MXPA98002580A - Derivatives of the fenoximetil piperid - Google Patents

Abstract

The present invention relates to phenoxymethyl piperidine derivatives, and pharmaceutically acceptable salts and N-oxides thereof, which are sodium channel blockers, so they have useful pharmacological properties, including the application for the treatment of neuropathic pain conditions

Description

DERIVATIVES OF THE PHENOXIMETHYL PIPERIDINE DESCRIPTION OF THE INVENTION The invention relates to compounds represented by the formula I: wherein: R1 is hydrogen, alkyl of 1 to 4 carbon atoms, - (CH2) m-cycloalkyl ?, - (CH2) ... NR'R8, or - (CH ^ NR'SOjR5; m is 1 to 3, - R7 and R8 are, independently of one another, hydrogen or alkyl of 1 to 4 carbon atoms, and R9 is alkyl of 1 to 4 carbon atoms: R2, R3, Rs and R6 are independently of each other, alkyl of the 4 carbon atoms. carbon, or halogen, R 4 is hydrogen, alkyl of 1 to 4 carbon atoms, hydroxyl, alkyloxy, fluoroalkyloxy, halogen or phenyl or mono or disubstituted phenyl, the substituents being selected from the group consisting of alkyloxy, amino, nitro or acetylamino; with the proviso that when R1 is hydrogen, at least two of R2, R3, R4, Rs, and R6 are other than hydrogen, and also with the proviso that when R1 is methyl and R2, R3, Rs and R6 are hydrogen, R4 is other than fluorine, or a pharmaceutically acceptable salt or an N-oxide thereof, as an individual isomer or as a mixture of racemic isomers or non-racemic The phenoxymethyl piperidine derivatives of formula I are sodium channel blockers, and therefore have useful pharmacological properties, including their application for the treatment of neuropathic pain conditions. Neuropathic pain can be described as pain associated with a permanent injury or alteration of the central or peripheral nervous system. The clinical manifestations of the neuropathic lesion include a sensation of burning or electric shock, sensations of bodily distortion, allodynia and hyperalgesia. Sodium channel blocking agents have been recognized as effective in the treatment of various disease states, and have found particular application as local anesthetics and in the treatment of cardiac arrhythmia. It has also been reported for many years that sodium channel blocking agents could be useful in the treatment of pain, including neuropathic pain; see for example, Tanelian et al. Pain Forum ("Forum of pain"). 1995, 4 (2), 75-80. Preclinical evidence showed that sodium channel blocking agents selectively suppressed abnormal ectopic neural fever in peripheral and central injured neurons, and it is through this mechanism that they are believed to be useful in mitigating pain. According to this hypothesis, it has been shown that the sodium channel accumulates in the peripheral nerve at the sites of axonal lesions (Devor et al., J. Neurosci., 1993, 132, 1976-1992). Alterations, either in the level of expression or in the distribution of sodium channels in the interior of an injured nerve, they have, therefore, a major influence on the pathophysiology of the pain associated with this type of trauma. This concept is based on the relative success of the use of sodium channel modulating agents (eg anticonvulsants, local anesthetics) for the treatment of neuropathic pain. However, pain relief has often been obtained simultaneously with numerous adverse effects and / or efficacy limitations, which have reduced the tolerability of these drugs. It can be seen that there is still a need for an oral active agent that is effective for the treatment of neuropathic pain, but which has fewer side effects. Various derivatives of phenoxymethyl piperidine have been described in the patent and non-patent literature. For example, WO 92/02501 (Smithkline &French) and WO 93/15052 (Smithkline Beecham) generally describe various optionally substituted derivatives of 3-phenoxymethyl piperidine and 3-phenoxyethyl piperidine, respectively, useful as blocking agents of the calcium channel. US Patent 3,634,437 (Todd) describes optionally substituted compounds of 3-phenoxymethyl piperidine, which can be used in the treatment of depressive illnesses, anxiety, neurotic states and epilepsy. US Pat. No. 3,709,892 (Leeming et al.) Discloses substituted 3-phenoxy-alkylamines, for example 3- [(2-cyclohexyl-ethyl) phenoxymethyl] -1-methylpiperidine, which possesses gastric antisegregatory activity. U.S. Patents 4,877,799; U.S. 4,985,446; and US 5,019,582 (Drejer et al.); and US 5,158,961 v TTQ . 277,379 (Jakobsen et al.) Describe derivatives of 4-phenyl-3-phenoxymethyl piperidine as inhibitors of calcium overload useful in the treatment of anoxia, ischemia, migraine and epilepsy. US Patent 4,508,724 (Taylor et al.) Describes the 3-phenoxymethyl-3-piperidinol derivatives having antiarrhythmic, antidepressant and antihypertensive activity. US Patent 4,822,778 (Aberg et al.) Describes the optionally substituted 2-phenoxymethyl piperidine derivatives, in particular N-methyl-2- [(2,6-xyloxy) methyl] -piperidine, which have anesthetic and antiarrhythmic activity. Arya et al. Indian J. Chem. 1977, 15B, 1125-1128 describes the synthesis and pharmacological activity of piperidyl ethers, in particular 3- (4-fluorophenoxymethyl) -1-methyl-piperidine, as central nervous system depressants. Balsamo et al. J. Med. Chem. 1987, 30, 222-225, describes the synthesis and antidepressant activity of the derivatives of 3- [(2-ethoxy-phenoxy) methyl] -piperidine. Objects of the invention are the compounds of formula I and pharmaceutically acceptable salts of the N-oxide thereof, racemic mixtures and their corresponding enantiomers, the preparation of the compounds mentioned above, medicaments containing them and their preparation as well as the use of the aforementioned compounds in the control or prevention of neuropathic pain conditions or for the preparation of the corresponding medicaments. The following definitions of the general terms used in the present description apply indeoend-ipn- if the terms in question appear alone or in combination. "From one to four carbons", as p. ex. in "1-4 carbon alkyl" means a branched or unbranched saturated mono-valent hydrocarbon chain containing 1,2,3 or 4 carbons, such that alkyl of 1 to 4 carbon atoms specifically includes example, methyl, ethyl, n-propyl, iso-propyl, or n-butyl. Similarly, "from one to two carbon atoms" as p. ex. in "alkyl of 1 to 2 carbon atoms" means a hydrocarbon chain containing 1 or 2 carbons, such that alkyl of 1 to 2 carbon atoms specifically includes methyl and ethyl. "Cycloalkyl" means a saturated monovalent carbocyclic radical containing from three to seven carbon atoms, e.g. ex. , cyclopropyl, 2-methylcyclopropyl, cyclobutyl, 3-ethyl-cyclobutyl, cyclopentyl, cyclohexyl or cyclohexylmethyl. "Alkoxy" means -O-R, wherein R is alkyl of 1 to 4 carbon atoms as defined above. "Fluoroalkyl" means alkyl of 1 to 4 carbon atoms as defined above substituted by 1 to 3 fluorine atoms, for example, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, and the like. "Fluoroalkyloxy" means -O-R ', wherein R' is fluoroalkyl. "Halogen" means fluorine, chlorine, bromine or iodine, preferably bromine or chlorine. "Optional" or "optionally" means that the event or circumstance described below may or may not occur, and that the description includes cases in which the event or circumstance occurs and cases in which it does not occur. "Inert organic solvent" or "inert solvent" means an inert solvent under the reaction conditions described in conjunction therewith, including for example, benzene, toluene, acetonitrile, tetrahydrofuran, dimethylformamide, chloroform (CHC13), dichloromethane, or methylene dichloride ( CH2C12), diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine and the like. Unless otherwise specified, the solvents used in the reactions of the present invention are inert solvents. "Protective group" means a chemical group that (a) preserves a reactive group from participating in an undesired chemical reaction; and (b) it can be easily removed after protecting the reactive group if it is not needed for a longer time. "Amino protecting group" or "N-protecting group" means a protecting group that preserves an amino reactive group that would otherwise be modified by certain chemical reactions. The definition includes the formyl group or lower alkanoyl groups with 2 or 4 carbon atoms, in particular the acetyl or propionyl group, the N- (9-fluoro-enylmethoxy-carbonyl) or "FMOC" group, the allyloxy-carbonyl group or other protective groups derived from halo-carbonates such as the aryl (from 6 to 12 carbon atoms) alkyl lower carbonates (such as the N-benzyl-oxycarbonyl group derived from benzylchlorocarbonate) or derivatives of biphenylalkyl halocarbonates, or alkyl tertiary halo carbonates, such as terebutylcarbonates, in particular tert-butylchlorocarbonate, or dialkyl (lower) -dicar-binnates, in particular, di (tert-butyl) -dicarbonate. "Hydroxyl protecting group" means a protecting group that preserves a hydroxyl group that would otherwise be modified by certain chemical reactions. Suitable hydroxyl protecting groups include ether-forming groups which can be readily removed upon completion of all other steps of the reaction, such as the benzyl or trityl group optionally substituted on its phenyl ring, silyl, trialkylsilyl ether groups and the like. "Loss group" means a labile group that is replaced in a chemical reaction by another group. Examples of loss groups are halogen, the optionally substituted phenoxyl group, the trifluoromethanesulfonyl-oxyl group, the mesyloxyl group, the tosyloxyl group or the acyloxy group. "N-oxide" refers to a stable amine oxide formed at the nitrogen atom of piperidine. "Stereoisomers are isomers that differ only in the way that atoms are arranged in space." Enantiomers "are a pair of stereoisomers that are non-superimposable mirror images of each other.A 1: 1 mixture of a pair of enantiomers is a sample "racemic" The compounds of the invention may possess an asymmetric center at the 3-position of piperidine, and consequently may exist as a mixture of stereoisomers as individual stereoisomers (R) or (S). Individual enantiomers can be obtained by separating a racemic or non-racemic mixture from an intermediate product at some appropriate stage of the synthesis, and then completing the synthesis so as to preserve the chirality, or by separating the compound of formula I by conventional means. The individual enantiomers, as well as the racemic and non-racemic mixtures thereof are encompassed within the purpose of the present invention, all of which are intended to be represented by structures of this specification unless otherwise specifically indicated. Specific examples of the separation of isomers are described in the examples. The use of the symbol "(R)" or "(S)" preceding a substituent means the absolute stereochemistry of this substituent according to the rules of Cahn-Ingold-Prelog (see Cahn et al., Angew., Chem., Inter. T. 1966, 5, 385, Errata 511, Cahn et al., Angew, Chem. 1966, 78, 413, Cahn and Ingold J. "Chem. Soc. (London) 1951, 612; Cahn et al., Experientia 1956, 12 , 81; Cahn J. Chem. Educ. 1964, 41, 116).

