzyloxy-2- (RS) -bromomethyl-2,3-dihydro-benzofuran. Example 37 fRS) -4-f 3 r 4-dimethyl-benzyl) -1-f 5-benzyloxy-2,3-dihydro-benzofuran-2-ylmethyl) -piperidin-4-ol The title compound MS: m / e = 458.6 (M + H *), was prepared from 4- (3,4-dimethyl-benzyl) -piperidin-4-ol and 5-benzyloxy-2- (RS) -bromomethyl-2,3 -dihydro-benzofuran.

Example 38 f RS 1 -4- 4-ethyl-benzyl) -l-5-benzyloxy-2, 3-dihydro-benzofuran-2-ylmethyl) -piperidin-4-ol The compound of the heading MS: m / e = 458 , 6 (M + H *), was prepared from 4- (4-ethyl-benzyl) -piperidin-4-ol and 5-benzyloxy-2- (RS) -bromomethyl-2,3-dihydro- benzofuran Example 39 fRS) -4-f 4-isopropyl-benzyl-1-f5-benzyloxy-2,3-dihydro-benzofuran-2-ylmethyl-1-piperidin-4-ol The compound of the MS heading: m / e = 472.6 (M + H *), was prepared from 4- (4-isopropyl-benzyl) -piperidin-4-ol and 5-benzyloxy-2- (RS) -bromomethyl-2,3-dihydro-benzofuran. Example 40 fRSl-4- S-methyl-benzyl-lf 5-benzyloxy-2,3-dihydro-benzofuran-2-ylmethyl) -piperidin-4-ol The title compound MS: m / e = 444.6 (M + H *), was prepared from 4- (2-methyl-benzyl) -piperidin-4-ol and 5-benzyloxy-2- (RS) -bromomethyl-2,3-dihydro-benzofuran. Example 41 f RS) -4-f 2,4-difluoro-benzyl) -1-f 5-benzyloxy-2,3-dihydro-benzofuran-2-ylmethyl) -piperidin-4-ol The compound of the heading MS: m / e = 486 , 6 (M + H *), was prepared from 4- (2,4-diluoro-benzyl) -piperidin-4-ol and 5-benzyloxy-2- (RS) -bromomethyl-2,3-dihydro- benzofuran Example 42 fRS) -4- f 4-trifluoromethoxy-benzyl) -1- f 5-benzyloxy-2,3-dihydro-benzofuran-2-ylmethyl) -piperidin-4-ol The compound of the heading MS: m / e = 514, 6 (M + H *), was prepared from 4- (4-trifluoromethoxy-benzyl) -piperidin-4-ol and 5-benzyloxy-2- (RS) -bromomethyl-2,3-dihydro-benzofuran. Example 43 (RS) -4-f 3-trifluoromethyl-benzyl) -if-5-benzyloxy-2-f 3-dihydro-benzofuran-2-ylmethyl) -piperidin-4-ol The compound of the heading MS: m / e = 498 , 6 (M + H *), was prepared from 4- (3-trifluoromethyl-benzyl) -piperidin-4-ol and 5-benzyloxy-2- (RS) -bromomethyl-2,3-dihydro-benzofuran. Example 44 fRS) -5-benzyloxy-2-phromomethyl-2,3-dihydro-benzofu-rano Suspended (RS- (4-benzyloxy-2- (2,3-dibromo-pro-pyl) -phenyl ester of acetic acid (5, 05 g, 11.3 mmol) in EtOH (50 ml) and sodium methoxide (620 mg, 11.3 mmol) was added and the mixture was stirred for 2 hours at room temperature. Then, distilled H20 was added (100 mL) and CH2C12 (100 mL) and, the organic phase, separated. The aqueous phase was extracted with CH2C12 (100 ml) and the combined organic extracts were dried with a saturated solution of NaCl (100 ml). After drying with Na 2 SO 4, and drying and evaporation, a yellow oil was obtained, which was chromatographed on SiO 2 (Merck 230-400 mesh), with CH 2 C 12, to give 5-benzyloxy-2- ( RS) -broraometi1-2, 3-dihydro-benzofuran, as a yellow oil (3.0 g, 9.39 mmol, 83%) MS: m / e = 318.0 (M *).

Example 45 fRS) -4-benzyloxy-2- f 2,3-dibromo-propyl) -phenyl ester of acetic acid To a solution of 2-allyl-4-bensyloxy-phenyl ester of acetic acid (3.30 g, , 7 mmol) in CC14 (30 ml) at a temperature of 0-5 ° C, bromine (0, 6 ml), 11.7 mmol), over a period of 10 minutes and the resulting mixture was stirred for 1 hour at 5-10 ° C. To quench the reaction, a solution of Na 2 C 3 (10%, 4 ml) and distilled H 2 O (10 ml) was added. The organic phase was separated, dried with Na 2 SO 4 and then evaporated to give a colorless oil which crystallized to give standing (RS) -4-benzyloxy-2- (2,3-dibromo-propyl) phenyl acetic acid ester (5.05 g, 11.4 mmol, 97%), melting point 71-74 ° C, MS: m / e = 440.0 (M *). EXAMPLE 46 2-Allyl-4-benzyloxy-phenyl-ester of acetic acid 2 Allyl-4-benzyloxy-phenol (2.87 g, 12 mmol) was taken up in acetic anhydride (40 ml) and NaOAc (150 mg. 1.8 mmol) and, the mixture was heated for a period of 18 hours, at a temperature of 80 ° C. After cooling, the reaction mixture was evaporated to give an oil which was partitioned between EtOAc and H20 (100 mL) and, the aqueous phase, extracted with EtOAc (100 mL) and, the combined organic phases, dried with MgSO4, filtered and evaporated, to give 2-allyl-4-benzyloxy-phenyl -acetic acid ester, as a pale yellow oil (3.30 g, 11.7 mmol), 97%), MS: m / e = 282.1 (M *).

