HRP980174A2 - Phenoxymethyl piperidine derivatives - Google Patents

Description

The invention relates to compounds represented by the general formula I:

[image]

where

R1 represents hydrogen, (C1-4)alkyl, -(CH2)mcycloalkyl, -(CH2)mR7R8, or -(CH2)m,NR7SO2R9;

m is 1 to 3;

R7 and R8 independently represent hydrogen or (C1-4)alkyl; and

R 9 is (C 1-4 )alkyl;

R 2 , R 3 , R 5 and R 6 independently represent hydrogen, (C 1-4 )-alkyl, or halogen;

R4 is hydrogen, (C1-4)alkyl, hydroxy, alkyloxy, fluoroalkyloxy, halogen, or phenyl or mono- or di-substituted phenyl, wherein the substituents are selected from alkyloxy, amino, nitro or acetylamino;

provided that if R 1 represents hydrogen, at least two of R 2 , R 3 , R 4 , R 5 and R 6 are other than hydrogen; and further provided that if R 1 represents methyl and R 2 , R 3 , R 5 and R 6 represent hydrogen, then R 4 is other than fluoro;

or their pharmaceutically acceptable salts or N-oxides, as individual isomers or as racemic or non-racemic mixtures of isomers.

Phenoxymethyl piperidine derivatives of formula 1 are sodium channel blockers and therefore exhibit useful pharmacological properties, which include use for the treatment of neuropathic pain conditions. Neuropathic pain can be described as pain associated with an injury or permanent change in the peripheral or central nervous system. Clinical manifestations of neuropathic pain include burning or electric shock sensations, sensations of body distortion, allodynia, and hyperalgesia.

It has been reported that agents that block sodium channels are effective in the treatment of various disease states, and special use has been found as local anesthetics and in the treatment of cardiac arrhythmia. It has also been reported many years ago that sodium channel blocking agents can be used to treat pain, including neuropathic pain; see, for example, Tanelian et al., Paln Forum. 1995, 4(2), 75-80. Preclinical evidence shows that sodium channel blocking agents selectively suppress abnormal ectopic neural firing in injured peripheral and central neurons, and it is believed that they can be used to relieve pain through this mechanism. Consistent with this hypothesis, sodium channels have been shown to accumulate in peripheral nerves on the side of axonal injury (Devor et al., J. Neurosci., 1993, 132, 1976-1992). Changes in the level of their expression or distribution of sodium channels within the injured nerve, therefore, have the most important influence on the pathophysiology of pain that accompanies this type of trauma. This concept is supported by the relatively successful use of sodium channel modulating agents (eg, anticonvulsants, local anesthetics) for the treatment of neuropathic pain. However, the pain relief obtained was often accompanied by numerous adverse effects and/or efficacy limitations that limit the tolerability of these drugs. It can be seen that there is a continuing need for an oral, active agent that is effective in the treatment of neuropathic pain but has fewer side effects.

Various derivatives of phenoxymethyl piperidine are described in patents and patent literature. For example, WO 92/02501 (Smithkline & French) and WO 93/15052 (Smithkline Beecham) generally disclose various arbitrarily substituted derivatives of 3-phenoxymethyl piperidine and 3-phenoxyethyl piperidine, which can be used as calcium channel blocking agents.

US 3,634,437 (Todd) discloses optionally substituted 3-phenoxymethyl piperidine compounds, which can be used to treat depressive disorders, anxiety, neurotic conditions and epilepsy. US 3,709,892 (Leeming et al.) discloses substituted 3-phenoxy-alkyl-amines, for example, 3-[(2-cyclohexylethyl)phenoxymethyl]-1-methylpiperidine, which have gastric antisecretory activity. US 4,877,799; US 4,985,446; and US 5,019,582 (Drejer et al.); and US 5,158,961 and US 5,227,379 (Jakobsen et al.) disclose 4-phenyl-3-phenoxymethyl piperidine derivatives as inhibitors of excessive calcium, which can be used in the treatment of anoxia, ischemia, migraine and epilepsy.

US 4,508,724 (Taylor et al.) discloses 3-phenoxymethyl-3-piperidinol derivatives that have antiarrhythmic, antidepressant and antihypertensive activity. US 4,822,778 (Aberg et al.) disclose optionally substituted derivatives of 2-phenoxymethyl piperidine, especially 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 action of piperidyl esters, especially 3-(4-fluorophenoxymethyl)-1-methylpiperidine, as central nervous system depressants. Balsamo et al., J. Med. Chem. 1987, 30, 222-225, describe the synthesis and antidepressant activity of 3-[(2-ethoxyphenoxy)-methyl]-piperidine derivatives.

The subject of the invention are compounds of formula I and their pharmaceutically acceptable salts or their N-oxides, racemic mixtures and their corresponding enantiomers, the preparation of the above-mentioned compounds, drugs containing them and their production, as well as the use of the above-mentioned compounds for the suppression or prevention of neuropathic pain conditions or for the production of appropriate medicines.

In the proposed description, the following definitions of general terms are used, regardless of whether the respective terms appear alone or in combination.

"C1-4", as in "(C1-4)alkyl" means a monovalent branched or unbranched saturated hydrocarbon chain containing 1, 2, 3 or 4 carbons, such that (C1-4)alkyl specifically includes for example methyl, ethyl , n-propyl, iso-propyl, or n-butyl. Similarly, "C1-2", as in "(C1-2)" alkyl means a saturated hydrocarbon chain containing 1 or 2 carbon atoms, so (C1-2)alkyl specifically includes methyl and ethyl.

"Cycloalkyl" means a monovalent saturated hydrocarbon radical containing from three to seven carbon atoms, eg, cyclopropyl, 2-methylcyclopropyl, cyclobutyl, 3-ethylcyclobutyl, cyclopentyl, cyclohexyl or cyclohexylmethyl.

"Alkyloxy" means -O-R where R represents (C1-4)alkyl as defined above.

"Fluoroalkyl" means (C1-4)alkyl as defined above substituted with 1 to 3 fluorine atoms, for example trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, and the like.

"Fluoroalkyloxy" means -O-R' where R' is fluoroalkyl.

"Halogen" means fluorine, chlorine, bromine or iodine, preferably bromine or chlorine.

"As necessary" or "arbitrary" means that the case or circumstance described below may or may not occur, and that the description includes examples when the case or circumstance does occur and examples where it does not.

"Inert organic solvent" or "inert solvent" means a solvent inert under the reaction conditions described with them, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran, dimethylformamide, chloroform (CHCl3), dichloromethane or methylene chloride (CH2Cl2). , diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert.butanol, dioxane, pyridine, and the like. Unless specifically stated otherwise, the solvents used in the reactions of the proposed invention are inert solvents.