"Pharmaceutically acceptable" means that which is useful in the preparation of a pharmaceutical composition, which is generally safe, non-toxic, is not undesirable neither biologically nor otherwise, and includes that which is acceptable for veterinary use as well as for employment human pharmacist "Pharmaceutically acceptable salts" refers to those salts that are pharmaceutically aceotabl-rr-r-r. e - = - defined above, and which possess and retain the desired pharmacological activity of the compounds of formula I. The compounds of formula I form acid addition salts by virtue of the presence of the basic nitrogen atom of piperidine. The acid addition salts can be formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, acid citric, benzoic acid, o- (4-hydroxybenzoyl) -benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo- [2.2.2] oct-2-en-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert.butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid , hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, tartaric acid and the like. Preferred pharmaceutically acceptable salts are salts formed by inorganic acids. A particularly preferred pharmaceutically acceptable salt is the hydrochloride salt. "Treatment" means any treatment of a condition in a mammal, particularly a human being, and includes: (i) preventing the disease from occurring in a subject who may be predisposed to the disease, but who it has not yet been diagnosed that he has it; (ii) inhibition of the condition, that is, stopping its development; or (iii) relief of the condition, that is, alleviating the pain symptom. "Condition of the disease that can be treated by administering a sodium channel blocker", is intended to cover all the disease states that are generally admitted in the specialty as being useful when they are generally treated with blockers of the channel. sodium, and those disease states that have been found useful in treating them by the specific sodium channel blocker of our invention, the compounds of formula I. These disease states include but are not limited by peripheral neuropathies, such as p. ex. trigeminal neuralgia, postherpetic neuralgia, diabetic neuropathy, glossopharyngeal neuralgia, lumbar and cervical radiculopathy, sympathetic reflex and causal dystrophy, and neuropathy secondary to metastatic infiltration, painful adi-posis and burn pain; and central painful conditions after a blow, thalamic lesions and multiple sclerosis. "Therapeutically effective amount" refers to the amount sufficient for the treatment, as defined above, to give results when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending on the subject and the state of the disease to be treated, the severity of the and the manner of administration, and can be determined routinely by an expert in the art. The name and number of the compounds of this invention is illustrated below. The nucleus of the phenoxymethyl piperidine of the compound of formula I is numbered as follows: The nomenclature used in this application is generally based on the recommendations of the IUPAC. However, because strict adherence to these recommendations can result in a substantial change in the name when only an individual substituent is changed, the compounds have been named so as to maintain the consistency of the nomenclature for the basic structure of the the molecule. Among the family of compounds of the present invention, certain compounds of formula I are preferred. Preferred compounds of formula I are those in which R 1 is hydrogen or alkyl of 1 to 4 carbon atoms, more preferably hydrogen, methyl or ethyl, and most preferably hydrogen or methyl, - preferably R 2 and R 6 are each independently hydrogen or alkyl, more preferably hydrogen or methyl and most preferably R2 and R6 are each methyl; and preferably R3 and Rs are each independently of one another hydrogen or alkyl of 1 to 4 carbon atoms, more preferably R 3 and Rs are each hydrogen; and R 4 is hydrogen or halogen, more preferably hydrogen or bromine, and most preferably, bromine. At present, the most preferred compounds include as an example: 3- (4-bromo-2,6-dimethylphenoxymethyl) -1-methylpiperidine; 3- (4-Bromo-2,6-dimethylphenoxymethyl) -1-methyl-piperidine N-oxide; (S) -3- (4-Bromo-2,6-dimethylphenoxymethyl) -l-methylpiperidine; 3- (4-bromo-2,6-dimethylphenoxymethyl) -piperidine; (S) -3- (4-Bromo-2,6-dimethylphenoxymethyl) -piperidine; 3- (2,6-dimethylphenoxymethyl) -l-methylpiperidine; N-oxide of 3- (2,6-dimethylphenoxymethyl) -1-methylpiperidine; and (S) -3- (2,6-dimethylphenoxymethyl) -1-methylpiperidine. The compounds of this invention can be obtained by methods depicted in the reaction schemes set forth below. The starting materials and reagents used in the preparation of these compounds can be purchased from commercial suppliers such as Aldrich Chemical Company or are prepared by methods known to those skilled in the art following the procedures indicated in references such as Fieser and Fieser 's Reagents for Organic Synthesis, volumes 1-15 (John Wiley and sons, 1991); Rodd 's Chemistry or f Carbon Compounds, volumes 1-5 and supplements (Elsevier Science Publishers, 1989); and Organic Reactions, volumes 1-40 (John Wiley and Sons, 1991). These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and proposed by one skilled in the art with reference to this description. The starting materials and intermediates of the reaction can be isolated and purified if desired, employing conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials can be characterized using conventional means, including physical constants and spectral data. Unless otherwise specified, the reactions described here take place at approximately atmospheric pressure at a temperature in the range of about -78 ° C to about 150 ° C, more preferably from about 0 ° C to about 125 ° C. C, and most preferably at about room temperature, p. ex. , around 20 ° C. The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by the processes described below, which are composed of: a) reaction of a compound of formula (i) with a compound of formula (2) wherein R1-Rs are as defined above and Y is hydrogen or -OY is a loss group, or b) deprotection of a compound of formula wherein R is an amino protecting group and R-R6 are as defined above, or c) alkylation or acylation of a compound of formula wherein R2-Rs are as described above, to give a compound of formula I, wherein R1 is alkyl of 1 to 4 carbon atoms, - (CH2) m-cycloalkyl, - (CH2) mNR7Rβ or - (CH2) mNR7S02R9, d) oxidation of a compound of formula I to give an N-oxide, or e) separation of a racemic mixture into its enantiomeric components, and f) if desired, conversion of a compound of formula I to a pharmaceutically acceptable salt. Variant a) of the process describes a method of preparing compounds of formula I from the reaction of a phenolic compound (1) with a piperidine compound (2) where Y is hydrogen or -OY is a loss group, and R1, R2, R3, R4, Rs and Rβ are as defined above. Scheme 1 In general, the phenolic compound (1) can be purchased commercially, for example from Aldrich Chemical Co., or it can be prepared by standard methods already known to those skilled in the art, for example as described in detail in Preparation 1.

A piperidine compound (2) wherein Y is hydrogen, can be purchased commercially or can be prepared by standard methods already known to those skilled in the art. Alternatively, a piperidine compound (2) wherein -OY is a loss group, is prepared from the piperidine compound (2) wherein Y is hydrogen, converting the hydroxyl group to an appropriate loss group. Suitable solvents for the reaction are inert organic solvents, such as halogenated or aromatic hydrocarbons, e.g. ex. , dichloromethane, 1,2-dichloroethane, carbon disulfide, and the like, preferably dichloromethane. Suitable loss groups are prepared by standard methods, for example by reaction of the piperidine compound (2) wherein Y is hydrogen, with an alkyl or aryl sulfonyl halide, such as benzenesulfonyl chloride, methanesulfonyl chloride, preferably chloride of p-toluenesulfonyl. The sulfonyl halides can be purchased commercially or can be prepared by methods such as those described in (i) Langer, R.F. Can. J. Chem. 1983, 61, 1583-1592; (ii) Aveta, R. et al. Gazetta Chimica Italiana 1986, 116, 649-652; (iii) King, J.F .; Hillhouse, J.H. Can J. Chem. 1976, 54, 498; and (iv) Szymonifka, M.J .; Heck, J.V. Tet. Lett. 1989, 30, 2869-2872. A typical preparation of a piperidine compound (2) is described in detail in preparation 2. A compound of formula I is prepared by coupling the compound phenolic post (1) with the piperidine compound (2) wherein Y is hydrogen. The reaction takes place in the presence of a combination of an organic phosphine such as triphenylphosphine, and a dialkyl azodicarboxylate such as diethyl azodicarboxylate, under Mitsunobu reaction conditions. Suitable solvents for the reaction are aprotic organic solvents such as dimethylformamide, N-methyl pyrrolidone, or tetrahydrofuran, preferably tetrahydrofuran. Alternatively, a compound of formula I is prepared by coupling the phenolic compound (1) with a piperidine compound (2) wherein -OY is a loss group. The reaction is carried out in an inert atmosphere in the presence of a base, e.g. ex. , cesium carbonate, sodium carbonate or potassium carbonate, preferably cesium carbonate. Suitable solvents for the reaction are aprotic organic solvents such as dimethylformamide, N-methyl pyrrolidone, tetrahydrofuran and the like, preferably dimethylformamide. A typical preparation of a compound of formula I is described in detail in example 2. Reaction scheme 2 describes an alternative method of preparing a compound of formula I through an N-protected piperidine intermediate of formula (3 ) wherein P is an amino protecting group and R1, R2, R3, R4, Rs and R6 are as defined above.

Scheme 2 An N-protected compound of piperidine (2a) wherein P is an amino protecting group, is prepared by conventional methods, for example by treating the piperidine compound (2) wherein R1 and Y are each hydrogen, with a protective agent of suitable amino, such as an acyl halide, sulfonyl halide, dialkyl dicarbonate (eg di-tert-butyl dicarbonate) or alkylhalocarbonate, preferably di-tert-butyl dicarbonate. Suitable solvents for the reaction are aprotic organic solvents such as dimethylformamide, N-methyl pyrrolidone or tetrahydrofuran, preferably tetrahydrofuran. A typical preparation of an N-protected piperidine compound of formula (2a) is described in detail in Preparation 2B.

An N-protected phenoxymethyl piperidine compound (3) is prepared by coupling the phenolic compound (1) with the N-protected piperidine compound and using the reaction conditions described for the preparation of compounds of formula I in the reaction scheme l. A typical preparation of an N-protected compound of phenoxymethyl piperidine of formula (3) is described in detail in preparation 3. A compound of formula la wherein R 1 is hydrogen, is prepared by removing the N-protected group of the compound of formula 3) . The deprotection reaction takes place in the presence of a strong organic acid, preferably trifluoroacetic acid, in an inert organic solvent such as halogenated or aromatic hydrocarbons, e.g. ex. , benzene, dichloromethane, 1,2-dichloroethane, carbon disulfide and the like, preferably dichloromethane. The reaction can also be carried out in the presence of a strong base, for example sodium hydroxide or potassium hydroxide, in a mixture of water and a protic organic solvent, e.g. ex. methanol or ethanol, preferably methanol. A typical preparation of a compound of formula la wherein R1 is hydrogen, is described in detail in example 1.

A compound of formula I wherein R 1 is methyl, can be prepared by the method described in reaction scheme I. Alternatively, a compound of formula I, wherein R 1 is methyl, is prepared by reducing the N-protection group of the compound of formula (3) wherein P is a protective amino group such as a carbamate (e.g., tert-butoxycarbonyl) with bornean, borane complexes or a metal hydride such as lithium aluminum hydride. The reaction takes place under an inert atmosphere in an aprotic organic solvent such as diethyl ether, dioxane or tetrahydrofuran, preferably tetrahydrofuran. Alternatively the compound of formula I wherein R 1 is methyl, is prepared by reductive alkylation of the compound of formula la, for example with formaldehyde and formic acid under the conditions of the Eschweiler-Clarke reaction.

Typical preparations of a compound of formula I wherein R 1 is methyl, are described in detail in examples 2 and 3. A compound of formula I wherein R 1 is alkyl of 2 to 4 carbon atoms or (CH- ^ cycloalkyl, preparing by acylation of the compound of formula la by reaction with an acyl halide (eg, cyclopropanecarbonyl chloride or acetyl chloride, preferably cyclopropanecarbonyl chloride), in the presence of an aqueous base, eg sodium bicarbonate or potassium bicarbonate The reaction takes place at low temperature, in an ice bath, under an inert atmosphere in an aprotic organic solvent such as dimethylformamide, ethyl acetate, N-methyl pyrrolidone or tetrahydrofuran, preferably ethyl acetate. The resin is then treated with an appropriate reducing agent such as a metal hydride, eg lithium aluminum hydride, in an aprotic organic solvent such as tetrahydrofuran.