- -. Example 47 2-Allyl-4-benzyloxy-phenol-l-benzyloxy-4-allyloxy-benzene (20.4 g, 84.9 mmol) dissolved in estylene (150 ml), heated at a temperature of 165 ° C for a period of Time course of 48 hours, under argon atmosphere. After cooling to room temperature, the resulting brown oil was chromatographed on Si02 (Merck 230-400 mesh), eluting with EtOAc-n-hexpr.o (1: 9), to give 2-allyl-4-benzyloxy. -phenol (17.45 g, 72.6 mmol, 85%), as a pale yellow oil MS m / e = 240.1) (M *). Example 48 l-benzyloxy-4-allyloxy-benzene 4-benzyloxyphenol (20 g, 100 mmol), K2CO3 (20.8 g, 150 mmol) and allyl bromide (12.7 mL, 150 mmol) were heated to reflux in reflux. acetone (200 ml), over a period of 18 hours. After filtration and evaporation of the solvent, l-benzyloxy-4-allyloxy-benzene (23.8 g, 99 ramol, 99%) was given as a beige solid, with a melting point of 56-57 ° C. , MS m / e = 240.1 (M *). Example 49 fS) -l-5-methoxy-2,3-dihydro-benzofuran-2-ylmethyl) -4-f4-methyl-benzyl) -piperidin-4-ol (S) -5-methoxy was suspended. 2,3-dihydro-benzofuran-2-ylmethyl-ester of toluenesulfonic acid (2.30 g, 6.88 ramol) and (4-methyl-benzyl) -piperidin-4-ol (1.62 g, 7.9 mmol) and Na2CO3 (1.10 g, 10.3 mmol) in DMF, and heated to a temperature of 110 ° C, for a period of time of 1 hour. After cooling to room temperature, distilled H20 and EtOAc (100 ml) were added and the mixture was stirred, the organic phase was separated and the acid phase was extracted with EtOAc (10 ml). The combined organic extracts were then washed with saturated NaCl solution (100 ml) and the organic phase was dried with Na 2 SO 4, filtered and evaporated to give a yellow oil. This foam was chromatographed on Si02 (Merck 230-400 mesh) with CH2C12 and then with CH2C12-MeOH (97: 3) to give (S) -l- (5-methoxy-2,3-dihydro- benzofuran-2-ylmethyl) -4- (4-methyl-benzylo) -piperidin-4-ol (2.20 g, 6.0 mmol, 87% yield), as a yellow oil MS: m / e = 368.2 (M + H *) [a] 20 D = + 45.8 (c = 1.0, CHC13). Following the general procedure of Example 49, Example 50 was prepared. Example 50 fS) -1- 5-methoxy-2,3-dihydro-benzofuran-2-ylmethyl) -4-f 4-chloro-benzyl) -piperidin-4- The compound of the heading MS was prepared: m / e = 387.9 (M + H *), from 4- (4-chloro-benzyl) -piperidin-4-ol and (S) -5-methoxy- 2,3-Dihydro-benzofuran-2-ylmethyl-ester of toluenesulfonic acid. Example 51 fS) -5-methoxy-2,3-dihydro-benzofuran-2-ylmethyl ester of toluenesulfonic acid A solution of (S) -5-methoxy-2,3-dihydro-benzofuran-2-carboxylic acid (2) was added. , 4 g, 12.4 mmol) in THF (30 ml) was added to a suspension of LIA1H4 (0.71 g, 18.5 mmol) in THF (20 ml) by dripping, over a period of 15 minutes, proceeding to cool simultaneously. The mixture was then heated to reflux for 1 hour and, after cooling, distilled H20 (0.7 ml) was added, followed by 4N NaOH (1.4 ml), and distilled H20 ( 2.1 ml). The whole mixture was dried over NaSO 4, filtered, and evaporated to give a slightly yellowish oil (220 g, 12.2 mmol). This oil was dissolved in pyridine (22 ml) and p-toluene-sulfonyl chloride (3.48 g, 18.3 mmol) was added and the mixture was stirred at room temperature for 1 hour. . H20 was added to the crude mixture and stirred vigorously for a period of 10 minutes; extraction with EtOAc (2x100 ml) and washing of the organic phase with 2 N HCl (150 ml), followed by saturated NaCl (100 ml), drying with Na 2 SO 4 and evaporation, gave a red oil. This oil was chromatographed on Si02 (Merck 230-400 mesh) with cyclohexane-EtOAc (4: 1) and, to provide (S) -5-methoxy-2,3-dihydro-benzofuran-2-ylmethyl) -ester toluenesulfonic acid (2.4 g, 7.2 mmol, 57% yield), as a white solid, of a melting point of 82-84 ° C MS: m / e = 334.1 (M *) [ a] 2 ° D = + 75.1 (c = 1.0, CHC13). Example 52 fS 1 -5-Methoxy-2,3-dihydro-benzofuran-2-carboxylic acid To a solution of R (+) - 1 - (naphthyl) ethylamine (3.80 g, 22.2 mmol) in acetone (40 g). ml), (RS) -5-methoxy-2,3-dihydro-benzofuran-2-carboxylic acid (4.1 g, 21.1 mmol) in acetone (80 ml) was added.; after stirring for 2-3 minutes at room temperature, a beige solid precipitated, the mixture was cooled to 0-5 ° C, and stirred for 30 minutes. The solid was filtered and washed with cold acetone (4 ° C) (3x20 ml) to give 6 g crystals of melting point 183-190 ° C. This solid was recrystallized twice from cold EtOH (60 ml) to give 4.0 g of white crystals, melting at 190-194 ° C. This material was suspended in EtOAc (100 ml). and washed with IN HCl (50 ml), the acidic aqueous phase, extracted with EtOAc (50 ml), the combined organic extracts were then washed with distilled H20 (50 ml) and then Na2SO4, and evaporated , to provide (S) -5-methoxy-2,3-dihydro-benzofuran-2-carboxylic acid (2.3 g, 11.8 mmol, 77%), as a pale yellow crystalline solid, from a melting at 85-87 ° C MS: m / e = 194.2 (M *) [a] 2 D = -9.2 (c = 1, 0, EtOH) Example 53 fRS1-5-methoxy acid -2.3-dihydro-benzofuran-2-carbo-xylic To a suspension of 5-methoxy-benzofuran-2-carboxylic acid (14 g, 72.8 mmol) in MeOH (600 mL), portions of magnesium (10, 6 g, 437 mmol) and the mixture was stirred vigorously by mechanical means for a period of time of 2 hours, keeping the temperature at a value below 3? "C. After a lapse of 2 hours, magnesium (10.6 g, 437 mmol) was further added and the mixture was stirred additionally for a further 4 hours, maintaining the temperature at a value below 30 ° C. After a lapse of 6 hours, the mixture was concentrated to -100 ml, and distilled H20 (600 ml) was added and the pH was adjusted to a value of 1-2, with sulfuric acid IN. The crude mixture was extracted with EtOAc (2x300 ml) and the combined extracts were washed with H20 (200 ml). The combined organic phase was dried with Na 2 SO 4, filtered, and evaporated to give a yellowish solid, which was recrystallized from hot toluene (100 ml) to provide white crystals (9.2 g, 47%). 