"Protecting group" means a chemical group that (a) protects a reactive group from participating in an undesired chemical reaction; and (b) can be easily removed when the protection of the reactive group is no longer required.

"Amino-protecting group" or "N-protecting group" means a protecting group that protects a reactive amino group that would otherwise be modified in certain chemical reactions. The definition includes a formyl group or lower alkanoyl groups with 2 to 4 carbon atoms, especially an acetyl or propionyl group, an N-(9-fluorenylmethoxy-carbonyl) iii "FMOC" group, an alkyloxycarbonyl group or protecting groups derived from halogen carbonates such as (C6- C12)aryl lower alkyl carbonates (as N-benzyloxy-carbonyl group derived from benzylchlorocarbonate), or derived from biphenylalkyl halogen carbonates, or tertiary alkyl halogen carbonates, such as, for example, tert.butyl halocarbonates, especially tert.butylchlorocarbonate, or di (lower)alkyl-dicarbonates, especially di-(tert.butyl)-di-carbonate.

"Hydroxy-protecting group" means a protecting group that protects a hydroxy group that would otherwise be changed in a particular chemical reaction. Suitable hydroxy protecting groups include ether-forming groups, which can be easily removed after completion of all reaction steps, such as a benzyl or trityl group optionally substituted in its phenyl ring, a silyl, trialkylsilyl ether group, and the like.

"Leaving group" means a labile group that is replaced by another group in a chemical reaction. Examples of leaving groups are halogen, optionally substituted phenoxy group, trifluoromethanesulfonyloxy group, mesyloxy group, tosyloxy group or acyloxy group.

"N-oxide" refers to a stable amine oxide formed on pyrperidine nitrogen oxide.

"Stereoisomers" are isomers that differ only in the arrangement of atoms in space.

"Enantiomers" are a pair of stereoisomers that relate as non-superimposable mirror images. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture.

The compounds of the invention may have a center of asymmetry in the 3-position of the piperidine and therefore may exist as a mixture of stereoisomers or as individual (R)- or (S)-stereoisomers. Individual enantiomers can be obtained by dissolving a racemic or non-racemic mixture of intermediates in an appropriate synthesis step, then completing the synthesis in a chirality-protected manner, or by separating the compound of formula 1 in a conventional manner. Individual enantiomers as well as their racemic mixtures are included within the scope of the proposed invention, whereby, unless stated otherwise, their structures are specifically indicated in this description. Special cases of isomer separation are described in the examples.

The use of the symbol "(R)" or "(S)" before the name indicates the absolute stereochemistry of the compound according to the Cahn-Ingold-Prelog rules (see Cahn et al., Angew. Chem. Inter. Edit. 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., Experimentia, 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

"Pharmaceutically acceptable" means that which can be used to prepare a pharmaceutical composition is generally safe, non-toxic and not biologically or otherwise undesirable, and includes that which is acceptable for veterinary as well as human pharmaceutical use .

"Pharmaceutically acceptable salts" refer to those salts which are pharmaceutically acceptable, as defined above, and which have and retain the desired pharmaceutical activity of the compounds of formula I. The compounds of formula I form acid addition salts due to the presence of a basic piperidine nitrogen atom. Acid addition salts can be obtained 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, cyclopentapropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid acid, benzoic acid, o-(4-hydroxybenzoyl)-benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methyl-bicyclo[2.2.2]oct-2-ene -l-carboxylic acid, gluco-heptonic acid, 3-phenylpropionic acid, trimethyl-acetic acid, tert.butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, tartaric acid and similar to. Preferred pharmaceutically acceptable salts are salts formed with inorganic acids. A particularly preferred pharmaceutically acceptable salt is the hydrochloride salt.

"Treatment" means any treatment of a condition in a mammal, especially a human, and includes:

(i) preventing the occurrence of a disease in a subject who may be prone to that disease, but the disease has not yet been diagnosed;

(ii) inhibition of the condition, i.e. prevention of its development; or

(iii) alleviation of the condition, i.e. relief from pain symptoms.

"Disease condition treated by administration of sodium channel blockers" is intended to encompass all disease states generally recognized in the art to be generally treatable with sodium channel blockers, and those diseases found to be treatable with a specific blocker. of a sodium channel according to our invention, with a compound of formula I. Such conditions include, but are not limited to, peripheral neuropathies, such as trigeminal neuralgia, postherpetic neuralgia, diabetic neuropathy, glossopharyngeal neuralgia, lumbar and cervical radiculopathy, reflex sympathetic dystrophy and causalgia, and neuropathy secondary to metastatic infiltration, adiposis dolorosa, and burning pain; and central pain conditions after stroke, thalamic lesions, and multiple sclerosis.

A "therapeutically effective amount" refers to an amount administered to a mammal in need of such treatment sufficient to effect the treatment, as defined above. The therapeutically effective amount depends greatly on the subject and the condition of the disease being treated, the severity of the disease and the method of administration and can be determined routinely by the expert.

The nomenclature and numerical designation of the compounds of this invention are shown below. The nucleus of the phenoxymethyl piperidine compound of formula I is numbered as follows:

[image]

The nomenclature used in this patent application is generally based on IUPAC recommendations. However, since strict adherence to these recommendations, if only one substituent is changed, may result in a substantial name change, the compounds are named in a form that maintains consistency of nomenclature based on the structure of the molecule.

In the family of compounds of the proposed invention, certain compounds of formula I are preferred. Preferred compounds of formula 1 are those in which R1 represents hydrogen or (C1-4)alkyl, even better hydrogen, methyl or ethyl, and best of all hydrogen or methyl; R 2 and R 3 independently of each other represent hydrogen or alkyl, even better hydrogen or methyl, and preferably each of R 2 and R 6 represents methyl; and preferably each of R3 and R5 independently represents hydrogen or (C1-4)alkyl, even better each of R3 and R5 represents hydrogen; and R 4 is hydrogen or halogen, more preferably hydrogen or bromine, most preferably bromine.

Currently, examples of particularly preferred compounds include:

3-(4-bromo-2,6-dimethylphenoxymethyl)-1-methylpiperidine;

3-(4-bromo-2,6-dimethylphenoxymethyl)-1-methylpiperidine-N-oxide;

(S)-3-(4-bromo-2,6-dimethylphenoxymethyl)-1-methyl-piperidine;

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)-1-methylpiperidine.

The compounds of this invention can be prepared by the methods shown in the reaction schemes below.

The starting materials and reagents used to prepare these compounds are available from commercial suppliers such as Aldrich Chemical Company, or can be prepared by methods known to those skilled in the art, such as those described in the literature as Fieser and Fieser's Reagents for Organic Synthesis, Vol.1-5 (John Wiley & Sons, 1991); Rodd's Chemistry of Carbon Compounds, Vol. 1-5 and Supplementals (Elsevier Science Publishers, 1989); and Organic Reactions, Vol. 1-40 (John Wiley & Sons, 1991). These schemes are merely illustrative of some of the methods by which the compounds of this invention may be synthesized, and various modifications may be made to these schemes, and those skilled in the art are directed to refer to this publication.