A typical preparation of a compound of formula I wherein R1 is (CH2) mcycloalkyl, is described in detail in example 4. A compound of formula I wherein R1 is - (CH2) mNR7Rβ, is prepared by reaction of the compound of formula with a compound of the formula Cl (CH 2) m 1 COCl in a two-phase system using an aqueous alkaline solvent such as aqueous sodium bicarbonate or potassium bicarbonate for the first phase; and an inert organic solvent such as diethyl ether, hexane and the like, preferably diethyl ether, for the second phase. The reaction takes place at about room temperature for about 30 minutes to 3 hours, preferably 2 hours. The product is dissolved in a protic organic solvent such as methanol or ethanol, cooled in an ice bath, treated with a compound of formula HNR7R8, and then treated with a suitable reducing agent such as a metal hydride, e.g. ex. lithium aluminum hydride, in an inert atmosphere in an aprotic organic solvent such as tetrahydrofuran. A typical preparation of a compound of formula I wherein R1 is - (CH2) mNR7R8, is described in detail in example 5. A compound of formula I wherein R1 is - (CH2) mNHS02R9, is prepared by reaction of a compound of formula I with a sulfonamide compound of formula Cl (CH2) nNHS02R9 in the presence of an inorganic base such as potassium carbonate or sodium carbonate, preferably potassium carbonate. They are suitable solvents for the reaction, the solvents aprotic, such as dimethylformamide, N-methyl pyrrolidone, or tetrahydrofuran, preferably tetrahydrofuran.

A typical preparation of a compound of formula I wherein R1 is - (CH2) mNHS02R9, is described in detail in example 6. Reaction scheme 3 alternatively describes methods of preparing compounds of formula I from the corresponding phenolic compounds intermediates of formula (Ib) wherein R 4 is hydroxyl; or of formula (ld) wherein R 4 is alkyloxy or fluoroalkyloxy, or of formula (I) wherein R 4 is phenyl or mono or disubstituted phenyl; and R1 is other than hydrogen, R2, R3, R5 and R6 are as defined above. Scheme 3 wherein P1 is a hydroxyl protecting group, and R4 is hydroxyl wherein A is alkyl or fluoroalkyl, and R4 is alkoxy or fluoroalkoxy (le) (lf) wherein R 4 is phenyl or substituted phenyl A compound of formula I wherein R 4 is hydroxyl, is prepared through an intermediate phenolic compound (Ib) wherein P 1 is a hydroxyl protecting group. The intermediate phenolic compound (Ib) is prepared by protecting the hydroxyl group of a compound of formula (la) by standard methods already known in the art, for example Corey, E.J .; Venkates arlu, A. J. Am. Chem. Soc, 1972, 94, 6190. Suitable hydroxyl protecting groups include the alkylsilyl groups, e.g. ex. tert-butyldimethylsilyl. Proceeding as in reaction scheme 1 or 2, but replacing the phenolic compound with the protected hydroxyl (Ib) by the phenolic compound (1) and copulating with the piperidine compound (2) or (2a), a phenoxymethyl piperidine compound is obtained with the protected hydroxyl. The compound of formula I wherein R 4 is hydroxyl, is then prepared by cleaving the protecting group by conventional and selective methods for the removal of the hydroxyl protecting groups such as the hydroxyl halides. alkylammonium, p. ex. tert-butylammonium fluoride, in the presence of an organic acid, e.g. ex. acetic acid, in an aprotic solvent such as tetrahydrofuran. A typical preparation that describes in detail the removal of the hydroxyl protecting group to form a compound of formula I wherein R 4 is hydroxyl is found in example 7. A compound of formula I wherein R 4 is alkyloxy or fluoroalkyloxy, is prepared by of an intermediate phenolic compound (ld) wherein A is alkyl or fluoroalkyl. An intermediate phenolic compound (ld) is prepared by reacting the p-hydroxy phenyl acetate compound (lc) with an alkylating agent of formula AY, wherein A is alkyl or fluoroalkyl and Y is a loss group such as a halo, alkylsulfonate or arylsulfonate, p. ex. , trifluoroethyl triflate. The reaction takes place under basic conditions such as potassium carbonate or sodium carbonate, in an aprotic organic solvent such as butanone, tetrahydrofuran or dimethylformamide, preferably butanone. The acetate group is then hydrolyzed under alkaline conditions using an alkoxide anion such as sodium methoxide, e.g. ex. in a protic organic solvent such as methanol or ethanol, preferably methanol. A typical preparation of the intermediate phenolic compound (ld) is described in detail in preparation IB. Proceeding as in reaction scheme 1 or 2, but substituting the intermediate phenolic compound (ld) for the Phenolic compound (1) and copulating with the piperidine compound (2) or (2a), the compound of formula I is prepared wherein R 4 is alkoxy or fluoroalkoxy. A compound of formula I wherein R 4 is phenyl or mono or disubstituted phenyl, is prepared through an intermediate phenolic compound (1), wherein R 4 is phenyl or mono or disubstituted phenyl. The intermediate phenolic compound (lf) is prepared by coupling, palladium catalyzed, the bromine compound of formula (le) with an arylboronic acid such as nitrophenylboronic acid and a palladium catalyst of zero valence such as tetrakis (triphenylphosphine) palladium (0), in the presence of an inorganic base such as sodium carbonate or potassium carbonate. Suitable solvents for the reaction are aprotic solvents, such as dimethylformamide, N-methyl pyrrolidone, or tetrahydrofuran, preferably tetrahydrofuran. By proceeding as in reaction scheme 1 or 2, but replacing the intermediate phenolic compound (I) with the phenolic compound (I) and coupling with the piperidine compound (2) or (2a), the compound of formula I is prepared, wherein R 4 is phenyl or phenyl mono or disubstituted. The compounds of formula I wherein R 4 is phenyl or mono or disubstituted phenyl, and R 1 is other than hydrogen, R 2, R 3, Rs and R 6 are as defined above, can be prepared from other compounds of formula I: For example, a compound of formula I wherein R 4 is 3-methoxyphenyl is prepared by coupling, palladium-catalyzed, of a compound of formula I wherein R 4 is bromine, with an arylboronic acid such as nitrophenylboronic acid and a zero valent palladium catalyst such as tetrakis (triphenylphosphine) aladin (0), in the presence of a base inorganic such as sodium carbonate or potassium carbonate. Suitable solvents for the reaction are aprotic solvents such as dimethylformamide, N-methyl pyrrolidone or tetrahydrofuran, preferably tetrahydrofuran. A typical preparation of a compound of formula I wherein R 4 is 3-methoxyphenyl, is described in detail in example 8. B. For example, a compound of formula I wherein R 4 is 3-aminophenyl, is prepared by reducing the group Nitro of the 3-nitrophenyl compound (prepared as described above in reaction scheme III wherein R 4 is phenyl or substituted phenyl), to an amino group. Suitable conditions for the reduction of the nitro group include the metal iron with ammonium chloride in ethanol / water, nickel boride in acidified methanol or catalytic hydrogenation using platinum or palladium catalyst (eg platinum oxide or shovel-on-carbon) in an alcohol solvent such as methanol or ethanol, preferably ethanol). The reaction takes place in an inert atmosphere. A typical preparation of a compound of formula I wherein R 4 is 3-aminophenyl, is described in detail in example 9.

C. For example, a compound of formula I, wherein R 4 is acetylaminophenyl, is prepared by treating the 3-aminophenyl compound described above in Section B with an acylating agent such as an acid halide or acid anhydride (e.g. eg, acetic anhydride) in the presence of an organic base (e.g., triethylamine or pyridine, preferably pyridine). Suitable solvents for the reaction are inert organic solvents, such as halogenated or aromatic hydrocarbons, e.g. ex. , benzene, dichloromethane, 1,2-dichloroethane, carbon disulfide and the like, preferably dichloromethane. A typical preparation of a compound of formula I wherein R 4 is 3-acetylaminophenyl, is described in detail in example 10. Reaction scheme 4 describes the preparation of an N-oxide of a compound of formula I wherein R 1 is different of hydrogen, and R2, R3, R4, Rs and R6 are as defined above, Scheme 4 Ib An N-oxide compound of formula Ib is prepared by oxidation of a compound of formula I with a suitable oxidizing agent such as a peroxide or peracid, e.g. ex. , m-chloro- perbenzoic or hydrogen peroxide, preferably m-chloroperbenzoic acid. Suitable solvents for the reaction are inert organic solvents, such as halogenated or aromatic hydrocarbons, e.g. ex. , benzene, dichloromethane, 1,2-dichloroethane and the like, preferably dichloromethane. A typical preparation of the N-oxide compound of formula Ib is described in detail in example 11. A compound of formula I can be separated into its individual (S) - and (R) - enantiomers by conventional separation methods, - for example separation (eg, fractional crystallization) of the diastereomeric salts formed by combining the compound of formula I with an optically active acid, at temperatures between 0 ° C and the reflux temperature of the solvent used for the fractional crystallization. Examples of such optically active acids are canfo-10-sulfonic acid, 2-bromo-campho-10-sulfonic acid, camphoric acid, menthoxyacetic acid, tartaric acid, dibenzoyltartaric acid, malic acid, diacetyltartaric acid, pyrrolidine-5-carboxylic acid. , and similars. The separated pure diastereomeric salts can then be cleaved by standard methods, such as treatment with a base, to obtain the (S) - or (R) -enantiomer of a compound of formula I. Alternatively, the (S) - or (R) - enantiomer of a compound of formula I can be prepared by conventional methods such as synthesis with an intermediate individual stereoisomer and reaction such that the center chiral is not affected. For example, the compounds of formula I can be prepared from optically pure hydroxymethyl piperidine compounds following the procedures described in reaction scheme II. An optically pure hydroxymethyl piperidine compound can be obtained by reducing an enantiomer of an ethyl piperidinecarboxylate derivative. The separation of the ethyl 3-piperidinecarboxylate with a salt of an optically active acid to form the (R) - and (S) - optically active enantiomers, has several examples in the chemical literature, for example, Zeng et al. , Chirali try 1995, 7, 90-95; and Akkerman et al. , Rec. Trav. Chim. Pays -Bas 1951, 70, 899-916. It has been found that the compounds of formula I and their pharmaceutically acceptable salts and N-oxides possess pharmacologically valuable properties. In particular, they have been found to be useful as sodium channel blockers in standard laboratory tests. The ability of the compounds of formula I to block sodium channels can be demonstrated by various assays already known to those skilled in the art, such as the Kourtney and Stricharz in vitro trial described in Local Anesthetics, Springer-Verlag, New York , 1987, or a modification thereof. The assay is described in example 18. The ability of the compounds of formula I to block sodium channels can also be demonstrated in in vivo assays, such as the allodynia mechanical assay described in FIG. example 19; the cold allodynia test as described in example 20; the mechanical hyperalgesia assay described in Example 21; and the thermal hyperalgesia described in example 22. Accordingly, these compounds and pharmaceutically acceptable compositions containing them are useful in regulating the physiological phenomena related to sodium channel blockage and are potentially effective therapies for a variety of syndromes of chronic neuropathic pain, including peripheral neuropathies such as trigeminal neuralgia, postherpetic neuralgia, glaso-pharyngeal neuralgia; neuropathy secondary to metastatic infiltration; and pain from burning. Clinical evidence confirms the therapeutic role of sodium channel blockers in the treatment of neuropathic pain originating in the peripheral nervous system, including cervical and lumbar radiculopathies (Nagaro et al., Japanese J. Anesthesiology 1995, 44, 862-867 , - Ferrante et al., Anesthesia &Analgesia 1996, 82, 91-97), diabetic neuropathy (Dejgard et al., Lancet 1988, 1, 9-11), neuralgic pain (Marchettini et al., Pain 1992, 48 , 377-382; Rowbotham, MC et al., Neurology 1991, 41, 1024-1028), and peripheral nerve injury (Chabal et al., Anesthesiology 1992, 76, 513-517). In addition to these conditions, two retrospective clinical studies have found that these agents provide partial or complete relief of pain associated with sympathetic reflex dystrophy and causalgia (Edwars et al., Regional Anesthesia 1985, 10, 1-6, Galer et al. , Neurology 1993, 43, 1233-1235). The conditions of central pain after a stroke, thalamic lesions and multiple sclerosis have also responded to treatment with these agents (Edmondson et al., Southern Med. J. 1993, 86, 1093- 5 1096; Nagaro et al., 1995). ). Clinical and experimental evidence confirms the therapeutic role of sodium channel blockers in the treatment of cancer pain (Nagaro et al., 1995 idem; Chong et al., J. Pain & Symptom Management 1997. 13, 112-117) and in many states of chronic non-malignant pain, including pain of musculoskeletal origin, painful adiposis (Arkinson et al., International J. Obesity 1982, 6, 351-357; Petersen, P. and Kastrup, J. Pain 1987, 28, 77-80) and cluster headaches (Robbins et al., Headache 1995, 35, 83-84) or headaches of migraine (Kudrow et al., Headache 1995, 35, 79-82; Maizels et al., JAMA 1996, 276, 319-321). The experimental evidence confirms the therapeutic role of sodium channel blockers as neuroprotective or cerebroprotective agents, and can provide an effective strategy against neurological injury (eg ischemia, head trauma, hypoxia, stroke). In rodent models, beneficial long-term effects on neurological deficit, cognitive deficit and brain injury after occlusion of the middle cerebral artery 25 were demonstrated (Smith, S.E., Neuroscience 1997, 77, 1123-1135); neuroprotective, anticonvulsive and sedative properties in transient global cerebral ischemia (Doble, A., Neurology 1996, 47 (6 Suppl 4), S233-41); and reduction of brain injury ischemic after the model of acute subdural hematoma (Tsuchida E. et al., J. of Neurosurgery 1996, 85, 104-111).