4 mmol, 65%), from a melting point of 98-100 ° C, MS; m / e = 194.1 (M *). Following the general procedure of Example 49, the compound of Example 54 was prepared. Example 54 fRS) -1-f 5-methoxy-2,3-dihydro-benzofuran-2-ylmethyl) -4-f4-methyl-benzyl) - piperidin-4-ol The title compound (2.40 g, 6.53 mmol, 76% yield) was prepared as a yellow oil MS: m / e = 368.2 (M + H *) [ ct] 2 ° D = - 44.0 ° (c = 1.0, CHC13) was prepared, from (R) -5-methoxy-2,3-dihydro-benzofuran-2-ylmethyl-ester of toluenesulfonic acid . Following the general procedure of Example 51, the compound of Example 55 was prepared. Example 55 fR) -5-Methoxy-2f 3-dihydro-benzofuran-2-ylmethyl-ester of toluenesulfonic acid The title compound was prepared (3 g, 9.0 mmol, 67% yield), as a white solid, with a melting point of 82-84 ° C, MS: m / e = 334.1 (M *) [a] 20D = - 74 , 9 ° (c = 1, 0, CHC13) > 99% e.e., by HPLC of chiral phase, from (R) -5-methoxy-2,3-dihydro-benzofu-ran-2-carboxylic acid. Example 56 Acid fR) -5-methoxy-2,3-dihydro-benzofuruan-2-fR -carboxylic acid To a solution of S (-) - l- (naphthyl) ethylamine (7.21 g, 41.6 mmol) in acetone ( 80 ml), (RS) -5-metho-xi-2,3-dihydro-benzofuran-2-sarboxylic acid (7.70 g, 39.4 mmol) was added in acetone (150 ml); After 2-3 minutes of stirring at room temperature, a beige solid was precipitated, the mixture was cooled to a temperature of 0-5 ° C and stirred for an additional 30 minutes. The solid was filtered, and this was washed with cold acetone (4 ° C) (3x20 ml), to give white crystals, (9.90 g), of a melting point of 145-160 ° C. This solid was recrystallized twice from hot EtOH (125 ml) to give 4.75 g of white crystals with a melting point of 185-194 ° C. This material, was suspended in EtOAc (100 ml), and washed with IN HCl (50 ml), the acidic aqueous phase was extracted with EtOAc (50 ml) and the combined organic extracts were then washed with distilled H20 (50 ml), and then dried with Na2SO4, and evaporated, to provide (R) -5-methoxy-2,3-dihydro-benzofuran-2-carboxylic acid (2.5 g, 12.9 mmol, 65%), as a pale yellow crystalline solid, with a melting point of 85-87 ° C, MS: m / e = 194.1 (M *) [a] 2 ° D = + 9.8 ° (c = 1, 0, EtOH).

. Example 57 Mixture of flRS.2RS1 and f 1RS) .2SR1-2-f 4-benzyloxy-4-f4-methyl-benzyl) -piperidin-1-ylmethyl 1-indan-1,5-diol 5-benzyloxy was heated -indan-l-one (2.38 g, 10 mmol), 4- (4-methyl-benzyl) -pipereidin-4-ol hydrochloride (2.41 g, 10 mmol), and paraformaldehyde (0.3 g, 10 mmol) in DMF (20 ml), at a temperature of 70 ° C, for a period of 20 hours. After cooling, EtOAs (150 ml), distilled H20 (200 ml) and 25% NH40H (4 ml) were added and the mixture was stirred. Then, the aqueous phase is further extracted are EtOAc (150 mol) and, the combined organic extracts, washed with saturated NaCl (2x100 ml) and dried with Na 2 SO 4 (40 ml), giving a yellow oil, after evaporation. This oil was dissolved in THF (40 ml) and added, over a period of 30 minutes, to a suspension of LY1H4 (1.87 g, 50 mmol, 5 equivalents) in THF (50 ml), using a cooling based on ice (5-15 ° C). The mixture was then left under stirring for an additional 2 hours at room temperature, the reaction then being quenched by the addition of distilled H20 (2 ml), 4N NaOH (4 ml), then H20 (4 ml), and stirred vigorously for 15 minutes. The whole mixture was dried then Na2SO4, filtered, washed with THF and evaporated to give a viscous-looking oil. The crude product was chromatographed on SI02 (Merck 230-400 mesh), eluting with CH2C12-Me0H (97: 3) and then CH2C12-MeOH (9: 1), to provide a white foam, which was obtained. I can recrystallize from EtOAc-Et20, providing (1RS, 2RS) and (1RS), 2SR) -2- [4-benzyloxy-4- (4-methyl-1-benzyl) -piperidin-1-ylmethyl] -indan-1 , 5-diol, as white crystals (1.89g, 4.13mmol, 41%), from a melting point of 131-132 ° C, MS m / e = 458.4 (M + H *) . Example 58 5-benzyloxy-indan-1-one A mixture of 5-hydroxy-indan-1-one (5.3 g, 35.5 mmol), KJ (0.6 g, 3.6 mmol) was heated in K2C03 (6.17 g, 44.6 mmol) and benzyl bromide (4.66 mL, 39.3 mmol) in DMF (50 mL), at a temperature of 100 ° C, over a period of 1 hour . Addition of H20 (150 ml) and extraction with RtOAc (3x30 ml), washing of the organic phase with saturated NaCl solution (100 ml), and drying with MgSO 4, and evaporation, gave a brown solid. This material was recrystallized twice from EtOH to give 5-benzyloxy-indan-1-one (6 g, 25.17 mmol, 70%), as yellow crystals, of a melting point of 105.degree. 106 ° C, MS m / e = 238.1 (M +). Example 59 5-hydroxy-indan-1-one 5-methoxy-indan-1-one (8 g, 49.3 mmol), and sodium salt of 4-tert.-butyl-2-methyl-benzenethiol ( 11.92 g, 59.2 mmol), at a temperature of 142 ° C, for a period of 1 hour, under an argon atmosphere. After being cooled to room temperature, water (80 ml) was added, followed by IN HCl (80 ml) and EtOAc (120 ml). The mixture was stirred and, the aqueous phase was extracted with EtOAc (100 ml), the combined organic extracts were washed with a saturated solution of NaCl (100 ml), and dried with Na 2 SO 4, filtered, and they evaporated. The residue was chromatographed on Si02 (Merck 230-400 mesh), eluting with EtOAc-octane (2: 3), yielding 5-hydroxy-indan-1-one (3.55 g, 22.6 mmol, 45.9 %), as orange crystals, with a melting point of 185-187 ° C, MS m / e = 148.2) (M *). Example 60 fRS) -1-f 5-methoxy-2 f 3-dihydro-lH-indol-2-ylmethyl) -4-f 4-methyl-benzyl) -piperidin-4-ol To a solution of (RS) - l- (5-methoxy-1- (toluene-4-sulfonyl) -2,3-dihydro-lH-indol-2-ylmethyl) -4- (4-methyl-benzyl) -piperidin-4-ol (300 g , 0.576 mmol) in toluene, sodium hydride and bis (2-methoxy-ethoxy) -aluminium hydride (3.5 M in THF) (0.66 ml, 2.31 mmol) were added thereto, and the mixture was added. refluxed for 18 hours. After cooling, 2N NaOH was added to a pH of 14, the mixture was extracted with EtOAc (3x25 ml) and the combined organic extracts were washed with a saturated solution of NaCl (25 ml) and dried (Na 2 SO 4). ), and then filtered and evaporated. The residue was chromatographed on Si02 (Merck 230-400 mesh), eluting with EtOAc-cyclohexane-Et3N (9: 10: 1), to give (RS) -1- (5-methoxy-2,3-dihydro-1H) -indol-2-ylmethyl) -4- (4-methyl-benzyl) -piperidin-4-ol, as a viscous, yellow-colored oil (158.4 mg, 0.433 mmol, 75%), MS m / e = 367.3) (M + H *).