Starting materials and reaction intermediates can be isolated and purified, if desired, using conventional procedures, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized in the usual way using physical constants and spectral data.

Unless otherwise stated, the reactions described here take place at approximately atmospheric pressure in the temperature range of approx. -78°C to approx. 150°C, even better than approx. 0°C to approx. 125°C, and best at approx. room (or ambient) temperature, eg at approx. 20°C.

The proposed compounds of formula 1 and their pharmaceutically acceptable salts can be produced by methods known in the art, for example by the methods described below, which include:

a) the reaction of the compound of the formula

[image]

with the compound formula

[image]

wherein R 1 R 6 are as defined above and Y is hydrogen or -OY represents a leaving group, or

b) deprotection of the compound of the formula

[image]

wherein R represents an amino protecting group and R2-R6 are defined as above, or

c) alkylation or acylation of a compound of the formula

[image]

in which R2-R6 are as described above, thereby obtaining a compound of formula I, in which R1 represents (C1-4)-alkyl, -(CH2)mcycloalkyl, -(CH2)mNR7R8 or -(CH2)mNR7SO2R99,

d) oxidation of the compound of formula I, which gives the N-oxide, or

e) separation of the racemic mixture into its enantiomeric compounds, i

f) optionally, converting the compound of formula 1 into a pharmaceutically acceptable salt.

The version of procedure a) describes the method of preparing compounds of formula I by the reaction of phenolic compound (1) with piperidine compound (2) where Y represents hydrogen or -OY represents a leaving group, and R1, R2, R3, R4, R5 and R6 are as defined above.

Scheme 1

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In general, the phenolic compound (1) is commercially available, for example from Aldrich Chemical Co., or can be prepared by standard methods known to those skilled in the art, as, for example, described in detail in Preparation 1.

The piperidine compound (2) in which Y represents hydrogen is commercially available or se; can be produced by standard methods known to those skilled in the art.

Alternatively, a piperidine compound of formula (2) in which -OY is a leaving group is prepared from a piperidine compound of formula (2) in which Y is hydrogen by converting a hydroxy group into a suitable leaving group. Suitable solvents for the reaction are inert organic solvents, such as halogenated or aromatic hydrocarbons, eg dichloromethane, 1,2-dichloroethane, carbon disulfide and the like, preferably dichloromethane.

Suitable leaving groups can be produced by standard methods, for example by reacting the piperidine compound (2) in which Y represents hydrogen, with an alkyl or aryl sulfonyl halide, such as benzenesulfonyl chloride, methanesulfonyl chloride, preferably p-toluenesulfonyl chloride. Sulfonyl halides are commercially available 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. Aunt. Lett. 1989, 30, 2869-2872.

An example of the preparation of a piperidine compound is described in detail in preparation 2.

The compound of formula 1 is produced by connecting the phenolic compound (1) with the piperidine compound (2) in which Y represents 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, the compound of formula I is produced by coupling the phenolic compound (1) with the piperidine compound (2) in which -OY represents the leaving group. The reaction takes place in an inert atmosphere in the presence of a base, eg 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.

An example of the 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 from an N-protected piperidine intermediate of formula (3) in which P represents an amino protecting group and R1, R2, R3, R4, R5 and R6 are as defined above.

Scheme 2

[image]

The N-protected piperidine compound (2a) in which P represents an amino protecting group is prepared in a conventional manner, for example by treating the piperidine compound (2) in which both R1 and Y are hydrogen, with a suitable amino protecting agent, such as acid 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.

An example of the preparation of the N-protected piperidine compound (2a) is described in detail in preparation 2B.

The N-protected phenoxymethyl piperidine compound (3) was prepared by coupling the phenolic compound (1) with the N-protected piperidine compound (2a) using the reaction conditions described for the preparation of compounds of formula I in reaction scheme 1.

An example of the preparation of the N-protected phenoxymethyl piperidine compound (3) is described in detail in preparation 3.

The compound of formula Ia in which R represents hydrogen was produced by removing the N-protecting group from 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 a halogenated or aromatic hydrocarbon, eg 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, eg methanol or ethanol, preferably methanol.

An example of the preparation of a compound of formula Ia, in which R is hydrogen, is described in detail in Example 1.

The compound of formula Ia in which R1 represents methyl can be prepared by the method described in reaction scheme I.

Alternatively, a compound of formula Ia, in which R1 represents methyl, is produced by reduction of the N-protecting group from a compound of formula (3), in which P represents an amino protecting group such as a carbamate (e.g., tert.butoxycarbonyl), with boron, a boron complex or a metal hydride such as lithium aluminum hydride. The reaction takes place in an inert atmosphere in an aprotic organic solvent such as diethyl ether, dioxane or tetrahydrofuran, preferably tetrahydrofuran.

Alternatively, a compound of formula Ia wherein R 1 is methyl is produced by reductive alkylation of a compound of formula Ia, for example with formaldehyde and formic acid under Eschweiler-Clarke reaction conditions.

An example of the preparation of a compound of formula I, in which R1 represents methyl, is described in detail in examples 2 and 3.

The compound of formula I, in which R1 represents (C2-4)alkyl or (CH2)mCycloalkyl, is produced by acylation of the compound of formula la by reaction with an acid halide (e.g. cyclopropanecarbonyl chloride or acetyl chloride, preferably cyclopropane-carbonyl chloride) in the presence of an aqueous base, eg sodium bicarbonate or potassium bicarbonate. The reaction takes place at ice-cold temperatures in an inert atmosphere in an aprotic organic solvent such as dimethylformamide, ethyl acetate, N-methyl pyrrolidone or tetrahydrofuran, preferably ethyl acetate. The residue is then treated with a suitable reducing agent such as a metal hydride, eg lithium aluminum hydride, in an aprotic organic solvent such as tetrahydrofuran.

An example of the preparation of a compound of formula I, in which R1 represents (CH2)mCycloalkyl, is described in detail in example 4.

phenyl; and R is other than hydrogen, and R 2 , R 3 , R 5 and R 6 are as defined above.

Scheme 3

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The compound of formula I, in which R4 represents hydroxy, is produced from the intermediate phenolic compound (Ib) in which P1 represents a hydroxy protecting group.

The intermediate phenolic compound (Ib) was prepared by protecting the hydroxy group of the compound of formula (Ia) by standard methods known in the art, for example Corey, E.J.;

Venkateswarlu, A. J. Am. Chem. Soc., 1972, 94, 6190. Suitable hydroxy protecting groups include alkylsilyl groups, eg tert-butyldimethylsilyl.