Clinical evidence confirms the therapeutic role of sodium channel blockers in priority analgesia at low, non-toxic systemic concentrations (Strichartz, G., Anesthesiology 1995, 83, 654-655). In many surgical procedures, hypersensitivity reactions to tactile and painful stimuli can result in disruption to soft tissues or a major nerve. This may be apparent for several weeks or even longer after the initial surgery. Since sodium channels play a fundamental role in neuronal hyperexcitability, priority treatment with a channel blocker can limit any potential hypersensitivity reaction to surgery. By applying the compounds of this invention to the treatment of the aforementioned conditions, the administration of the active compounds and their salts described herein can be by any of the accepted modes of administration, including oral (including sublingual or buccal), nasal, parenteral and other systemic routes of administration. Any pharmaceutically acceptable mode of administration, including solid, semi-solid or liquid dosage forms, such as for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, sprays or the like, preferably in dosage forms, may be employed. units suitable for the individual administration of dosages Precisely, or in delayed or controlled release dosage forms for prolonged administration of the compound at a predetermined rate. The compositions typically include a conventional pharmaceutical carrier or excipient and an active compound of formula I or the pharmaceutically acceptable salts thereof, and in addition, may contain other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc. The amount of active compound administered will obviously depend on the subject to be treated, the severity of the disease, the manner of administration and the opinion of the prescribing physician. However, an effective dose for oral, parenteral and other systemic routes of administration is in the range of about 0.1-5 mg / kg / day. For an average of 70 kg of humans, this represents an amount of approximately 10-350 mg per day. An expert normally skilled in the treatment of these diseases will be able, without undue experimentation and depending on the personal knowledge and description of this application, to determine the therapeutically effective amount of a compound of formula I for a given disease. For solid compositions, conventional non-toxic solid supports include, for example, pharmaceutical grades of mannitol, lactose, cellulose, cellulose derivatives, croscarmellose sodium, starch, magnesium stearate, sodium saccharine, talc, glucose, sucrose, carbonate. of magnesium and the like. The active compound as has been defined above, can be formulated in the form of suppositories, using for example, polyalkylene glycols, acetylated triglycerides and the like as supports. The pharmaceutically administrable liquid compositions can, for example, be prepared by dissolving, dispersing, etc. an active compound as defined above and optional pharmaceutical adjuvants, in a support, such as for example, water, saline, aqueous dextrose, glycerin, ethanol and the like, to form a solution or suspension thereof. If desired, the pharmaceutical composition to be administered may also contain small amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate , triethanolamine oleate, etc. The composition of the formulation to be administered will in any case contain an amount of the active compound (s) in an amount effective to alleviate the symptoms of the subject to be treated. Dosage forms or compositions containing the active ingredient (compounds of formula I or their salts) in the range of 0.25 to 95% with the remaining% complete with a non-toxic support can be prepared. For oral administration, a pharmaceutically acceptable non-toxic composition is formed by the incorporation of any excipients normally employed, such as, for example, pharmaceutical grades of mannitol, lactose, cellulose, cellulose derivatives, crosscarmellose sodium, starch, magnesium stearate, sodium saccharin, talc, glucose, sucrose, magnesium carbonate and the like. These compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, delayed-release formulations and the like. Said compositions may contain l% -95% active ingredient, more preferably 2-80%, and most preferably 5-50%. Parenteral administration is generally characterized by injection, either subcutaneous, intramuscular or intravenous. The injectables can be prepared in conventional ways, as liquid solutions or as suspensions, solid forms suitable for solution or suspension in liquid before injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerin, ethanol or similar. In addition, if desired, the pharmaceutical compositions to be administered may also contain small amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as, for example, sodium acetate, sorbitan monolaurate, oleate of triethanolamine, triethanolamine sodium acetate, etc. A more recently invented method for parenteral administration uses the implant of a slow release or uninterrupted release system, such that a constant level of dosage is maintained. See p. ex. the U.S. patent No. 3,710,795. The percentage of active compound contained in said parental compositions is highly dependent on the specific nature of the same, as well as the activity of the compound and the needs of the subject. However, percentages of active substance from 0.1% to 10% in solution can be used, and will be higher if the composition is a solid which must then be diluted in the above percentages. Preferably, the composition will comprise 0.2-2% of the active agent in solution. The composition of the present invention can also be formulated for administration in any convenient form by analogy with other topical compositions adapted for use in mammals. These compositions may be presented for use in any conventional manner with the aid of a wide variety of pharmaceutical carriers or carriers. For such topical administration, a non-toxic pharmaceutically acceptable formulation can take a semi-solid, liquid or solid form such as, for example, gels, creams, lotions, solutions, suspensions, ointments, powders, or the like. As an example, the active components can be formulated in a gel using ethanol, propylene glycol, propylene carbonate, polyethylene glycols, diisopropyl adipate, glycerin, water, etc., with appropriate gelling agents, such as Carbomers, Klucels, etc. If desired, the formulation may also contain small amounts of non-toxic auxiliary substances such as preservatives, antioxidants, pH buffering agents, surfactants, and the like. Current methods for preparing such dosage forms are already known, or will be apparent to those skilled in the art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 19th edition, 1995. Preferably, the pharmaceutical composition is administered in an individual unit dosage form for continuous treatment or in an individual "ad libitum" unit dosage form when it is specifically necessary to relieve symptoms. Representative pharmaceutical formulations containing a compound of formula I are described in examples 12-17. EXAMPLES The following preparations and examples are provided to enable those skilled in the art to better understand and practice the invention. They should not be considered as a limit for the purpose of the invention, but as merely illustrative and representative of them. PREPARATION 1 Preparation of compounds of formula (1) A. Preparation of (1), wherein R2 and R6 are methyl, R3 and Rs are hydrogen and R4 is 3-nitrophenyl To a solution of 4-bromo-2,6-dimethylphenol (2.58 g, 12.8 mmol) and 3-nitrophenylboronic acid (2.08 g, 12.5 mmol) in toluene (50 mL), tetrakis (triphenylphosphine) palladium (0) (0.48 g, 0.42 mmol) and 2M sodium carbonate (6.3 ml, 13 mmol). The mixture was stirred at 100 ° C for 22 hours after which more palladium catalyst (150 mg) was added. The mixture was heated for a further 20 hours and then cooled to room temperature. The mixture divided between water and ethyl acetate. The organic layer was dried and concentrated. The residue was purified on silica gel, eluting with 12% ethyl acetate in hexanes, to give 4- (3-nitrophenyl) -2,6-dimethylphenol as a yellow solid (0.932 g, 31%) . B. Preparation of (ld) wherein R2 and Rs are methyl, R3 and Rs are hydrogen and A is 2,2,2-trifluoroethyl. 2,2,2-trifluoroethyl triflate (1.02 g, 4.40 mmol) was added. and potassium carbonate (1.10 g, 1.01 mmol) to a solution of 4-hydroxy-2,6-dimethylphenyl acetate (673 mg, 3.73 mmol) in 2-butanone (15 mL). The mixture was stirred at 70 ° C for 72 hours, then cooled to room temperature and concentrated. The residue was partitioned between water and ethyl acetate. The organic layer was washed twice with water and brine and dried. The solvent was removed in vacuo and the residue was purified with silica gel eluting with 10% ethyl acetate in hexanes, obtaining 2,6-dimethyl-4- (2,2,2-trifluoroethoxy) phenyl acetate (733 mg, 75%). The 2,6-dimethyl-4- (2,2,2-trifluoroethoxy) phenyl acetate (733 mg, 2.80 mmol) in methanol (10 ml) was treated with sodium metal and stirred at room temperature during the night. The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed twice with brine and dried. The solvent was removed obtaining 2,6-dimethyl-4- (2,2,2-trifluoroethoxy) phenol. PREPARATION 2 Preparation of compounds of formula (2) A. Preparation of (2) wherein R 1 is methyl and Y is p-toluenesulfonyl A solution of (R) -3-hydroxymethyl-1-methylpiperidine (2.6 g, 20 mmol) in dichloromethane (70 ml) was cooled to 5 ° C and tosyl chloride (3.8 g, 20 mmol) was added in portions over 15 minutes. After the addition was complete, the reaction was allowed to warm to room temperature and was stirred for 20 hours. The reaction mixture was then concentrated and the residue was partitioned between 10% potassium hydroxide (50 ml) and ether (100 ml). The ether layer was separated and the aqueous phase was extracted once more with ether (50 ml). The combined ether layers were dried with magnesium sulfate and concentrated to give (R) -3-tosyloxymethyl-1-methylpiperidine as a white solid (2.4 g, 42% mp 74.5-81.0). ° C). B. Preparation of (2a) wherein P is tert-butoxycarbonyl) The ethyl 3-piperidinecarboxylate (200 g) was combined with (-) - D-tartaric acid (191 g) in hot 95% ethanol. The resulting precipitate was filtered and recrystallized six times from 95% ethanol to obtain the (S) -3-piperidinecarboxylate ethyl D-tartrate salt of high optical purity as determined by chiral HPLC analysis. Aqueous sodium hydroxide (31.2 g in 100 ml of water) was added to a solution of (S) -ethyl-3- piperidine carboxylate D-tartrate salt (100 g) in tetrahydrofuran (1 liter) maintaining the temperature below 8CC. Once the addition was complete, di-tert-butyl dicarbonate was added (100 g) in tetrahydrofuran (200 ml), dropwise, at a temperature maintained below 10 ° C. After 2.5 hours, the reaction was partitioned between ethyl acetate (2 liters) and water (2 liters). The organic layer was removed, washed with water (2 X 500 ml) and brine (300 ml), dried with magnesium sulfate and concentrated. The residue was dissolved in dry tetrahydrofuran (1 liter) and cooled to 10 ° C. Lithium borohydride (200 ml of a 2.0 M solution in tetrahydrofuran) was added, dropwise, at a temperature maintained below 10 ° C, and the reaction was stirred at room temperature for 24 hours. An additional amount of lithium borohydride solution (20 ml) was added and the reaction mixture was stirred another 20 hours at room temperature. Sodium sulfate decahydrate (50 g) was added slowly, and the mixture was filtered. The solids were washed with ethyl acetate (200 ml), concentrated, and partitioned between ether (1 liter) and brine (500 ml): The ether layer was dried with magnesium sulfate obtaining (S) -N - (tert-butoxycarbonyl) -3-hydroxyethylpiperidine in the form of a white solid (47 g). PREPARATION 3 Preparation of compounds of formula (3) A. Preparation of (3) wherein R2 and Rs are methyl, R3, R4 and R5 are hydrogen, and P is tert-butoxycarbonyl (S) -N- ( butoxycarbonyl) -3-hydroxy-methylpiperidine (11.0 g, 51.1 mmol) and triphenylphosphine (14.7 g, 56.2 mmol) under a dry nitrogen atmosphere, to a solution of 2,6-dimethylphenol (6, 24 g, 51.1 mmol) dissolved in tetrahydrofuran if * rn (rsrs mi - T ---. -. «I ..-- • < - - - * - • - ice and diethyl azodicarboxylate (6.9 ml, 56.2 mmol) in tetrahydrofuran (40 ml) was added dropwise at a suitable rate to maintain the temperature below 10 ° C. Once the addition was complete, the mixture was allowed to stir at room temperature for 48 hours. The reaction mixture was partitioned between ethyl acetate (1 liter) and water (1 liter). The organic layer was washed with water (3 X 300 ml), brine (200 ml), dried, filtered and chromatographed on silica gel, eluted with ethyl acetate / hexanes (9: 1) and concentrated to obtain the (S) -N- (tert-butoxycarbonyl) -3- (2,6-dimethyl-phenoxymethyl) piperidine in the form of a clear oil (13.0 g, 45.2%). B. Preparation of (3) wherein R2 and R6 are methyl, R3 and R5 are hydrogen. R 4 is bromine, and P is tert-butoxycarbonyl. A solution of diethyl azodicarboxylate (16.1 ml, 102.2 mmol) in tetrahydrofuran (50 ml) was added dropwise over 1 hour., 5 hours to an ice-cooled solution of (S) -N- (tert-butoxycarbonyl) -3-hydroxymethylpiperidine (20.0 g, 92.9 mmol), 4-bromo-2,6 dimethylphenol (18.7 g , 92.9 mmol), and triphenylphosphine (26.8 g, 102.2 mmol) in tetrahydrofuran (300 mL), keeping the temperature below 10 ° C. After the addition was complete, the reaction was stirred at room temperature for 48 hours and partitioned between ethyl acetate (1 liter) and water (1 liter). After extracting the aqueous phase with more ethyl acetate (2 X 200 ml), the combined ethyl acetate layers were washed with brine (250 ml), dried with magnesium sulfate, and concentrated to obtain a thick yellow oil. The oil was combined (T-n hova n / ---- r-r- ~ .t »-« • - ' minutes The resulting white precipitate was removed by filtration and washed with more hexane (50 ml). The combined filtrates were concentrated to obtain crude (S) -N- (tert-butoxycarbonyl) -3- (4-bromo-2,6-dimethyl phenoxymethyl) piperidine, in the form of a clear yellow oil (44 g) . EXAMPLE 1 Preparation of compounds of formula A. Preparation of. wherein R2 and R6 are methyl, R3 and R5 are hydrogen, and R4 is bromine. Trifluoroacetic acid (80 ml) was added dropwise, over 20 minutes, to a solution of (S) -N-fterc-butoxycarbo-nil) - 3- (4-Bromo-2,6-dimethylphenoxymethyl) piperidine (37.0 g, 92.9 mmol) in dichloromethane (250 ml) at a temperature of 5 ° C. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The solvent was then evaporated and the residue was partitioned between 25% aqueous sodium hydroxide (200 ml) and ether (500 ml). The organic layer was removed and the aqueous phase was extracted with more ether (2 X 300 ml). The combined ether layers were washed with brine (100 ml), stirred with magnesium sulfate for 2 hours, and filtered, whereby a solution of (S) -3- (4-bromo-2, 6-dimethylphenoxymethyl) piperidine. The (S) -3- (4-bromo-2,6-dimethylphenoxymethyl) piperidine in ether was treated with 1M solution of hydrochloric acid in ether (102 ml). The resulting white precipitate was filtered, and dried in vacuo, yielding (S) -3- (4-bromo-2,6-dimethylphenoxymethyl) hydrochloride i.t- ?, r > -.- -i -? .- 280 ° C). B. Similarly, substituting (S) -N- (tert-butoxycarbonyl) -3- (4-bromo-2,6-dimethylphenoxymethyl) piperidine for other compounds of formula (3), and following the procedures of Example IA, the following compounds of the formula were prepared: 3- (4-bromo-2,6-dimethylphenoxymethyl) piperidine hydrochloride, mp 263, 3-264, 7 ° C; 3- (2,6-Dimethylphenoxymethyl) piperidine hydrochloride, p. F. 204, 1-205, 7 ° C; (S) -3- (2,6-Dimethylphenoxymethyl) piperidine hydrochloride, m.p. 228.4-229, 8 ° C; 3- (4-Chloro-2,6-dimethylphenoxymethyl) piperidine hydrochloride, m.p. 176.1-178, 2 ° C. EXAMPLE 2 Preparation of a compound of formula I Preparation of I. wherein R1 R2 and R6 are methyl. R3 and R5 are hydrogen, and R4 is bromo A. 3-hydroxymethyl-1-methylpiperidine (0.4 ml, 3.14 mmol) and triphenylphosphine (1.01 g, 3.85 mmol) were added to a solution of 4. -bromo-2, 6-dimethylphenol (517 mg, 2.57 mmol) in tetrahydrofuran (10 ml) at 0 ° C under dry nitrogen, and then diethyl azodicarboxylate (0.57 ml, 3%) was added dropwise. , 60 mmol). The mixture was stirred at 0 ° C for 4 hours and the solvent was removed in vacuo. The residue was purified with silica gel eluting with 5% methanol in dichloromethane containing 0.25% ammonium hydroxide, yielding 3- (4-bromo-2,6-dimethylphenoxymethyl) -l-methylpiperidine as an ointment. ------- _--- • - - • • The 3- (4-bromo-2,6-dimethylphenoxymethyl) -l-methyl-piperidine was treated with 1 N hydrochloric acid in ether, and the precipitated salt was recrystallized from acetonitrile / erc-butyl methyl ether, yielding the hydrochloride of 3N. - (4-bromo-2,6-di-methylphenoxymethyl) -l-methylpiperidine, mp 180, 9-183, 5 ° C. B. Similarly, following the procedures of example 2A above, but substituting 4-bromo-2,6-dimethylphenol with other compounds of formula (1), other compounds of formula I were prepared: Hydrochloride of 3- (2, 6 dimethylphenoxymethyl) -l-methylpiperi-dine, mp 163, 2-163, 7 ° C. Fumarate of 3- (fluoro-2,6-dimethylphenoxymethyl) -1-methyl-piperidine, m.p. 155, 4-155, 9 ° C; 3- (4-Chloro-2,6-dimethylphenoxymethyl) -1-methylpiperidine hydrochloride, m.p. 160, 1-161, 3 ° C; 3- (4-Methoxy-2,6-dimethylphenoxymethyl) -1-methyl-piperidine fumarate, m.p. 171, 1-172, 3 ° C; 3- [4-2,2, 2-Trifluoroethoxy) -2,6-dimethyl-phenoxymethyl) -l-methylpiperidine hydrochloride, m.p. 124, 7-125, 8 ° C; 3- (2,4-, 6-Trimethylphenoxymethyl) -1-methyl-piperidine hydrochloride, m.p. 169, 0-171, 2 ° C; 3- (2,6-Dimethyl-4-phenylphenoxymethyl) -l-methylpiperidine hydrochloride, m.p. 243, 6-244, 6 ° C; 3-Phenoxymethyl-1-methylpiperidine hydrochloride, m.p. 155, 2-156, 2 ° C; 3- (4-Chlorophenoxymethyl) -1-methylpiperidine hydrochloride, m.p. 211, 4-211, 6 ° C; 3- (4-Bromophenoxymethyl) -1-methylpiperidine hydrochloride, D.f. -i. 3- (4-Methoxyphenoxymethyl) -1-methylpiperi-dine hydrochloride, m.p. 148, 3-148, 9 ° C; 3- (2-Methylphenoxymethyl) -l-methylpiperidine hydrochloride, m.p. 191, 6-192, 3 ° C; Hydrochloride 3- (3-methylphenoxymethyl) -1-methylpiperidine, m.p. 140, 8-141, 9 ° C; 3- (4-Methylphenoxymethyl) -l-methylpiperidine hydrochloride, m.p. 173, 8-174, 5 ° C; 3- (2,4-Dimethylphenoxymethyl) -1-methylpipe-ridine hydrochloride, m.p. 180, 3-183, 5 ° C; 3- (3,5-Dimethylphenoxymethyl) -1-methylpipe-ridine hydrochloride, m.p. 182, 0-182, 5 ° C; 3- (4-Bromo-2-methylphenoxymethyl) -1-methyl-piperidine hydrochloride, m.p. 192, 9-193, 3 ° C; 3- (2,6-Dichlorophenoxymethyl) -1-methylpiperidine hydrochloride, m.p. 170, 5-172, 2 ° C; 3- (2,6-Dichloro-4-fluorophenoxymethyl) -1-methylpiperidine hydrochloride, m.p. 151, 0-151, 7 ° C; 3- (2,4,6-Trichlorophenoxymethyl) -1-methyl-piperidine hydrochloride, m.p. 159, 9-160, 4 ° C; 3- [2,6-Dimethyl-4- (3-nitrophenyl) phenoxymethyl] -l-methylpiperidine hydrochloride, m.p. 198, 5-199, 5CC; and 3- [4- (tert-Butyldimethylsilyloxy) -2,6-dimethylphenoxymethyl] -l-methylpiperidine, XH NMR (300 MHz, CDC13): δ 0.16 (s, 6H), 0.96 (s, 9H) , 1.10-1.19 (m, HH), 1.63-1.96 (m, 5H), 2.10-2.18 (m, HH), 2.19 (s, 6H), 2, 30 (s, 3H), 2.79 (br d, J »11 Hz, ÍH), 3.11 (br d, J = 11 Hz, ÍH), 3.56 (d, J = 6 Hz, 2H) 6.45 (s, 2H).