- - Example 61 fRS) -1-r 5-methoxy-l-ftoluene-4-sulfonyl) -2,3-dihydro-l-indol-2-ylmethyl] -4- 4-methyl-benzyl) -Piperidin-4-ol Heating (RS) -5-methoxy-1- (toluene-4-sulfonyl) -2,3-dihydro-1H-indol-2-ylmethyl ester of toluene-4-sulfonic acid (200 mg) was carried out. , 0.41 mmol) and 4- (4-methyl-benzyl) -piperidin-4-ol (337 g, 1.64 mmol) in mesitylene (10 ml), over a period of 20 hours, at a temperature of 140 ° C. After cooling, 4H-CHCl was added to a pH of 1, and the mixture was extracted with EtOAc (3x25 ml) and the extracts were dried (Na2SO4), then filtered and evaporated. Purification of the crude material on Si02 (Merck 230-400 mesh), eluting with EtOAc-cyclohexane-Et3N (9: 10: 1), gave the title compound, as a yellow solid 15 (155.9 mg , 0.3 mmol, 73%), MS: m / e = 521.4 (M + H *). Example 62.sup.-fRS) -5-methoxy-1-ftoluene-4-sulfonyl) -2.3-dihydro-1H-indol-2-yl-ethyl ester of toluene-4-sulfonic acid. The mixture was stirred (RS) - 5-methoxy-2,3-dihydro-lH-indol-2-yl) -methanol, (100 mg, 0.46 mmol), p-toluenesulfonyl chloride (177 mg, 0.93 mmol), triethylamine, (0.21 ml, 1.48 mmol) and N, N-dimethylamino-pyridine (2 mg), over a period of 18 hours, at room temperature, in CH2C12 (25 ml). C1H IN (10 mL) was added, the mixture was extracted with CH2C12 (2x25 mL) and the extracts were washed with a solution of NaCl (20 mL) and dried (Na2SO4). The crude material was chromatographed on Si02 (Merck 230-400 mesh), eluting with EtOAc-epigraph, as a yellow oil (172.8 mg, 0.35 mmol, 76%), MS: m / e = 488, 0 (M + H *). Example 63 fRS-f 5-methoxy-2,3-dihydro-lH-indol-2-yl) -methanol. (RS) -5-methoxy-2,3-dihydro-1H methyl ester was added dropwise. -indole-2-carboxylic acid (2.5 g, 12.06 mmol) in THF (130 ml), to a suspension of LIA1H4 in THF (80 ml) at a temperature of 4 ° C and, the mixture was left in stirring regime, at room temperature, overnight and then heated to a temperature of 65 ° C, for a time course of 4 hours. After cooling, H20 (20 ml) was added cautiously and the mixture was stirred for 20 minutes, then filtered and the filtration product was extracted with water.

EtOAc (3x50 ml), the extracts were washed with a saturated solution of NaCl (50 ml), dried (Na2SO4), filtered, and evaporated. The crude oil was chromatographed on Si02 (Merck 230-400 mesh), eluting with CH2C12-Me0H (9: 1), yielding (RS) - (5-methoxy-2,3-dihydro-lH-indol-2-yl) -methanol, as a yellow oil (1.41 mg, 7.86 mmol, 65%), MS: m / e = 179.1 (M *). Example 64 fRS) -5-methoxy-2,3-dihydro-l-indole-2-carboxylic acid methyl ester To 5-methoxy-lH-indole-2-carboxylic acid ethyl ester (5 g, 22, 8 mmol) in MeOH (150 ml), portions of magnesium (2.2 g, 91.6 mmol, 4 equivalents) were added and the mixture was stirred vigorously in a mechanical manner (10- ^ 30 ° C). ), over a period of 2 hours. 4N HCl (to a pH of 1-2), then 25% NH40H (to a pH of 7) was added and the mixture was extracted with EtOAc (4x100 5 mL). The combined extracts were then washed with saturated NaCl solution (50 ml), dried (Na2SO4), filtered, and evaporated. The crude oil, green in color, was chromatographed on Si02 (Merck 230-400 mesh), elution being EtOAc-nHexane (1: 3), to give the compound of epí-9 10 grafe (3.21 g, 15.5 mmol, 68%), as a yellow solid with a melting point of 59-61 ° C, MS: m / e = 207.1 (M *). EXAMPLE 65 Ethyl ester of 5-methoxy-1H-indole-2-carboxylic acid. 5-Methoxy-1H-indole-2-carboxylic acid (10 g, 52.3 mmol) in EtOH was heated to reflux. 400 ml) containing 36% H2SO4 (7 ml), over a period of 18 hours. After cooling, the mixture was neutralized with NaOH 2N (up to a pH of 7), and extracted with ETOAc (3x150 ml), the combined 20 extracts were washed with 10% NAHC03 (2x25 ml), dried (MgSO4), filtered, and evaporated, to provide 5-methoxy-1H-indole-2-carboxylic acid ethyl ester, as a brown solid (9.52 g, 43.3 mmol), 82%), with a melting point of 154-155 °. C, MS: m / e = 219.1 25 (M *).