The procedure as in reaction scheme 1 or 2, but replacing the hydroxy protected phenolic compound (Ib) with the phenolic compound (1) and connecting it with the piperidine compound (2) or (2a) gives the hydroxy protected phenoxymethyl piperidine compound. The compound of formula I, wherein R4 is hydroxy, is then prepared by deprotection by conventional methods and selective removal of the protecting groups such as alkylammonium halides, eg tert-butylammonium fluoride in the presence of an organic acid, eg acetic acid, in an aprotic solvent such as is tetrahydrofuran.

An example of the preparation in which the removal of the hydroxy protecting group is described in detail, thereby obtaining a compound of formula I in which R4 represents hydroxy, is given in example 7.

The compound of formula I in which R 4 represents alkoxy or fluoroalkyloxy is produced from the intermediate phenolic compound (Id) in which A represents alkyl or fluoroalkyl.

The intermediate phenolic compound (Id) was produced by the reaction of the p-hydroxy phenyl acetate compound (lc) with an alkylating agent of the formula AY, in which A represents alkyl or fluoroalkyl, and Y is a leaving group such as halo, alkylhalosulfonate or aryl sulfonate, e.g. 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, eg in a protic organic solvent such as methanol or ethanol, preferably methanol. An example of the preparation of the intermediate phenolic compound (Id) is described in detail in the preparation IB.

By the procedure as in the reaction scheme 1 or 2, but by replacing the intermediate phenolic compound (Id) with the phenolic compound (1) and connecting it with the piperidine compound (2) or (2a), the compound of formula I was produced in which R4 represents alkoxy or fluoroalkyloxy.

The compound of formula I in which R4 represents phenyl or mono- or di-substituted phenyl is produced from the intermediate phenolic compound (If) in which R4 represents phenyl or mono- or di-substituted phenyl.

The intermediate phenolic compound (1f) was produced by coupling using palladium as a catalyst the bromine compound of formula (1e) and arylboronic acid also as nitrophenylboronic acid and with a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) in the presence of an inorganic base 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 the procedure as in reaction scheme 1 or 2, but by replacing the intermediate phenolic compound (If) with the phenolic compound (1) and connecting with the piperidine compound (2) or (2a), the compound of formula I was produced in which R4 represents phenyl or mono- or di -substituted phenyl.

Compounds of formula I, in which R 4 represents phenyl or mono- or di-substituted phenyl, and R 2 , R 3 , R 5 and R 6 are defined as above, can be prepared from other compounds of formula 1:

A. For example, a compound of formula I wherein R 4 is 3-methoxyphenyl is prepared using palladium as a catalyst by coupling a compound of formula I wherein R is bromine with an arylboronic acid such as nitrophenylboronic acid and a palladium(0) catalyst 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.

An example of the preparation of a compound of formula I in which R4 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 nitro group of a 3-nitrophenyl compound (prepared as described above in reaction scheme III, where R 4 is phenyl or substituted phenyl) to an amino group. Conditions suitable for reduction of the nitro group include metallic iron with ammonium chloride in ethanol/water, nickel boride in acidic methanol, or catalytic hydrogenation using platinum or palladium on activated carbon) in an alcoholic solvent such as methanol or ethanol, preferably ethanol). The reaction takes place in an inert atmosphere.

An example of the preparation of a compound of formula I in which R4 is 3-aminophenyl is described in detail in Example 9.

C. For example, a compound of formula I, wherein R4 is 3-acetylaminophenyl, is prepared by treating the 3-aminophenyl compound described above under B with an acylating agent such as an acyl halide or an acyl anhydride (eg, acetic anhydride) in the presence of an organic bases (eg triethylamine or pyridine, preferably pyridine). Suitable solvents for the reaction are inert organic solvents such as halogenated or aromatic hydrocarbons, eg benzene, dichloromethane, 1,2-dichloroethane, carbon disulfide and the like, preferably dichloromethane.

An example of the preparation of a compound of formula I in which R4 is 3-acetylaminophenyl is described in detail in Example 10.

Reaction Scheme 4 describes the preparation of the N-oxide of a compound of formula I wherein R 1 is other than hydrogen and R 2 , R 3 , R 4 , R 5 and R 6 are as defined above.

Scheme 4

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The N-oxide compound of formula Ib is produced by oxidizing the compound of formula I with a suitable oxidizing agent such as a peroxide or peracid, eg m-chloroperbenzoic acid or hydrogenated peroxide, preferably m-chloroperbenzoic acid. Suitable solvents for the reaction are inert organic solvents such as halogenated or aromatic hydrocarbons, eg benzene, dichloromethane, 1,2-dichloroethane, and the like, preferably dichloromethane.

An example of the preparation of the N-oxide compound of formula Ib is described in detail in Example 11.

The compound of formula I can be resolved into its individual (S)- and (R)-enantiomers by conventional resolution procedures; for example by separating (eg by fractional crystallization) diastereomeric salts formed by combining a compound of formula I with an optically active acid, at temperatures between 0ºC and the reflux temperature of the solvent used for fractional crystallization. Examples of such optically active acids are camphor-10-sulfonic acid, 2-bromo-camphor-10-sulfonic acid, camphoric acid, menthoxyacetic acid, tartaric acid, dibenzoyltartaric acid, malic acid, diacetyltartaric acid, pyrrolidone-5-carboxylic acid and the like. . The separated pure diastereomeric salts can then be cleaved by standard means, such as treatment with a base, to the desired (S)- or (R)-enantiomeric compound of formula I.

Alternatively, the (S)- or (R)-enantiomeric compound of formula I may be prepared in a conventional manner such as by synthesis with a single stereoisomeric intermediate and reaction in such a manner that the center of chirality is not affected. For example, compounds of formula I can be prepared starting from optically pure hydroxymethyl piperidine compounds by the procedure described in reaction scheme II. Optically pure hydroxymethyl piperidine compound can be obtained by reducing the enantiomeric derivative of ethyl piperidinecarboxylate. For the cleavage of ethyl 3-piperidinecarboxylate with an optically active acid salt, to obtain optically active (R)- or (S)-enantiomers, there are good examples in the chemical literature, for example, Zeng et al., Chirality 1995, 7, 90- 95; and Akkerman et al., Rec. Trav. Chem. Pays-Bas 1951, 70, 899-916.

The compounds of formula I and their pharmaceutically acceptable salts and their N-oxides have been found to have valuable pharmacological properties. In particular, standard laboratory tests have shown that they can be used as sodium channel blockers.

The ability of compounds of formula I to block sodium channels can be demonstrated using various assays known to those skilled in the art, such as the in vitro assay described by Kourtney and Stricharz in Local Anesthetics, Springler-Verlag, New York, 1987, or modifications thereof. The experiment is shown in example 18.