C. Alternatively, a solution of (R) -3-tosyl-oxymethyl-1-methylpiperidine (100 mg, 0.35 mmol), 4-bromo-2,6-dimethylphenol (75 mg, 0.37 mmol), and Cesium carbonate (240 mg, 0.74 mmol) in dimethylformamide (4 ml) was heated at 65 ° C under a nitrogen atmosphere for 1.5 hours. The solution was cooled to room temperature and partitioned between ethyl acetate (50 ml) and water (30 ml). The organic layer was separated and the aqueous phase was extracted once more with ethyl acetate (30 ml ml). The combined ethyl acetate layers were dried with magnesium sulfate and concentrated to obtain (R) -3- (4-bromo-2,6-dimethylphenoxymethyl) -l-methylpiperidine as a clear oil. This material was identical to that prepared in Example 2E when analyzed by chiral HPLC (Chiralpak AD, 97: 3: 0.1 hexane / 2-propanol / diethylamine). D. Alternatively, formic acid (16.7 ml, 333 mmol) and aqueous formaldehyde (37%, 9.1 ml) were added dropwise to (S) -3- (4-bromo-2,6-dimethylphenoxymethyl) piperidine (24.1 g, 80.8 mmol), cooling in an ice bath. Once the addition was complete, the reaction was placed in an oil bath at a temperature of 95 ° C for 4 hours. The mixture was cooled to room temperature and partitioned between 15% aqueous sodium hydroxide (200 ml) and ether (600 ml). The aqueous phase was extracted twice more with an additional amount of ether (300 ml), and the ether layers were combined, washed with brine (150 ml), dried and concentrated. The residue was chromatographed with silica gel, eluting with acetone / hexanes (1: 1) and concentrated to give (S) -3- (4-bromo-, 6-dimethylphenoxymethyl) -l-methylpiperidine as an oil. transparent. (S) -3- (4-Bromo-2,6-dimethylphenoxymethyl) -1-methyl-piperazine was dissolved in ether (600 ml) and treated with an IN solution of hydrochloric acid in ether (90 ml). . The resulting white precipitate was filtered and dried in vacuo to obtain (S) -3- (4-bromo-2,6-dimethylphenoxymethyl) -1-methyl-piperidine hydrochloride (25.5 g 87%, mp 209.7). -210, 5 ° C). E. Similarly, substituting (S) -3- (4-bromo-2, 6-dimethylphenoxymethyl) -piperidine for (R) -3- (4-bromo-2,6-dimethylphenoxymethyl) -piperidine and following In the procedures of example 2D above, the compound (J2 -3- (4-bromo-2,6-dimethylphenoxymethyl) -1-methylpperidine, mp211.6-212, 6 ° C was prepared. EXAMPLE 3 Alternative preparation of a compound of formula I Preparation of I wherein R.sup.1, R.sup.2 and R.sup.6 are methyl R.sup.3 R.sup.4 and R.sup.s are hydrogen A. A solution of aluminum lithium aluminum hydride in tetrahydrofuran (45 ml, 45 moles) was added dropwise over 30 minutes at (S) -N- (tert-butoxycarbonyl) -3- (2, 6-dimethylphenoxymethyl) piperidine (13.0 g, 40.6 mmol) in dry tetrahydrofuran (250 ml) under a dry nitrogen atmosphere. After the addition was complete, the reaction mixture was heated at reflux for 4 hours, stirred at room temperature for 20 hours, and quenched by cautiously adding sodium sulfate decahydrate (70 g). The sodium sulfate was removed by filtration and washed with ethyl acetate (3 X 150 ml). The combined filtrates were concentrated and the residue was chromatographed with silica gel, eluting with dichloromethane methanol (9.5: 0.5) to obtain (S) -3- (2,6-dimethylphenoxymethyl) -l-methylpiperidine as a clear oil (8.0 g). The (S) -3- (2,6-dimethylphenoxymethyl) -l-methylpiperidine (8.0 g) was dissolved in ether (500 ml) and treated with an IN solution of hydrochloric acid in ether (37.7 ml). . The thick white precipitate was filtered off, washed with ether (75 ml) and dried to obtain (S) -3- (2,6-dimethylphenoxymethyl) -1-methylpiperidine hydrochloride (8.6 g, 93%). , mp 149.8-151, 3 ° C). B. Similarly, substituting (S) -N- (tert-butoxycarbonyl) -3- (2,6-dimethylphenoxymethyl) piperidine for other compounds of formula (3), and following the procedures of Example 3A above, the following compounds of formula I were prepared: (R) -3- (2,6-dimethylphenoxymethyl) -1-methyl-piperidine hydrochloride, mp 151, 7-152, 8 ° C; (S) -3- (4-Chloro-2,6-dimethylphenoxymethyl) -1-methylpiperidine hydrochloride, m.p. 172, 0-173, 0 ° C; (S) -3-phenoxymethyl) -l-methylpiperidine hydrochloride, m.p. 152, 7-153, 2 ° C; and (R) -3-phenoxymethyl) -1-methylpiperidine hydrochloride, m.p. 152, 5-153, 4 ° C. EXAMPLE 4 Alternative preparation of a compound of formula I Preparation of I wherein R 1 is cyclopropylmethyl. R2 and R6 are methyl, and R3, R4 and R5 are hydrogen A. Cyclopropylcarbonyl chloride (1.7 ml, 18 mmol) was added dropwise over 15 minutes to an ice-cooled mixture containing (S) -3- (2,6-di-ethylphenoxymethyl) piperidine hydrochloride (4, 4 g, 17 mmol), aqueous sodium bicarbonate (75 ml), and ethyl acetate (100 ml). After the addition was complete, the reaction was stirred at room temperature for one hour, and the resulting ethyl acetate layer was separated and concentrated. The residue was dissolved in dry tetrahydrofuran (125 ml) under a dry nitrogen atmosphere and an IVM lithium aluminum hydride solution in tetrahydrofuran (18.9 ml) was added dropwise. After the addition was complete, the reaction mixture was heated to reflux for 2 hours, then cooled to room temperature. Sodium sulfate decahydrate (10 g) was added slowly while stirring, and the mixture was filtered. The filtrate was concentrated and chromatographed with silica gel, eluting with acetone / hexanes (1: 3) to obtain (S) -l-cyclopropylmethyl-3- (2,6-dimethyl-phenoxymethyl) piperidine as an oil. The (S) -l-cyclopropylmethyl-3- (2,6-dimethylphenoxymethyl) piperidine was dissolved in anhydrous ether (125 ml) and treated with IN hydrochloric acid in ether (18.9 ml). The white precipitate was collected and dried under vacuum to obtain the hydrochloride of (S) -l-cyclopropylmethyl-3- (2,6-dimethylphenoxymethyl) -piperidine (3.6 g, 66%, p.f. 137, 3-137, 5 ° C). B. Similarly, replacing the hydrochloride of (S) -3- (2,6-dimethylphenoxymethyl) piperidine by other compounds of formula la, and optionally substituting cyclopropylcarbonyl chloride for other acid chlorides, and following In the procedures of Example 4A above, the following compounds of formula I were prepared: l-cyclopropylmethyl-3- (2,6-dimethylphenyl-oxymethyl) piperidine hydrochloride, m.p. 147, 5-148, 0 ° C; (R) -l-Cyclopropylmethyl-3- (2,6-dimethyl-phenoxymethyl) piperidine hydrochloride, m.p. 137, 2-138, 1 ° C; 3- (2,6-Dimethylphenoxymethyl) -1-ethylpipe-ridine hydrochloride, m.p. 157, 2-160, 0 ° C; 3-Phenoxymethyl-1-ethylpiperidine hydrochloride, m.p. 168, 3-169, 8 ° C; and 3-Phenoxymethyl-1-cyclopropylmethylpiperi-dine hydrochloride, m.p. 151, 7-153, 3 ° C. EXAMPLE 5 Alternative preparation of a compound of formula I Preparation of I wherein R 1 is 2-dimethylaminoethyl. R2 and R6 are methyl, and R3. R4 and R5 are hydrogen Chloroacetyl chloride (1.5 ml, 19 mmol) was added dropwise to a mixture of 3- (2,6-dimethyl-phenoxymethyl) piperidine hydrochloride (4.0 g, 16 mmol) in saturated aqueous sodium bicarbonate solution (70 ml) and ether (10 ml) cooled with an ice bath. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The ether layer was separated and concentrated, and the residue was treated with anhydrous methanol (100 ml) by cooling in an ice bath. Dimethylamine gas was bubbled through the solution slowly for 15 minutes and the mixture was stirred at room temperature for 20 hours. The solvent was evaporated and the residue was treated with anhydrous tetrahydrofuran (150 ml) under nitrogen, and an IVM lithium aluminum hydride solution in tetrahydrofuran (17.2 ml) was added. The reaction mixture was refluxed for 4 hours and stirred at room temperature for 20 hours. Sodium sulfate decahydrate (25 g) was added slowly and the mixture was filtered. The solid was washed twice with ethyl acetate (100 ml) and the combined organic layers were concentrated. The residue was partitioned between 10% hydrochloric acid (40 ml) and ether (50 ml). The aqueous layer was basified with 50% potassium hydroxide and extracted with ether (3 X 50 ml). The combined ether layers were washed with brine (100 ml) and dried to obtain a solution of 3- (2,6-dimethylphenoxymethyl) -1- (2-dimethylaminoethyl) piperidine. The solution of 3- (2,6-dimethylphenoxymethyl) -1- (2-dimethylaminoethyl) piperidine was treated with an INM solution of hydrochloric acid in ether (17.2 ml). The resulting precipitate was separated by filtration, then dried in vacuo to obtain 3- (2,6-dimethylphenoxymethyl) -1- (2-dimethylaminoethyl) piperidine hydrochloride (4.0 g, 71%, mp 263.2-). 263, 5 ° C). EXAMPLE 6 Alternative preparation of a compound of formula I Preparation of I wherein R 1 is 3-methanesulfonamidopropyl. R2 and R6 are methyl, and R3. R4 and R5 are hydrogen The 3- (2,6-dimethylphenoxymethyl) piperidine hydrochloride (1.0 g, 3.9 mmol) in ethyl acetate (60 ml) was suspended and washed with 10% aqueous sodium hydroxide. (50 ml).