Preparation of the intermediates for examples 22 and 23 Example 66 f RS) -N- f 2-bromomethyl-2,3-dihydro-benzofuran-5-yl) -methanesulfonamide (RS) -2-bromomethyl-2,3-dihydro-benzofuran -5-ilamine (410 g, 1.80 mmol), matansulfonyl chloride (206 mg, 1.8 mmol), Rt3N (182 mg, 1.80 mmol), were dissolved in CH2C12 (50 mL) and stirred for overnight at room temperature. The solvent was evaporated and the residue was chromatographed on Si02 (Merck 230-400 mesh), eluting with CH2C12-Me? H (95: 5), to give (RS) -N- (2-bromoraethyl-2,3 -dihydro-benzofuran-5-yl) -methansulfonamide (516 mg, 94%), as an oil. MS: m / e = 305.9 (M *). Following the procedure described in the example 44, (RS) -2-bromomethyl-2,3-dihydro-benzofuran-5-yl-amine was prepared. Preparation of the intermediates for Examples 24 and 25 Example 67 fRS) -l-f6-Ratoxy-2-phenyl-3-dihydro-benzo-uran-2-ylmethyl) -4-f-4-methyl-1-benzyl) -piperidin-4-ol (RS) -6-methoxy-2,3-dihydro-benzofru-ran-2-ylmethyl ester of the toluene-4-sulfoniso acid (110 mg, 0.33 mmol) and 4- (4-methyl-bensyl) were dissolved. ) -piperidin-4-ol (148 g, 0.72 mmol) in DMF (3 ml), and was heated to a temperature of 130 ° C, during a 1 hour transport time. The DMF was evaporated, the residue was dissolved in CH2C12 (5 ml), and washed with H20 (5 ml). The organic phase was dried over Na2SO4 and concentrated. The residue was chromatographed on Si02 (Merck 230-400 mesh), eluting with CH2C12-MeOH (19: 1), to give (RS) -1- (6-methoxy-2,3-dihydro-benzofuran-2-ylmethyl) ) -4- (4-methyl-benzyl) -piperidin-4-ol (80 mg, 66%), as a yellow solor oil, MS: m / e = 368.4 (M + H *). Example 68 fRS) -6-methoxy-2-r 3-dihydro-benzofuran-2-ylmethyl-dihydroxy-4-sulphonic acid To a solvation of (RS) - (6-methoxy-2,3-dihydro- benzo-furan-2-yl) -methanol (0.09 g, 0.5 mmol), Et 3 N (0.1 mL, 0.75 mmol), DMAP (1 mg, 0.01 mmsl) in CH 2 Cl 12 (1, 5 ml), at a temperature of 0 ° C, a solution of paratoluenesulfonic chloride (115 mg, 0.6 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature, and was stirred for a transsurface of 4 hours, before the addition of H20 (2 ml). The aqueous phase was extracted with CH2C12 (2x5 ml). The combined organic phases were dried over Na2SO4, and concentrated. The residue was chromatographed on Si02 (Merck 230-400 mesh), eluting with n-hexane-EtOAc (4: 1), to give (RS) -6-methoxy-2,3-dihydro-benzofuran-2-ylmethyl- ester, of toluene-4-sulfoniso acid (120 mg, 72%), is a colorless oil, MS: m / e = 334 (M *). Example 69 1-f 6-methoxy-benzofuran-2-ylmethyl-1-4-f4-methyl-ben-sil) -piperidin-4-ol To a solution of 6-ratoxy-2-benzofuran-methanol (89 mg, 0.5 mmol ) in dioxane (3 ml), at room temperature - added - by dripping, SOC12 (0.11 ml, 1.5 mmol). After a lapse of time of 1.5 hours, the retractive mixture was concentrated at room temperature, under the application of high vacuum. The residue was dissolved in dioxane (3 ml) and treated with 4- (4-methyl-benzyl) -piperidin-4-ol (225 mg, 1.1 mmol). After proceeding to stir during a transsurface of 17 hours at room temperature, the solvent was evaporated. The residue was taken up in H20 (4 ml) and extracted with CH2C12 (6x4 ml). The combined organic phases were dried over Na 2 S 4, and concentrated. The residue was chromatographed on Si02 (Merck 230-400 mesh), eluting with CH2-MeOH (19: 1), to give 1- (6-methoxy-benzofuran-2-ylmethyl) -4- (4-methyl-ben -sil) -piperidin-4-ol (140 mg, 77%), as a yellow solor, MS: m / e = 366.3 (M + H *). Example 70 fRS) -f 6-methoxy-2,3-dihydro-benzofuran-2-yl) -methanol A solution of (RS) -6-methoxy-2,3-dihydro-ben-zofuran-2-sarboxylyl (158 mg) , 0.813 mmol) in THF (2 ml) was added, dropwise, to a suspension at 0 ° C of the temperature of LY1H4 (31 mg, 0.813 mmol) in THF (2 ml) After 30 minutes of stirring at a temperature of 0 ° C, the retractive mixture was refluxed for a 30-minute time delay, the retractive mixture was cooled to 0 ° C and treated successively as H20 (0 ° C)., 05 ml), 5 N NaOH (0.05 ml), H20 (0.15 ml). After stirring during a 20 minute time course at room temperature, EtOAs were added, followed by Na 2 SO 4. The solid of this obtained form was filtered and, the product of the filtration, evaporated. The residue was chromatographed on Si02 (Merck 230-400 mesh), eluting with n-hexane-EtOac (4: 1), to give (RS) - (6-methoxy-2,3-dihydro-benzofuran-2-yl) ) -methanol (102 mg, 70%), as a colorless oil, MS: m / e = 180 (M *). Following the procedure of example 70, Example 71 was prepared. Example 71 6-methoxy-2-benzofuranmethanol The title compound MS was prepared: m / e = 178 (M *), from 6-methoxy-2- acid benzofurancarboxyl. Following the procedure of example 53, the compound of example 72 was prepared. Example 72 Acid RS) -6-methoxy-2 f 3-dihydro-benzofuran-2-sarbo-xylyl The title substance was prepared from a melting point from 108-110 ° C MS: m / e = 194 (M *), from 6-methoxy-2-benzofuransarboxyl acid. The 6-methoxy-benzofuransarboxyl acid was prepared according to the following literature: S. Tanaca, J. Arm. Chem. Soc. 73., 1951, 872 Example 73 fRS) -4-benzyl-l-f6-bensyloxy-chroman-2-ylmethyl) -pipe-ridin-4-ol They were refluxed (RS) -6-benzyloxy -2-bromome-tyl-sroman (0.52 g, 1.56 mmol) and 4 (bensyl) -piperidin-4-ol (0.66 g, 3.43 mmol) in toluene (20 ml), for a period of time course of 18 hours, under argon atmosphere. After removal of the solvent, the crude mixture was chromatographed on Si02 (Merck 230-400 mesh) CH2Cl2-Me0H-NH40H (100: 5: 0.25), to give the title