The ability of compounds of formula I to block sodium channels can also be demonstrated by in vivo experiments, such as the mechanical allodynia experiment described in Example 19; the cold allodynia experiment is described in example 20; the mechanical hyperalgesia experiment is described in example 21; and thermal hyperalgesia is described in Example 22.

Accordingly, these compounds and pharmaceutically acceptable compositions containing them can be used to regulate physiological phenomena associated with sodium channel blockade and provide effective therapies for various chronic neuropathic pain syndromes, including peripheral neuropathies such as trigeminal neuralgia, postherpetic neuralgia , glossopharyngeal neuralgia; neuralgia secondary to infiltration of metastases; and burning pain.

Clinical evidence supports a therapeutic role for sodium channel blockers in the treatment of neuropathic pain originating in the peripheral nervous system, including cervical and lumbar radiculopathy (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, M.C. et al. al., Neurology 1991, 41, 1024-1028) and peripheral nerve injuries (Chabel et al., Anesthesiology 1992, 76, 513-517). In addition to these conditions, these agents have been found in two retrospective clinical studies to provide partial to complete relief of pain associated with reflex sympathetic dystrophy and causalgia (Edwards et al., Regional Anesthesia 1985, 10, 1-6; Galer et al. , Neurology 1993, 43, 1233-1235). In the setting of central post-stroke pain, thalamic lesions and multiple sclerosis, responses to treatment with these agents have also been obtained (Edmondson et al., Southern Med. J. 1993, 86, 1093-1096; Nagaro et al., 1995 idem).

Clinical and experimental evidence supports a therapeutic role for 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 chronic, nonmalignant conditions. pain, which includes pain originating in skeletal muscles, adiposis dolorosa (Arkinson et al., International J. Obesity 1982, 6, 351-357; Peterson, P. and Kastrup, J. Pain 1987, 28, 77-80) and numerous headaches (Robbins et al., Headache 1995, 35, 79-82; Maizels et al., JAMA 1996, 276, 319-321).

Experimental evidence supports a therapeutic role for sodium channel blockers as neuroprotective or cerebroprotective agents and may provide an effective strategy against neuralgic injury (eg, ischemia, head trauma, hypoxia, stroke). Long-term beneficial effects on neurological deficit, cognitive deficit and brain injury after middle cerebral artery occlusion (Smith, S.E., Neuroscience 1997, 77, 1123-1135); neuroprotective, anticonvulsant and sedative properties in transient global cerebral ischemia (Doble, A., Neurology 1996, 47 (6 Suppl 4) S 233-42); and reduction of ischemic brain injury in a model after acute subdural hematoma (Tsuchida E. et al., J. of Neurosurgery 1996, 85, 104-111) were demonstrated in a rodent model.

Clinical evidence supports a therapeutic role for sodium channel blockers for preemptive analgesia at low, non-toxic systemic concentrations (Strichartz, G., Anesthesia 1995, 83, 654-655). In many surgical procedures, hypersensitivity reactions to tactile and painful stimuli can be the result of piercing soft tissue or a major nerve. This can occur within weeks or even much later after the initial surgery. Because sodium channels play a fundamental role in neuronal hypersensitivity, preemptive treatment with a channel blocker may limit any potential hypersensitivity reaction to surgery.

When using the compounds of this invention to treat the above conditions, administration of the active compounds and salts described herein may be by any accepted route of administration, including oral (including sublingual or buccal), nasal, parenteral, or other systemic routes of administration. Any pharmaceutically acceptable method of administration can be used, 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 unit dosage forms for single administration of exact dosage, or in forms of continuous or controlled dosage 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 a pharmaceutically acceptable salt thereof, and may additionally contain other medicinal agents, pharmaceutical agents, carriers, additives, etc.

The amount of a given active compound depends, of course, on the treated subject, the severity of the disease, the method of administration and the assessment of the competent physician. However, the effective dose for oral, parenteral and other systemic routes of administration ranges from approx. 0.1 – 5 mg/kg/day. For a person with an average weight of 70 kg, this will be an amount of approx. 50 – 350 mg per day.

An expert in the treatment of such diseases will be able to determine the therapeutically effective amount of the compound of formula I for a given disease, without experiments and on the basis of personal knowledge and the contents of this patent application.

For solid compositions, common nontoxic solid carriers include, for example, pharmaceutical grade mannitol, lactose, cellulose, cellulose derivatives, croscarmellose sodium, starch, magnesium stearate, sodium saccharin, talc, glucose, sucrose, magnesium carbonate, and the like. The active compound, as defined above, can be formulated as a suppository using, for example, polyalkylene glycols, acetylated triglycerides, and the like as carriers. Liquid pharmaceutical compositions that can be administered can be prepared, for example, by dissolving, dispersing, etc. the active compound as defined above and optionally pharmaceutical additives in a carrier such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, resulting in a solution or suspension. If desired, the pharmaceutical composition for administration may also contain small amounts of non-toxic excipients, such as wetting agents or eluents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc. Composition or formulation for the administration in each case contains an amount of the active compound(s) in an amount effective to alleviate the symptoms of the treated subject.

It is possible to prepare dosage forms or compositions containing the active ingredient (compound of formula I or its salts) in the range of 0.25 to 95%, and the rest is a non-toxic carrier.

For oral administration, a pharmaceutically acceptable non-toxic composition is prepared using any excipient normally used, such as, for example, mannitol, lactose, cellulose, cellulose derivatives, croscarmellose sodium, starch, magnesium stearate, talc, glucose, sucrose , magnesium carbonate, and similar pharmaceutical quality. Such compositions can be in the form of solutions, suspensions, tablets, pills, capsules, powders, formulations for sustained release and the like. Such compositions can contain from 1 - 95% of active substance, even better 2 - 80%, best 5 - 50%.

Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly, or intravenously. Injectable preparations may be produced in the usual forms, as liquid solutions or suspensions, as solid forms suitable for dissolving or suspending in a liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol. In addition, if desired, pharmaceutical compositions can also be provided that also contain small amounts of non-toxic excipients such as wetting agents or elugating agents, pH buffering agents and the like, such as, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, triethanolamine sodium acetate, etc.

The approach, which has recently been found for parenteral administration, uses the implantation of a slow or sustained release system, so that a constant dosage level is maintained. See, for example, patent no. 3, 710, 795.

The percentage of the active compound contained in such parenteral compositions is highly dependent on its specific nature, as well as on the action of the compound and the needs of the subject. However, a percentage of active ingredient from 0.1% to 10% in solution can be used, and will be higher if the composition is solid, and which is then diluted to the above percentage. The composition in the solution primarily contains 0.2-2% of the active ingredient.