After the ethyl acetate was removed, it was dried and concentrated and the residue was dissolved in dimethylformamide (15 ml). Potassium carbonate (0.65 g, 4.7 mmol) was added, and then N- (3-chloropropyl) -methanesulfonamide (810 mg, 4.7 mmol) was added dropwise to the mixture which was then stirred at room temperature for 20 hours, and partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous phase was extracted with more ethyl acetate (2 X 50 ml), and the combined layers of ethyl acetate were washed with brine (60 ml), dried and concentrated. The residue was chromatographed with silica gel, eluting with acetone / hexanes (1: 1) containing 1% triethylamine, and concentrated to obtain 3- (2,6-dimethylphenoxymethyl) -1- (3-methanesulfonamido) propylpiperidine in the form of a transparent oil. The 3- (2,6-dimethylphenoxymethyl) -1- (3-methanesulfonamido) propyl-piperidine was dissolved in ether (30 ml) and treated with INM hydrochloric acid in ether (4.7 ml). The resulting white precipitate was filtered off to obtain 3- (2,6-dimethylphenoxymethyl) -1- (3-methanesulfon-amido) propylpiperidine hydrochloride (650 mg, 43%, m.p., decreased to 51 ° C). EXAMPLE 7 Alternative preparation of a compound of formula I Preparation of I wherein R1. R2 and R6 are methyl, R3 and Rs are hydrogen, and R4 is hydroxyl To a solution of 3- [4- (erc-butyldimethylsilyloxy) -2,6-dimethylphenoxymethyl] -1-methylpiperidine (3.2 g, 8.8 mmoles) in tetrahydrofuran (50 ml) containing 20% acetic acid (5.5 ml, 19 mmol) at 0 ° C, tetrabutylammonium fluoride was added IM in tetrahydrofuran (17.5 ml). The mixture was stirred at 0 ° C to room temperature overnight and concentrated in vacuo. The residue was partitioned between water and dichloromethane. The organic layer was dried and concentrated and the residue was purified with silica gel, eluted with 5% methanol in dichloromethane containing 0.25% ammonium hydroxide, obtaining 3- [4-hydroxy-2,6-dimethylphenoxymethyl] ] -1-methylpiperidine. This product was converted to the hydrochloride salt and recrystallized from ethanol / tert-butyl methyl ether to obtain 3- [4-hydroxy-2,6-dimethylphenoxymethyl] -1-methyl-piperidine hydrochloride (1.46 g, 58%). %, mp 224, 5-225, 5 ° C). EXAMPLE 8 Conversion of compounds of formula I into other compounds of formula I Preparation of I wherein R1. R2 and R6 are methyl. R3 and Rs are hydrogen, and R4 is 3-methoxyphenyl To a solution of 3- [4-bromo-2,6-dimethylphenoxymethyl] -1-methylpiperidine (531 mg, 1.70 mmol) in toluene (10 ml) was added 3-methoxyphenylboronic acid (319 mg, 2.10 mmol), tetrakis- (triphenylphosphine) palladium (0) (58 mg, 0.05 mmol), and carbonate 2M sodium (1.7 ml, 3.4 mmol). The mixture was stirred at 100 ° C overnight and cooled to room temperature. The solution was partitioned between water and ethyl acetate. The organic layer was washed twice with water, brine and dried. The solvent was removed and the residue was purified with silica gel, eluting with 5% methanol in dichloromethane containing 0.25% ammonium hydroxide, obtaining 3- [4- (3-methoxyphenyl) -2,6-dimethylphenoxymethyl] -l-methylpiperidine.