compound (RS) -4-benzyl- 1- (6-benzyloxy-chroman-2-yl-methyl) -piperidin-4-ol, as a yellow oil (0.6 g, 1.35 mmol 86%), MS: m / e = 444, 5 M + H *). Example 74 fRS) -6-benzyloxy-2-bromomethyl-chroman (RS) -6-benzyloxy- (sroman-2-yl) -methanol (0.97 g, 3.58 mmol) and 1,1'-carbonyldiimidazole ( 0.58 g, 3.58 mmol), and allyl bromide (19.9 mmol), were removed in asetonitrile at a temperature of 80 ° C, during a transsurface of time of 4 hours. The crude mixture was evaporated continuously until dried and chromatographed on Si02 (Merck 230-400 mesh), eluting with CH2C12. This yielded (RS) -6-benzyloxy-2-bromo-methyl-sroman (0.28 g, 0.84 mmol), as a solid from solid, with a melting point of 61-63 ° C, MS m / e = 332.0 (M *). Example 75 fRS) -6-benzyloxy- (chroman-2-yl) -methanol To a stirred suspension of LYALH4 (0.352 g, 9.26 mmol) in THF, at a temperature of 10 ° C, a solids addition was added. (RS) -6-hydroxy-sroman-2-sarboxylyl in THF (25 ml), in a 15-minute time course. After allowing to settle to room temperature, 4 N HCl (25 ml) and EtOAs (100 ml) were added and the mixture was agitated. The aqueous phase was extracted with EtOAc (100 ml) and the combined organic extracts were washed with a saturated solution of NaCl (50 ml), dried over Na 2 SO 4 and evaporated. The resulting solid was taken up in acetone (50 ml) and then K2C03 (0.94 g, 6.8 mmol) and benzyl bromide (0.81 ml, 6.8 mmol) were added and the mixture was added. it was refluxed for 18 hours. The reaction mixture was filtered, evaporated until sessed, and chromatographed on Si02 (Mersk 230-400 mesh), eluting are EtOAs-sislohe-xano (3: 7), to provide (RS) -6-bensiloxi- ( sroman-2-yl) -methanol (1.0 g, 3.7 mmol, 60%), as a solor white solid, with a melting point of 80-82 ° C, MS m / e = 270 , 1 (M *). EXAMPLE 76 fRS) -6-hydroxy-sroman-2-sarboxylyl acid. (RS) -6-methoxy-sroman-2-sarboxylyl acid (1.12 g, 5.37 mmol) and pyridinium hydrosulphide (11, 2 g, 96.6 mmol), at a temperature of 180 ° C, during a transsurface of 2 hours, under an argon atmosphere and under agitation. After cooling to room temperature, H20 (100 ml) and EtOAc (50 ml) were added and stirred. The aqueous phase was extracted with EtOAs (50 ml), and the extrames were washed with a saturated solution of NaCl (50 ml) and, then continued, are Na2SO4, and evaporated, to give acid (RS) -6-hydroxy-sroman-2-sarboxylyl, sunscreens (0.94 g, 4.84 mmol, 90%), from a melting point of 175-177 ° C, MS m / e = 194, 1 (M *). Example 77 fRS) -6-methoxy-chroman-2-carboxylic acid A vigorously stirred mixture of 6-methoxy-sromenon-2-sarboxylyl acid (2.20 g, 10 mmol) and Pd / C (10%), (300 mg) in acetic acid (200 ml), was heated at a temperature of -60 ° C, over a period of 5 hours, under a hydrogen atmosphere. The catalyst was removed and the solution was evaporated to give (RS) -6-methoxy-chroman-2-carbo-xylyl acid (2.04 g, 9.8 mmol), as solor yellowish-to-one crystals. of fusion 131-135 ° C, MS m / e = 208.1 (M *). Bibligraphy: N. Cohen and solegas, J. Med. Chem. 1989, 32, 1842-1860; and D.T. Witaik et al., J. Med. Chem. 1971, 14, 758-766. Example 78 f 1RS .2RS) -1-f 6-benzyloxy-l-hydroxy-l .2.3.4-tetrahydro-naphthalen-2-ylmethyl) -4- 4-methyl-bensyl) -piperidin-4-ol (RS) -6-bensyloxy-2- [4-hydroxy-4- (4-meth1-bensi1) -piperidin-1-ylmethyl] -3,4-dohydro-2H-naphthalen-1-one (1.30 g 2.77 mmol) in THF (15 ml) was added dropwise to a suspension of LIA1H4 (0.6 g, 15.5 mmol) in THF (20 ml) over a period of 15 minutes ( 5-10 ° C) and, subsequently, it was stirred at room temperature, during a transsurface of 2.5 hours. Distilled H20 (1 ml) and a 4N solution of NaOH (2 ml) were added, followed by H20 (2 ml) adisional, to quench the reassumption, and proceeded to shake vigorously for 15 minutes, the mixture is then dried with Na 2 SO 4, and filtered and evaporated. The resulting crude liquid was chromatographed on Si02 (Merck 230-400 mesh), eluting with CH2C12-Me0H-NH40H (100: 5: 0.25), to give the title compound, as a white foam (0, 75 g, 1.6 mmol, 57%), MS m / e = 472.4 (M + H *). Following the general procedure of Example 78, Example 79 was prepared. Example 79 f 1RS .2RS) -1-f 6-bensyloxy-1-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-ylmethyl) -4-bensil-piperidin-4-ol The title compound was obtained as an insolubile MS: m / e = 458.6 (M + H *), prepared from (RS) -2- (4-bensil) -4-hydroxy-piperidin-1-ylmethyl) -6-bensyloxy-3,4-dihydro-2H-natalen-1-one. Example 80 f RS) -6-bensyloxy-2- T 4-hydroxy-4-f 4-methy1-bensi1) -piperidin-1-ylmethyl 1-3,4-dihydro-2H-naphthalen-1-one 6-bensyloxy was heated -l-tetralone (1.26 g, 5 mmol), 4- (methyl-bensyl) -piperidin-4-ol hydroschloride (1.20 g, 5 mmol) and paraformaldehyde (150 mg, 5 mmol) in DMF (10 mg). ml) at a temperature of 70 ° C, during a transsurse of time of 17 hours. The crude mixture was partitioned between distilled H20 (15 ml), 25% NH40H (2 ml), and EtOAc (100 ml). The aqueous phase was extracted additionally with EtOAs (100 ml) and the extracted extra-organelles were washed two times with saturated NaCl solution (100 ml), blasted with Na2SO4, filtered and evaporated to provide an orange solor sauce. The chromatography on Si02 (Mersk 230-400 mesh), eluting are EtOAs-Et3N (19: 1), gave (RS) -6-benzyloxy-2- [4-hydroxy-4- (4-methyl-bensyl) -piperidine) -1-ylmethyl] -3,4-dihydro-2H-naphthalen-1-one, as an amber oil (1.34 g, 2.85 ml, 57%), MS m / e = 470, 3 (M *). Following the general procedure of Example 80, Example 81 was prepared.