The compositions of the present invention may also be formulated for administration in any conventional manner analogous to other surface compositions adapted for use in mammals. These compositions may be prepared for use in any conventional manner using any of a number of different pharmaceutical carriers or vehicles. For such topical administration, a pharmaceutically acceptable non-toxic formulation may take the form of a semi-liquid, liquid, or solid, such as a gel, cream, lotion, solution, suspension, ointment, powder, or the like. For example, the active components can be formulated into a gel using ethanol, propylene glycol, propylene carbonate, polyethylene glycol, diisopropyl adipate, glycerol, water, etc. with suitable gelling agents, such as Carbomers, Klucels, etc. Preferably, the formulation can also contain small amounts of non-toxic auxiliary substances such as preservatives, antioxidants, buffering agents for pH, surfactants and the like. Methods for preparing such dosage forms are known or available to those skilled in the art; see, for example, Remington's Pharmaceutical Science, Mark Publishing Company, Easton, Pennsylvania, 19th ed., 1995.

A preferred pharmaceutical composition is administered in single unit form for continuous treatment or in single unit dosage form ad libitum if specific relief of symptoms is desired. Typical pharmaceutical formulations containing a compound of formula I are described in Examples 12-17.

Examples

The following preparations and examples are provided to enable one skilled in the art to more clearly understand and practice the proposed invention. They must not be considered as a limitation of the scope of the invention, but must be taken mainly as an illustration and representation thereof.

Preparation 1

Preparation of compounds of formula (1)

A. Preparation of the compound of formula (1) in which R2 and R6 represent methyl, R3 and R5 are hydrogen and R4 is 3-nitrophenyl

Tetrakis (triphenyl- phosphine)palladium(0) (0.48 g, 0.42 mmol) and 2M sodium carbonate (6.3 mL, 13 mmol). The mixture was stirred for 22 hours at 100°C, during which time more palladium catalyst (150 mg) was added. The mixture is heated for another 20 hours and then cooled to room temperature. The mixture is partitioned between water and ethyl acetate. The organic layer is dried and thickened. The residue was purified on silica gel eluting with 12% ethyl acetate in hexane to give 4-(3-nitrophenyl)-2,6-dimethylphenol as a yellow solid (0.932 g, 31%).

B. Preparation of the compound of formula (Id) in which R2 and R6 represent methyl, R3 and R5 represent hydrogen and A is 2,2,2-trifluoroethyl

2,2,2-Trifluoroethyl triflate (1.02 g, 4.40 mmol) and potassium carbonate (1.10 g, 1.01 mmol) were added to a solution of 4-hydroxy-2,6-dimethylphenyl acetate (673 mg , 3.73 mmol) in 2-butanone (15 ml). The mixture is stirred for 72 hours at 70°C, then cooled to room temperature and thickened. The residue was partitioned between water and ethyl acetate. The organic layer is washed twice with water and with salt solution and dried. The solvent was removed in vacuo and the residue was purified on silica gel eluting with 10% ethyl acetate to give 2,6-dimethyl-4-(2,2,2-trifluoroethoxy)phenyl acetate (733 mg, 75%) .

2,6-Dimethyl-4-(2,2,2-trifluoroethoxy)phenyl acetate (733 mg, 2.80 mmol) in methanol (10 mL) was mixed with sodium metal and stirred overnight at room temperature. The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer is washed each time with salt solution and dried. The solvent was removed to give 2,6-dimethyl-4-(2,2,2-trifluoroethoxy)phenol.

Preparation 2

Preparation of compounds of formula (2)

A. Preparation of the compound of formula (2) in which R1 represents 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). After the addition, the reaction mixture is allowed to warm to room temperature and stirred for 20 hours. The reaction mixture was then concentrated and the residue partitioned between 10% potassium hydroxide (50 ml) and ether (100 ml). The ether layer was removed and the aqueous phase was extracted once more with ether (50 ml). The combined ether layers were dried over 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 the compound of formula (2a) in which P represents tert.butoxycarbonyl

Ethyl 3-piperidinecarboxylate (200 g) was mixed with (-)-D-tartaric acid (191 g) in hot 95% ethanol. The resulting precipitate is filtered off and recrystallized six times from 95% ethanol to give (S)-ethyl 3-piperidinecarboxylate 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-piperidinecarboxylate D-tartrate salt (100 g) in tetrahydrofuran (1 L) while maintaining the temperature below 8°C. At the end of the addition, while maintaining the temperature below 10°C, di-tert.butyl dicarbonate (100 g) in tetrahydrofuran (200 ml) is added drop by drop. After 2.5 hours, the reaction mixture was partitioned between ethyl acetate (2 L) and water (2 L). The organic layer is removed, washed with water (2 x 500 ml) and with salt solution (300 ml), dried over magnesium sulfate and concentrated. The residue is dissolved in dry tetrahydrofuran (1 1) and cooled to 10°C.

While maintaining the temperature below 10°C, a solution of lithium borohydride (200 ml of a 2.0 M solution in tetrahydrofuran) is added drop by drop and the reaction mixture is stirred for 24 hours at room temperature. More lithium borohydride solution (20 ml) was added and the reaction mixture was stirred for another 20 hours at room temperature. Sodium sulfate decahydrate (50 g) is added slowly and the mixture is filtered. The solids were washed with ethyl acetate (200 mL), concentrated and partitioned between ether (1 L) and brine (500 mL). The ether layer was dried over magnesium sulfate and concentrated to give (S)-N-(tert.butoxycarbonyl)-3-hydroxymethylpiperidine as a white solid (47 g).

Preparation 3

Preparation of terms of the formula (3)

A. Preparation of compounds of formula (3) in which R2 and R6 represent methyl, R3, R4, and R5 represent hydrogen and P is tert.butoxycarbonyl

(S)-N-(tert.butoxycarbonyl)-3-hydroxymethylpiperidine (11.0 g, 51.1 mmol) and triphenylphosphine (14.7 g, 56.2 mmol) were added, under an atmosphere of dry nitrogen, to a solution of 2 ,6-dimethylphenol (6.24 g, 51.1 mmol) dissolved in dry tetrahydrofuran (200 ml). The solution was cooled in an ice bath at a rate at which the temperature was maintained below 10°C, and diethyl azodicarboxylate (6.9 ml, 56.2 mmol) in tetrahydrofuran (40 ml) was added dropwise. After the addition is complete, the mixture is allowed to stir for 48 hours at room temperature. The reaction mixture is partitioned between ethyl acetate (1 1) and water (1 1). The organic layer is washed with water (3 x 300 ml), with brine (200 ml), dried, filtered and chromatographed on silica gel, washing with ethyl acetate/hexane (9:1) and concentrated, which gives (S)- (N-tert.butoxycarbonyl)-3-(2,6-dimethyl-phenoxymethyl)piperidine as a clear oil (13.0 g, 45.2%).