The product was converted to the hydrocarbon salt and crystallized with ethyl acetate to obtain 3- [4- (3-methoxyphenyl) -2,6-dimethylphenoxymethyl] -1-methylpiperidine hydrochloride (301 mg, 45%, mp 175 , 2-178, 8 ° C). EXAMPLE 9 Alternative conversion of compounds of formula I into other compounds of formula I Preparation of I wherein R1. R2 and R6 are methyl, R3 and R5 are hydrogen, and R4 is 3-aminophenyl A mixture of 3- [2,6-dimethyl-4- (3-nitrophenyl) phenoxymethyl] -l-methylpiperidine (785 mg, 2.21 mmoles), ethanol (10 ml), and ethyl acetate (5 ml) was hydrogenated overnight with platinum oxide (50 mg) at 1 atmosphere of hydrogen. The reaction was purged with nitrogen and filtered through Celite. The solids were washed with methanol and ethyl acetate. The filtrate and the washings were concentrated obtaining 3- [4- (3-aminophenyl) -2,6-dimethylphenoxymethyl] -l-methylpiperidine as a yellow oil (735 mg, quantitative). A portion of the oil (175 mg) was treated with IN hydrochloric acid in ether and crystallized from methanol / ether, yielding 3- [4- (3-aminophenyl) -2,6-dimethylphenoxymethyl] -1-methylpiperidine dihydrochloride ( 193 mg, mp 272.3-273, 9 ° C). EXAMPLE 10 Alternative conversion of compounds of formula I into other compounds of formula I Preparation of I wherein R1. R2 and R6 are methyl. R3 v R5 are hydrogen, and R4 is 3-acetylaminophenyl To a solution of 3- [4- (3-aminophenyl) -2,6-dimethylphenyl-oxymethyl] -1-methylpiperidine (513 mg, 1.58 mmol) in dichloromethane at 0 ° C was added pyridine (1.3 ml. , 16 mmol) and acetic anhydride (0.75 ml, 8.0 mmol). The mixture was stirred overnight at a temperature in the range of 0 ° C to room temperature, and diluted with water and ethyl acetate. The aqueous layer was extracted with dichloromethane (3X) and the organic layers were dried and concentrated. The residue was purified with silica gel eluting with 10% methanol / dichloromethane containing 0.5% ammonium hydroxide, obtaining 3- [4- (3-acetylaminophenyl) -2,6-dimethylphenoxymethyl] -1-methylpiperidine (479 mg , 82%). The 3- [4- (3-acetylaminophenyl) -2,6-dimethylphenoxymethyl] -l-methylpiperidine was treated with IN hydrochloric acid in ether and crystallized with methanol / tert-butyl methyl ether, obtaining the hydrochloride of 3- [ 4- (3-acetylaminophenyl) -2,6-dimethylphenyl-oxymethyl] -1-methylpiperidine, (mp 231, 0-231, 9 ° C). EXAMPLE 11 Preparation of an N-oxide of a compound of formula I Preparation of an N-oxide of I. wherein R1, R2 and R6 are methyl. R3 and Rs are hydrogen, and R4 is bromo. The hydrochloride of (S) -3- [4-bromo-2,6-dimethylphenoxymethyl] -1-methylpiperidine (338 mg, 0.97 mmol) was partitioned between ether and hydroxide. aqueous sodium. The ether was dried and concentrated to give an oil which was dissolved in dichloromethane (10 ml). To this solution was added m-chloroperbenzoic acid (327 mg, 50-60%). After 30 minutes, the reaction mixture was diluted with dichloromethane, then it was washed once with 10% aqueous sodium thiosulfate and three times with aqueous sodium bicarbonate. After drying, the dichloromethane solution was concentrated and the residue was recrystallized from ethyl acetate to obtain (S) -3- [4-bromo-2,6-dimethylphenoxymethyl] -1-methylpiperidine-N-oxide (90.1 mg, mp 210, 0-211, 0 ° C). B. Similarly, replacing the hydrochloride of (5,1-3- [4-bromo-2,6-dimethylphenoxymethyl] -1-methylpiperidine by (S) -3- (2,6-dimethylphenoxymethyl) -1-methylpiperidine hydrochloride, and following the procedures of the above example HA, (S) -3- (2,6-dimethylphenoxymethyl) -1-methyl-piperidine-N-oxide was prepared (mp 203, 5-204, 8 ° C) EXAMPLE 12 This example illustrates the preparation of a representative pharmaceutical formulation for oral administration containing an active compound of formula I, eg, (S) -3- (4-bromo-2,6-dimethylphenoxymethyl) -1-methoxychloride; Tilpiperidine Ingredients Amount per tablet, mgs.

Active compound 200 Lactose, spray dried 148 Magnesium stearate 2 The above ingredients are mixed and filled into a hard shelled gelatin capsule. Other compounds of the formula T -np-r can be used. active compound in the preparation of orally administrable formulations of this example. EXAMPLE 13 This example illustrates the preparation of another representative pharmaceutical formulation for oral administration containing an active compound of formula I, p. ex. , (S) -3- (4-Bromo-2,6-dimethylphenoxymethyl) -1-methyl-piperidine hydrochloride. Ingredients Amount per tablet, mgs.