Example 81 fRS) -2- f 4-bensyl-4-hydroxy-piperidin-1-ylmethyl 1 -6-hencyloxy-3,4-dihydro-2H-naphthalen-1-one The composition of the example was obtained as a color yellow MS: me = 456.6 (M + H *), prepared from 6-benzyloxy-l-tetralone, 4-bensyl-4-hydroxy-piperidine hydrochloride and paraformaldehyde. Example 82 6-benzyl-l-tetralone 6-hydroxy-l-tettralone (10 g), 61.65 mmol), bensyl bromide (8.1 ml, 67.82 mmol) and K2C03 (21.3 g, 154 mmol) in asetone (40 ml), were stripped under reflux, during a transsurface of 2.5 hours. After filtration and evaporation of the solvent, the material was assiduously assimilated to a pH value of 1, an IN solution of HCl, and partitioned between H20 (150 ml) and EtOAs (150 ml). The asuosa phase was extracted addicionally with EtOAs (100 ml) and the extracts were bent (Na2SO4), filtered and evaporated to provide 6-bensyloxy-l-tetralone as an orange solid (12, 37 g, 49.3 mmol, 80%), from a melting point of 97-100 ° C, MS m / e = 252.1 (M *). Example 83 6-Hydroxy-1-tetralone 6-methoxy-1-tetralone (80 g, 453 mmol) was added in 48% HBr (270 ml), at a temperature of 4 ° C, and then stirred at room temperature. during a 4 hours time transsurse. Distilled H20 (11) was added, the mixture was allowed to cool to a temperature of 4 ° C and, the solid precipitate was filtered, washed with H20 and recrystallized twice with Et0H-H20 (4: 1), to give the reaction medium. -hydroxy-i-tetralone, as a solid of solor beige (59.7 g, 368 mmol, 81%), of a melting point of 153-155 ° C, MS m / e = 162.1 (M *) . Example 84 fRS) -1-f 6-methoxy-l r 2 f 3,4-tetrahydro-naphthalen-2-ylmethyl) -4- f 4-methyl-bensyl-piperidin-4-ol Salts (RS) -6 -methoxy-l, 2,3,4-tetrahydro-naph-talen-2-ylmethyl-ester of the toluene-4-sulfoniso acid (1.32 g, 3.81 mmol) and 4- (methyl-bensyl) -piperidin -4-ol (3.13 g, 15.24 mmol) in mesitylene (100 ml), at a temperature of 140 ° C, in a transsurface time of 20 hours. Following evaporation of the solvent, the crude material was partitioned between CH2C12 (50 ml) and a 5% NaHCO3 solution (30 ml), the aqueous phase was extracted with CH2C12 (2x100 ml), washed with a saturated solution NaCl (50 ml), was sessed (Na2SO4), filtered, and evaporated. The produsto srudo, was chromatographed on Si02 (Mersk 230-400 mesh), eluting are EtOAs-n-hexane (1: 3), then (1: 1), to provide (RS) -l- (6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl-ethyl) -4- (4-methyl- bensil-pipe-ridin-4-ol, as a white solid (972 mg, 2.56 mmol, 67.3%), of a melting point of 91-94 ° C, MS: m / e = 380.3 (M + H *). Example 85 f RS) -6-methoxy-l .2.3.4-tetrahydro-naphthalen-2-ylmethyl ester of toluene-4-sulfoniso acid They were stirred together (RS) - (6-methoxy-l, 2.3, 4- tetrahydro-naphthalen-2-yl) -methanol (939 mg, 4.88 mmol), p-toluenesulfonyl-chloride (934 mg, 4.9 mmol), triethylamine (1.12 mL, 7.88 mmol) and N, N-dimethylaminopyridine (10 mg) and CH2C12 (10 ml), at room temperature, during a 24-hour time lapse. The acidifisation with an INN HCl solution (pH 1-2), extractions of the asuosa phase are CH2C12 (2x2 ml), sessed (Na2S04), filtration and evaporation, proportional to a produsto srudo that was chromatographed on Si02 (Mersk 230 400 mesh ), eluyeno are EtOAs-n-hexane (1: 3), to provide the produsto of the epigraph, we are a colorless ase (1.37 g 3.95 mmol), 81%), MS: m / e = 346.1 (M *). Example 86 fRS 1 -f 6-methoxy-l .2.3 f 4-tetrahydro-naphthalen-2-yl) -methol Ethyl acid ester (RS) -6-methoxy-2,3 was added dropwise. , 4-tetrahydro-naphthalene-2-carboxylic acid (1.3 g, 5.93 mmol) in THF (20 ml), to a suspension of LIA1H4 (47 mg, 12.46 mmol), at a temperature of 0-10 ° C, in a time transsurs of 15 minutes. The reaction was stirred during a 1-hour time at ambient temperature and was quenched, quenched by the addition of a 4N NaOH solution (15 ml) and water (20 ml). After shaking vigorously during a 15-minute time transsurface, the mixture was extracted with EtOAc (25 ml), the aqueous phase was further extracted with EtOAc (2x25 ml), the somatic organic extracts were washed with saturated NaCl solution (30 ml), dried (Na2SO4), they filtered and evaporated or, to provide the raw product, a solor slaro. The chromatographic purification on Si? 2. (Mersk 230-400 mesh) eluyeno with EtOAs-n-hexane (1: 3), yielded (RS) - (6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl) -methanol, as a colorless oil (989 mg, 5.14 mmol, 86%), MS: m / e = 192.1 (M *). EXAMPLE 87 FRS) -6-methoxy-1,2,3-tetrahydro-naphthalene-2-carboxylic acid ethyl ester We vigorously agitated ester ethyl ester (RS) -6-methoxy-l-oxo-l, 2,3,4-tetrahydro-naphthalene-2-sarbo-xylyl (2.0 g, 8.05 mmol) in MeOH (20 ml) and Pd / C (10%) (200 mg), under hydrogen atmosphere, during a transsurface of 3 hours and at room temperature. The satallizer was removed and the solvent was evaporated, to provide a sample, which was purified by chromatography on Si02 (Mersk 230-400 mesh), eluting with EtOAc-n-hexane (1: 9), to provide ethyl ester of the acid (RS) -6-methoxy-1,2,3,4-tetrahydro-naphthalene-2 -sarboxíliso, somo an insidious aseite (1.88 g, 6.14 mmol, 76%), MS: m / e = 234.1 (M *). EXAMPLE 88 Ethyl ester of the acid fRS) -6-methoxy-l-oxo-l .2.3.4-tetrahydro-naphthalene-2-sarboxyliso The 6-methoxy-te-tralone (10 g, 56.75 mmol) was successively excised. ), diethyl sarbonate (20.6 ml, 170.2 mmol), and sodium hydride (5.06 g, 210.8 mmol), at a temperature of 65 ° C, in THF (400 ml), during a transsurge of time of 18 hours. After cooling, glacial acetic acid (15 ml, 250 mmol) was cautiously added, followed by toluene (2 × 200 ml), and then coevaporated to remove the excess of the azetiso acid. The residue was redissolved in EtOAs (400 ml). , H20 (400 ml), and stirred, extracting the asuosa phase are EtOAs (2x100 ml) and washing the extracted combined organisoses is a saturated solution of NaCl (100 ml), sesseo (Na2S04), filtering, and washing, The prodrug was recrystallized from EtOAs-n-Hexane to give the title of the epigrapher, som a solid of yellow solor (8.39 g, 33.4 mmol), 58%), MS: m / e = 248, 1 (M *).

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, property is claimed as contained in the following:

Claims (16)

1. CLAIMS 1.- A formula of the formula characterized in that X means -O-, -NH-, -CH2-, -CH =, -CHOH-, -CO-, -S-, -SO-, or -S02-: R1-R4 are, independently the one is with respect to the other, hydrogen, hydroxy, lower alkyl-sulfonylamino, 1- or 2-imidazoyl or asetamido; R5-R8 are, independently, one being the other, hydrogen, hydroxy, lower alkoyl, halogen, also-lower xi, trifluoromethyl or trifluoromethyloxy; a and b are, independently the one is respect to the other, or double enlases or not, are the sondisión that, if "a" is a double link, "b" can not be a double link; n is 0-2; m is 1-3; p is 0 or 1 and salts thereof, assumable from the pharmaceutical point of view.