B. Preparation of compounds of formula (3) in which R2 and R6 represent methyl, R3 and R5 represent hydrogen, R4 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 1.5 h to an ice-cold solution of (S)-N-(tert-butoxycarbonyl)-3-hydroxymethylpiperidine ( 20.0 g, 92.9 imnol), 4-bromo-2,6-dimethylphenol (18.7 g, 92.9 mmol) and triphenylphosphine (26.8 g, 102.2 mmol) in tetrahydrofuran (300 ml) while keeping the temperature below 10°C. After the addition is complete, the reaction mixture is stirred for 48 hours at room temperature and partitioned between ethyl acetate (1 l) and water (1 l). After extraction of the aqueous phase with additional ethyl acetate (2 x 200 ml), the combined layers of ethyl acetate are washed with salt solution (250 ml), dried over magnesium sulfate and concentrated, resulting in a thick yellow oil. The oil was mixed with hexane (500 ml) and ether (50 ml) and stirred for 30 minutes. The resulting precipitate was removed by filtration and washed with additional hexane (50 ml). The combined filtrates were concentrated to give crude (S)-N-(tert.butoxycarbonyl)-3-(4-bromo-2,6-dimethylphenoxymethyl)piperidine as a clear yellow oil (44 g).

Example 1

Preparation of compounds of formula Ia

A. Preparation of compounds of formula Ia in which R2 and R6 represent methyl, R3 and R5 represent hydrogen and R4 is bromine

Trifluoroacetic acid (80 ml) was added dropwise over 20 minutes to a solution of (S)-N-(tert.butoxycarbonyl)-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 is complete, the reaction mixture is stirred for 2 hours at room temperature. The solvent was evaporated and the residue was partitioned between 25% aqueous sodium hydroxide solution (200 ml) and ether (500 ml). The organic layer was removed and the aqueous phase was extracted with additional ether (2 x 300 ml). The combined ether layers were washed with brine (100 ml), stirred for 2 hours over magnesium sulfate and filtered to give a solution of (S)-3-(4-bromo-2,6-dimethylphenoxymethyl)piperidine.

(S)-3-(4-Bromo-2,6-dimethylphenoxymethyl)piperidine in ether was mixed with a 1M solution of hydrochloric acid in ether (102 ml). The resulting white precipitate was filtered off and dried in vacuo to give (S)-3-(4-bromo-2,6-dimethylphenoxymethyl)-piperidine hydrochloride (29.5 g, 94.5%, melting point >280°C) .

B. Similarly, by replacing (S)-N-(tert.butoxycarbonyl)-3-(4-bromo-2,6-dimethylphenoxymethyl)piperidine with other compounds of formula (3) and then by the procedure described in Example 1A above, the following were obtained compounds of formula Ia:

3-(4-bromo-2,6-dimethylphenoxymethyl)piperidine hydrochloride, melting point 263.3-264.7°C;

3-(2,6-dimethylphenoxymethyl)piperidine hydrochloride, melting point 204.1-205.7°C;

(S)-3-(2,6-dimethylphenoxymethyl)piperidine hydrochloride melting point 228.4-229.8°C;

3-(4-chloro-2,6-dimethylphenoxymethyl)piperidine hydrochloride, melting point 176.1-178.2°C.

Example 2

Preparation of compounds of formula I

Preparation of compounds of formula Ia in which R1, R2 and R6 represent methyl, R3 and R5 represent hydrogen and R4 is bromine

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 0ºC under dry nitrogen, then diethyl azodicarboxylate (0.57 mL, 3.60 mmol) was added dropwise. The mixture was stirred for 4 hours at 0°C and then the solvent was removed in vacuo. The residue was purified on silica gel eluting with 5% methanol in dichloromethane containing 0.25% ammonium hydroxide to give 3-(4-bromo-2,6-dimethylphenoxymethyl)-1-methylpiperidine as an oil (531 mg, 66%).

3-(4-Bromo-2,6-dimethylphenoxymethyl)-1-methylpiperidine is mixed with 1N hydrochloric acid in ether and the precipitated salt is recrystallized from acetonitrile/tert.butyl methyl ether to give 3-(4-bromo-2 ,6-dimethylphenoxymethyl)-1-methyl-piperidine hydrochloride, melting point 180.9-183.5°C.

B. Similarly, by the process described in example 2A above, but replacing 4-bromo-2,6-dimethylphenol with other compounds of formula (1), the other compounds of formula I were produced:

3-(2,6-dimethylphenoxymethyl)-1-methylpiperidine hydrochloride, melting point 163.2-163.7°C;

3-(4-fluoro-2,6-dimethylphenoxymethyl)-1-methyl-piperidine fumarate, melting point 155.4-155.9°C;

3-(4-chloro-2,6-dimethylphenoxymethyl)-1-methylpiperidine hydrochloride, melting point 160.1-161.3°C;

3-(4-methoxy-2,6-dimethylphenoxymethyl)-1-methylpiperidine fumarate, melting point 171.0-172.3°C;

3-[4-(2,2,2-trifluoroethoxy)-2,6-dimethylphenoxymethyl]-1-methylpiperidine hydrochloride, melting point 124.7-125.8°C;

3-(2,4,6-trimethylphenoxymethyl)-1-methylpiperidine hydrochloride, melting point 169.0-171.2°C;

3-(2,6-dimethyl-4-phenylphenoxymethyl)-1-methylpiperidine hydrochloride, melting point 243.6-244.6.2°C;

3-phenoxymethyl-1-methylpiperidine hydrochloride, melting point 155.2-156.2°C;

3-(4-chlorophenoxymethyl)-1-methylpiperidine hydrochloride, melting point 211.4-211.6°C;

3-(4-bromophenoxymethyl)-1-methylpiperidine hydrochloride, melting point 236.0-237.3°C;

3-(4-methoxyphenoxymethyl)-1-methylpiperidine hydrochloride, melting point 148.3148.9°C;

3-(2-methylphenoxymethyl)-1-methylpiperidine hydrochloride, melting point 191.6-192.3°C;

3-(3-methylphenoxymethyl)-1-methylpiperidine hydrochloride, melting point 140.8-141.90C;

3-(4-methylphenoxymethyl)-1-methylpiperidine hydrochloride, melting point 173.8-174.5°C;

3-(2,4-dimethylphenoxymethyl)-1-methylpiperidine hydrochloride, melting point 180.3-183.5°C;

3-(3,5-dimethylphenoxymethyl)-1-methylpiperidine hydrochloride, melting point 182.0-182.5°C;

3-(4-bromo-2-methylphenoxymethyl)-1-methylpiperidine hydrochloride, melting point 192.9-193.3°C;