Active compound 400 Corn starch 50 Lactose 145 Magnesium stearate 5 The above ingredients are intimately mixed and compressed into tablets with an individual notch. Other compounds of formula I can be used as the active compound in the preparation of the orally administrable formulations of this example. EXAMPLE 14 This example illustrates the preparation of a representative pharmaceutical formulation containing an active compound of formula I, p. ex. (S) -3- (4-Bromo-2,6-dimethylphenoxymethyl) -l-methylpiperidine hydrochloride. An oral suspension is prepared with the following composition: Ingredients Active compound 1-0 g Fumaric acid 0.5 g Sodium chloride 2.0 g Methyl paraben 0.1 g Granulated sugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.) 1 , 0 g Flavor 0.035 ml Dye 0.5 mg Distilled water cs for 100 ml Other compounds of formula I can be used as active compound in the preparation of administrable formulations of this example. EXAMPLE 15 This example illustrates the preparation of a representative pharmaceutical formulation for oral administration containing an active compound of formula I, p. ex. , (S) -3- (4-Bromo-2,6-dimethylphenoxymethyl) -1-methylpiperidine hydrochloride. A buffered injectable preparation is prepared at a pH of 4, which has the following composition: Ingredients Active compound 0.2 g Sodium acetate buffer solution (0.4 M) 2.0 ml HCl (1 N) q.s. for pH 4 Water (distilled, sterile) q.s. for 20 ml Other compounds of formula I can be used as active compound in the preparation of injectable formulations of this example. EXAMPLE 16 This example illustrates the preparation of a representative pharmaceutical formulation for topical application, containing an active compound of formula I, e.g., (S) -3- (4-bromo-2,6-dimethylphenoxymethyl) -hydrochloride. 1-methylpiperidine. Ingredients grams Active compound 0, 2-10 Span 60 2 Tween 60 2 Mineral oil 5 Vaseline 10 Methyl paraben 0.15 Propyl paraben 0.05 BHA (hydroxy anisole butylated) 0.01 Water q.s. for 100 ~~ Mix all the above ingredients, except water, and heat to 60 ° C, stirring. Then a sufficient amount of water is added at 60 ° C with vigorous stirring to emulsify the ingredients, and water q.s. for 100 g. Other compounds of formula I can be used as active compound in the preparation of topical formulations of this example. EXAMPLE 17 This example illustrates the preparation of a representative pharmaceutical formulation containing an active compound of formula I, p. ex. (S) -3- (4-Bromo-2,6-dimethylphenoxymethyl) -l-methylpiperidine hydrochloride. A suppository with a total weight of 2.5 grams is prepared, with the following composition: Ingredients Active compound 500 mg Witepsol H-15 * rest (* saturated vegetable fatty acid triglycerides, a product of Riches-Nelson, Inc., New York, N.Y.) Other compounds of formula I can be employed as the active compound in the preparation of suppository formulations of this example. EXAMPLE 18 In Vitro Sodium Channel Blocking Test This test determines the effectiveness of the compounds of formula I as sodium channel blockers in an in vi tro model by inhibiting the potential propagation of the action of the compound in nerve preparations. isolated The sodium channel assay was carried out as described in Kourtney and Stricharz Local Anesthetics, Springer Publishing, New York, 1987. It consists briefly of separatingthe vagus nerves of the rat, continually superfusing them with control solutions or solutions of the compounds that are investigated. Electrical shock was applied to the nerve to stimulate the propagation of nerve impulses. The amplitude of the synchronized potential of the action of the compound was measured; this was reduced when the sodium channel was blocked by the perfused compounds. These studies suggest that when tested with this method, the compounds of formula I behave as potent blockers of the sodium channel depending on the way they are used, particularly at high frequencies. EXAMPLE 19 Test of mechanical allodynia in vivo This test determines the effectiveness of the compounds of formula I in alleviating one of the symptoms in an in vivo model of neuropathic pain produced by spinal nerve ligation, ie, mechanical allodynia. Tactile allodynia was induced in the rats using the procedures described by Kim and Chung, Pain 1992, 50: 355-363. Briefly, the rats were anesthetized with an intraperitoneal dose of sodium pentobarbital (65 mg / kg) with additional doses of anesthetic as needed. Each animal was then placed in the prone position, a 3 cm lateral incision was made, and the left paraspinal muscles of the spinous process were separated at the L4-S2 level. The transverse process L6 was then removed in order to visually identify the spinal nerves L4-Ls. Next, the rafnn '- pn-3 T nerves were separated individually. silk. The wound was then closed in layers with silk sutures. These procedures produced rats that developed a significant increase in sensitivity to mechanical stimuli relative to normal rats, which did not induce any response. The mechanical sensitivity was determined using a procedure described in Chaplan et al. , J. Neurosci. Methods 1994, 53: 55-63. Briefly, a series of eight von Frey filaments of different stiffness strength were applied to the plantar surface of the hind paw on the same side of the ligatures with just enough force to bend the filament. The filaments were held in this position for no more than three seconds or until a positive allodynic response occurred in the rat. A positive alodinic response is that the affected leg is lifted and convulsions or shaking immediately occur. The order and frequency with which the individual filaments were applied was determined using the Dixon top-down method. The test was started with the central filament of each series, applying the following filaments consecutively, either ascending or descending, according to whether a negative or positive response, respectively, was obtained with the initial filament. The results showed that after one hour after oral administration, the compounds of formula I had a minimum effective dose as low as 300 mg / kg. Overall, it was found that the compounds of the present invention were effective in reversing similar mechanical symptoms to allodynia, when tested with this test. EXAMPLE 20 In vivo test of cold allodynia This test determines the efficacy of the compounds in the suppression of one of the symptoms of neuropathic pain produced by unilateral mononeuropathy, namely, cold allodynia. Unilateral mononeuropathy occurred in rats using the chronic oppression lesion model, effected essentially as described by Bennet and Xie, Pain 1988, 33: 87-107. Briefly, the rats were anesthetized with an intraperitoneal dose of sodium pentobarbital (65 mg / kg). The lateral part of the hind paw of each rat was shaved and rubbed with Novasan. Using an aseptic technique, an incision was made in the lateral part of the hind leg at the level of the middle of the thigh. The biceps femoris was dissected frankly to expose the sciatic nerve. On the right hind leg of each rat, four ligatures were performed without tightening strongly, around the sciatic nerve, separated approximately 1-2 millimeters. On the left side of each rat an identical dissection was performed but the sciatic nerve was not ligated. The muscle was closed with a continuous suture model, and the skin was closed with staples for wounds. Rats that presented unilateral mononeuropathy were accepted for the acute and chronic cold allodynia sensitivity test. In summary, each rat was placed separately in a Plexiglas chamber with a metal plate 6 cm from the bottom. This chamber was filled with ice water to a 2.5 cm thickness above the metal plate, maintaining the bath temperature at 0 ° C throughout the experiment. A chronometer was started and the response time of the rat was measured to an approximation of one tenth of a second. A "response" was defined as a rapid retraction of the right hind leg attached, completely out of the water while the animal was still and without turning. An exaggerated lameness while the animal walked was not taken into account as an answer. The maximum immersion time was 20 seconds with an interval of 20 minutes between the tests. The classification criteria were 1) the average of two tests was less than or equal to 13 seconds, and 2) there was a consistency between the values of the two tests. The animals were screened for hypersensitivity to cold on days 4 after surgery for 10 days and selected for inclusion in the dose response studies, based on the criteria described above. The values of the scan carried out before the administration of the dose were used as cold allodynia values of the baseline of the animal. For severe studies, the animals received oral injections and were screened for allodynia at 1, 3, and sometimes 5 hours after dosing. The doses were based on the free base form of the compounds of formula I. When tested in acute cold allodynia tests, the compounds of formula I generally had anti-allodynic effects at a dose of 100 mg / kg. At higher doses (up to 600 mg / kg), the Inhibition of the effects of cold allodynia lasted up to 5 hours after dosing. For chronic studies, animals received oral injections of the vehicle (deionized water, 10 ml / kg) or compounds of formula I (10 or 20 mg / kg (, twice daily for 4 days and once on day 5. they explored the animals to detect allodynia on day 1 after 1, 3 and 5 hours after the 8 am dose, and on days 3 and 5 at 5 hours after the 8 am dose. Two days later (day 7) ) the animals were screened for cold allodynia to determine if the drug to be tested had been removed After this classification for cold allodynia, the animals received either oral injections of the vehicle or compounds of formula I at a time. dose that had previously been shown to have produced significant anti-allodynic effects in severe cases (300 mg / kg po) .An hour after this dosing, the animals were again tested for cold allodynia. , the compounds of formula I, administered orally at doses below the threshold, can produce as a strong antiallodynic effect at acute doses 15 times higher (compare p. ex. 20 mg / kg chronic versus 300 mg / kg acute) on day 5 of the dosage. After a 48 hour elimination period on day 7, the animals were analyzed again and found to have returned to their baseline values of allodynia, suggesting that the relief provided by the compounds of formula I were symptomatic without any effect disease modifier in the underlying pathophysiology of neuropathy. Significantly, the acute active doses of the compounds of formula I (300 mg / kg) administered at the end of the chronic studies (ie, day 7) produced significant anti-allodynic effects, indicating that there was no tolerance to the effects of a chronic administration. The long duration of the effective effects tested in this assay provided strong support for the application of the compounds of the present invention in the treatment of neuropathic pain. EXAMPLE 21 In vivo hyperalgesia assay This assay determines the effectiveness of the compounds in alleviating one of the symptoms of neuropathic pain produced by unilateral mononeuropathy, namely, mechanical hyperalgesia. A chronic contractive injury was produced by a strong unstrained ligature of the right common sciatic nerve, as described by Bennet and Xie, Pain 1988, 33: 87-107. The left common sciatic nerve was visualized but not manipulated to produce simulated conditions. Rats with a chronic constriction lesion were explored to detect mechanical hyperalgesia with the stimulus of a pin prick, as described by Koch et al. , Analgesia 1996, 2 (3), 157-164. Briefly, the rats were placed in individual compartments in a Plexiglas box with a heated and bored metal floor. The duration of the withdrawal of the hind paw was measured after a gentle pin prick on the plantar surface of the hind legs attached (right) and simulated (left). The compounds of the present invention produced a long duration (5 hours) of reversal of mechanical hyperalgesia induced by the stimulation of a pin prick in rats with a chronic constriction lesion, when tested by this method. EXAMPLE 22 Thermal hyperalgesia assay This test determines the effectiveness of the compounds in alleviating one of the symptoms of neuropathic pain produced by unilateral mononeuropathy, namely, thermal hyperalgesia. Rats that had undergone surgery as described in Example 21A were screened for sensitivity to thermal hyperalgesia at least 10 days after surgery. In summary, the rats were placed under inverted plexiglass cages on a raised glass platform and a radiant heat source was directed under the glass to the plant on the hind foot. The time elapsed until the rear leg was removed from the crystal with an accuracy of one tenth of a second was measured. The closing time for the heat stimulus was 20 seconds, and the light was calibrated so that this duration of the stimulus would not burn or cause blisters on the skin. For the measures of duration were taken for each hind leg in each analysis session, alternately the left and right hind legs, with intervals of 5 minutes between essays . The latencies on each side were averaged and a score difference was obtained. After 12 days after surgery, the pre-selected rats were randomly assigned to receive injections of the drug or vehicle. Oral administration of the compounds of the present invention produced energetic and effective anti-hyperalgesic effects in rats with unilateral mononeuropathy. Doses of up to 300 mg / kg were tested without adverse effects. The potency and efficacy of the compounds of formula I for the inhibition of thermal hyperalgesia in rats with unilateral mono neuropathy, together with their clean safety profile after oral administration, suggests that the compounds of the present invention will be therapeutically effective in the treatment of neuropathic pain with a low probability of adverse effects when tested by this method. While the present invention has been described with reference to specific versions thereof, it should be understood by those skilled in the art that various changes can be introduced and equivalents can be substituted without departing from the true spirit and purpose of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition or subject, process, step or steps of a process, to the objective spirit and purpose of the present invention. It is intended that all these modifications are within the purpose of the claims appended thereto.

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 (8)

CLAIMS 1. A compound of formula I: characterized because
1. R1 is hydrogen, alkyl of 1 to 4 carbon atoms, - (CH2) mCycloalkyl ?, - (CH2) mNR7Rβ, O - (CH2), NR7S02R8; m is 1 to 3, - R7 and R8 are, independently of each other, hydrogen or alkyl of 1 to 4 carbon atoms; and R9 is alkyl of 1 to 4 carbon atoms, - R2, R3, R5 and R6 are independently of each other, hydrogen, alkyl of 1 to 4 carbon atoms, or halogen, - R4 is hydrogen, alkyl of the 4 carbon atoms, carbon, hydroxyl, alkyloxy, fluoroalkyloxy, halogen or phenyl or mono- or disubstituted phenyl, the substituents being selected from the group consisting of alkyloxy, amino, nitro or acetylamino; with the proviso that when R1 is hydrogen, at least two of R2, R3, R4, Rs, and R6 are other than hydrogen; and further with the proviso that when R1 is methyl and R2, R3, R5 and R6 are hydrogen, R4 is other than fluorine; or a pharmaceutically acceptable salt or an N-oxide thereof, as an individual isomer or as a mixture of racemic or non-racemic isomers.
2. 2. The compound of claim 1, characterized in that R1 is hydrogen, alkyl of 1 to 4 carbon atoms, or - (CH2) m-cycloalkyl.
3. 3. The compound of claim 2, characterized in that R1 is hydrogen, methyl, ethyl, or - (CH2) m-cycloalkyl.
4. 4. The compound of claim 3, c-ra --- tErizab for which £ 2 R3 R5 and Rβ are independently of each other, hydrogen or alkyl of 1 to 4 carbon atoms.
5. 5. The compound of claim 4, c-aracerate because R2, R3 Rs and R6 are independently hydrogen, methyl or ethyl.
6. 6. The compound of claim 5, characterized in that R4 is hydrogen or halogen. The compound of claim 6, characterized in that - R 4 is hydrogen, bromine or chlorine. 8. THE compound of the 7, characterized in that £ i R3 and R5 are hydrogen, R2 and R6 are methyl and R4 is bromine. 9. The compound of claim 7, characterized in that R? R2 and R6 are methyl, R3 and Rs are hydrogen and R4 is bromine. 10. The compound of 7, characterized in that RI RZ and R6 are methyl and R3, R4 and R5 are hydrogen. 11. The compound of the i ^ claim 1, characterized in that the individual isomer is the (S) isomer. 12. The compound of claim 1, characterized in that the pharmaceutically acceptable salt is the hydrochloride. 13. A compound selected from the group consisting of; 3 - (4-bromo-2, 6-dimethyl-phenoxymethyl) -l-methylpiperidine, - 3- (4-Bromo-2,6-dimethylphenoxymethyl) -l-methyl-piperidine N-oxide; (S) -3- (4-Bromo-2,6-dimethylphenoxymethyl) -l-methylpiperidine; 3- (4-bromo-2,6-dimethylphenoxymethyl) -piperidine; (S) -3- (4-bromo-2,6-dimethylphenoxymethyl) -piperidine; 3- (2,6-dimethylphenoxymethyl) -1-methylpiperidine, 3- (2,6-dimethylphenoxymethyl) -1-methylpiperidine N-oxide; and (S) -3- (2,6-dimethylphenoxymethyl) -l-methylpiperidine. 14. An agent, characterized in that it contains one or more compounds of any one of claims 1-13 or a pharmaceutically acceptable salt or N-oxide thereof and at least one pharmaceutically acceptable excipient for the treatment of diseases. 15. A medicament according to claim 14, for the control or treatment of diseases, based on the therapeutic indications of a sodium channel blocker, which includes the control or treatment of neuropathic pain conditions. 16. A process for the preparation of a compound of formula I as defined in claim 1, characterized in that it comprises: a) reaction of a compound of formula with a compound of formula (2) wherein R1-R6 are as defined above and Y is hydrogen or -OY is a loss group, or b) deprotection of a compound of formula wherein R is an amino protecting group and R2-R6 are as defined above, or c) alkylation or acylation of a compound of formula wherein R2-R6 are as described above, to give a compound of formula I, wherein R1 is alkyl of 1 to 4 carbon atoms, - (CH2) mcycloalkyl, - (CH2) mNR7R8 or - (CH2) mNR7S02R9, d) oxidation of a compound of formula I to give an N-oxide, or e) separation of a racemic mixture into its enantiomeric components, and f) if desired, conversion of a compound of formula I into a pharmaceutically acceptable salt. 1
7. 7. Compounds according to any one of claims 1-13 provided that they are prepared by a process claimed in claim 16 or by an equivalent method. 1
8. 8. The use of a compound according to any one of claims 1-13 for the control or treatment of diseases based on the therapeutic indications of a sodium channel blocker, which includes neuropathic pain conditions, or for the preparation of a medicine that contains said compound.