2. 2. A package according to claim 1, characterized in that X is -0-.
3. 3. A compound according to claim 2, selected from the following group: (RS) -1- (5-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl) -4- (4-methyl- benzyl) -piperidin-4-ol, (RS) -4-bensyl-1- (5-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl) -piperidin-4-ol, (RS) -4- ( 4-fluoro-benzyl) -1- (5-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl) -piperidin-4-ol, (RS) -4- (4-ethyl-bensyl) -l- ( 5-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl) -piperidin-4-ol, (S) -1- (5-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl) -4- ( 4-methyl-bensyl) -piperidin-4-ol, (S) -1- (5-hydroxy-2,3-dihydro-benzo-uran-2-ylmethyl) -4- (4-sloro-bensyl) -piperidine- 4-ol, (RS) -N- [2-. { 4-hydroxy-4- (4-methyl-benayl) -piperidin-1-ylmethyl} -2, 3-dihydrobenzofuran-5-yl] methanesulfonamide (RS) -N- [2-. { 4-hydroxy-4- (4-methyl-bensyl) -piperidin-1-ylmethyl} -2, 3-dihydrobenzofuran-5-yl] methanesulfonamide
4. 4. A compound according to claim 1, characterized in that X is -CHOH-.
5. 5. A composition according to claim 4, selected from the following group: (1RS, 2RS) and (lRS, 2RS) -2- [4-hydroxy-4- (4-methyl-ben-cil) - piperidin-1-ylmethyl] -indan-1, 5-diol, (1RS, 2RS) -1- (1,6-dihydroxy-l, 2,3, 4-tetrahydro-naphthalen-2-ylmethyl) -4 - (4-methyl-benzyl) -piperidin-4-ol y (1RS, 2RS) -2- (4-bensyl-4-hydroxy-piperidin-1-ylmethyl) -6-hydroxy-l, 2,3 , 4-tetrahydronaphthalen-1-ol.
6. 6. A package according to claim 1, characterized in that X is -CH2- or -CH =.
7. 7. A compound according to claim 6, selected from the following group: (RS) -l- (5-hydroxy-indan-2-ylmethyl) -4- (4-methyl-ben -yl) -piperidin-4 -ol and (RS) -1- (6-hydroxy-l, 2,3,4, tetrahydro-natalen-2-ylmethyl) -4- (4-methyl-bensyl) -piperidin-4-ol.
8. 8. A package according to claim 1, characterized in that X is -NH-.
9. 9. A compound according to claim 8, selected from the following group: (RS) -2- [4-hydroxy-4- (4-methy1-bensi1) -piperidin-1-ylmethyl] -2, 3 -dihydro-lH-indol-5-ol.
10. 10. A compound according to claim 1, characterized in that X is -CO-.
11. 11. A set according to claim 1, characterized in that X is -S-, -S? 4-, or -S02-.
12. 12. The medicament characterized in that it contains one or more compounds of any one of claims 1 to 11, or a salt thereof obtainable from the pharmaceutical standpoint iso, for the treatment of diseases.
13. 13. A medisamento according to claim 12, for the treatment of diseases based on therapeutic indices for the selective blockers of the NMDA receptor subtype, which include acute forms of neurodegeneration caused, for example, by shock and trauma of brain and chronic forms of neurodegeneration, such as Alzheimer's disease, Parkinson's disease, Hun-tingston's disease, ALS (amyotrophic lateral sclerosis - [arserotrophic iateral sslerosis] -) and assorted neurodegeneration are basterian or viral infesions.
14. 14. A process for the preparation of a compound of formula I, as defined in claim 1, characterized in that it comprises: a) the reaction of a compound of formula wherein R1-R4, X, a, b, n and m, have the meaning given in claim 1 and, L is OH or a leaving group, for example, halogen or -O-tosyl, are a compound of the formula wherein R5-R8 and p, have the meaning given in claim I fc > ) the reaction of a compound of formula wherein the substituents have the meaning given in claim 1, with a compound of the formula in the presence of paraformaldehyde, to provide a formula of the formula wherein m is 1 and, the other substituents, have the meaning given in claim 1, or c) the dehydration of a compound of the formula to provide a compound of formula wherein, m is 1 and the other substituents have the meanings given in claim 1, or d) the redussion of a compound of formula IA, to provide a compound of formula IB, or e) the de-biosylation of a compound of formula I; formula V wherein the substituents have the meaning given in claim 1 of) the reaction of a compound of formula I, wherein one of R1-R4 is an amino group with an lower alkyl-halogenosulfonyl, to provide a compound of formula I, wherein one of the R1-R4 is a lower alkyl sulfonylamino group, or g) the hydrogenation of the double bond isolated in a compound of formula I, or the division or cleavage of the group (s) of protons. hydroxy or amino, present (s) as (a) substituent (s) R1 R4 or as X '= - N (protecting group), or i) oxidation of a compound of formula I, e where, X represents -S - or -SO-, to provide the corresponding sulphonyl group (-S02), and j) if desired, the conversion of the obtained molar form I obtained in an admissible adduction salt from the pharmaceutic point of view.
15. 15. Compounds according to any of the claims 1-11, when they are prepared by a procedure as claimed in claim 14, or by an equivalent performance.
16. 16. The use of a package according to any one of claims 1-11, for the treatment of diseases based on therapeutic indis- eases for the selective blockers of the NMDA receptor subtype, which include acute forms of neurodegeneration, for example, , by stroke and trauma of brain and sénisas forms of neurodegeneration, such as Alzheimer's disease, Parkinson's disease, Huntingston's disease, ALS (amyotrophic lateral sclero sis and neurodegeneration associated with bacterial or viral infections, or for the fabrication of a medisamento that are so produsto. SUMMARY The present invention refers to 4-hydroxy-piperidine derivatives of the general formula where X means -O-, -NH-, -CH2-, -CH =, -CHOH-, -CO-, -S-, -SO-, or -S02-: R1-R4 are, independently, one is respect to the other, hydrogen, hydroxy, lower alkyl-sulfonylamino, 1- or 2-imidazoyl or aseta gone; R5-R8 are, independently, one being the other, hydrogen, hydroxy, lower alkyl, halogen, also-xi lower, trifluoromethyl or trifluoromethyloxy; a and b can be a double link, they are the sonsion that, if "a" is a double link, "b" can not be a double link; n is 0-2; m is 1-3; p is 0 or 1 and salts thereof, assumable from the pharmaceutical point of view. The compounds of the present invention are selective blockers of the NMDA receptor subtype (N-methyl-D-aspartate), which can be used in mediating processes subordinated to the development of the CNS, including the function of learning and memory formation.