3-(2,6-dichlorophenoxymethyl)-1-methylpiperidine hydrochloride, melting point 170.5-172.2°C;

3-(2,6-dichloro-4-fluorophenoxymethyl)-1-methylpiperidine hydrochloride, melting point 151.0-151.7°C;

3-(2,4,6-trichlorophenoxymethyl)-1-methylpiperidine hydrochloride, melting point 159.9-160.4°C;

3-[2,6-dimethyl-4-(3-nitrophenyl)phenoxymethyl-1-methyl]-piperidine hydrochloride, melting point 198.5-199.5°C;

3-[4-(tert.butyldimethylsiloxy)-2,6-dimethylphenoxy-methyl]-1-methylpiperidine,

1H NMR (300 MHz, CDCl 2 ): δ = 0.16 (s, 6H); 0.96 (s, 9H); 1.10-1.19 (m, 1H); 1.63-1.96 (m, 5H); 2.10-2.18 (m, 1H); 2.19 (s, 6H); 2.30 (s, 3H); 2.79 (broad d, J=11 Hz, 1H); 3.11 (broad d, J=11 Hz, 1H); 3.56 (d, J=6Hz, 2H); 6.45 (s, 2H) .

C. Alternatively, a solution of (R)-3-tosyloxymethyl-1-methyl-piperidine (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) is heated for 1.5 hours in a nitrogen atmosphere at 65°C. The solution was cooled to room temperature and partitioned between ethyl acetate (50 ml) and water (30 ml). The organic layer was removed and the aqueous phase was extracted once with ethyl acetate (30 ml). The combined acetate layers were dried over magnesium sulfate and concentrated to give (R)-3-(4-bromo-2,6-dimethylphenoxy-methyl)-1-methylpiperidine as a clear oil. Chiral HPLC analysis shows that this material is identical to that of Example 2E (Chiralpk AD, 97:3:0.1 hexane/2-propanol/diethylamine).

D. Alternatively, formic acid (16.7 mL, 333 mmol) and aqueous formaldehyde (37% alcohol, 9.1 mL) were added dropwise to (S)-3-(4-bromo-2,6- dimethylphenoxymethyl)piperidine (24.1 g, 80.8 mmol) which was cooled in an ice bath. After the addition is complete, the reaction mixture is kept in an oil bath for 4 hours at 95°C. 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 with additional ether (300 ml) and the ether layers were combined, washed with brine (150 ml), dried and concentrated. The residue was chromatographed on silica gel eluting with acetone/hexane (1:1) and concentrated to give (S)-3-(4-bromo-2,6-dimethylphenoxymethyl)-1-methyl-piperidine as a clear oil.

(S)-3-(4-Bromo-2,6-dimethylphenoxymethyl)-1-methyl-piperidine was dissolved in ether (600 ml) and mixed with 1M hydrochloric acid in ether (90 ml). The resulting white precipitate was filtered off, dried in vacuo to give (S)-3-(4-bromo-2,6-dimethylphenoxymethyl)-1-methylpiperidine hydrochloride (25.5 g, 87%, melting point 209, 7-210 , 5°C).

E. In the same way, replacing (S)-3-(4-bromo-2,6-dimethyl-phenoxymethyl)piperidine with (R)-3-(4-bromo-2,6-dimethyl-phenoxy methyl)piperidine and then by the procedure described in example 2D, the compound (R)-3-(4-bromo-2,6-dimethyl-phenoxy methyl)-1-methylpiperidine was produced, melting point 211.6-212.6°C.

Example 3

Alternative preparation of the compound of formula I

Preparation of the compound of formula I in which R1, R2 and R6 represent methyl, and R3, R4 and R5 represent hydrogen

A. A 1M solution of lithium aluminum hydride in tetrahydrofuran (45 mL, 45 mmol) was added dropwise over 30 min to (S)-N-tert.butoxycarbonyl)-3-(2,6-dimethylphenoxy-methyl)piperidine (13.0 g, 40.6 mmol) in dry tetrahydrofuran (250 ml) under a dry nitrogen atmosphere. After the addition is complete, the reaction mixture is heated for 4 hours under reflux, stirred for 20 hours at room temperature and quenched by careful addition of solid 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 on silica gel eluting with dichloromethane/methanol (9.5:0.5) to give (S)-3-(2,6-dimethyl phenoxy methyl)-1-methylpiperidine as a clear oil (8.0g).

(S)-3-(2,6-Dimethylphenoxymethyl)-1-methylpiperidine (8.0 g) was dissolved in ether (500 ml) and mixed with 1M hydrochloric acid in ether (37.7 ml). The thick white precipitate was isolated by filtration, washed with ether (75 mL) and dried to give (S)-3-(2,6-dimethylphenoxymethyl)-1-methylpiperidine hydrochloride (8.6 g, 93%, mp 149, 8-151.3°C).

B. Similarly, by replacing (S)-N-tert.butoxycarbonyl)-3-(2,6-dimethylphenoxymethyl)piperidine with other compounds of formula (3) and then by the procedure described in example 3A above, the compounds of formula I were produced:

(R)-3-(2,6-dimethylphenoxymethyl)-1-methylpiperidine hydrochloride, melting point 151.7-152.8°C;

(S)-3-(4-chloro-2,6-dimethylphenoxymethyl)-1-methyl-piperidine hydrochloride, melting point 172.0-152.8°C;

(S)-3-phenoxymethyl-1-methylpiperidine hydrochloride, melting point 152.7-153.2°C; and

(R)-3-phenoxymethyl-1-methylpiperidine hydrochloride, melting point 152.5-153.4°C.

Example 4

Alternative preparation of compounds of formula I

Preparation of compounds of formula I in which R1 represents cyclopropylmethyl, R2 and R6 represent methyl, and R3, R4 and R5 represent hydrogen

A. Cyclopropylcarbonyl chloride (1.7 mL, 18 mmol) was added dropwise over 15 min to an ice-cold mixture containing (S)-3-(2,6-dimethylphenoxymethyl)piperidine hydrochloride (4.4 g, 17 mmol ), aqueous sodium bicarbonate (75 ml) and ethyl acetate (100 ml). After the addition is complete, the reaction mixture is stirred for 1 hour at room temperature and the resulting ethyl acetate layer is separated and thickened. The residue was dissolved in dry tetrahydrofuran (125 ml) under a dry nitrogen atmosphere and a 1M solution of lithium aluminum hydride in tetrahydrofuran (18.9 ml) was added dropwise. After the addition is complete, the reaction mixture is heated for 2 hours under reflux, then cooled to room temperature. Solid sodium sulfate decahydrate (10 g) is slowly added with stirring and the mixture is filtered. The filtrate is concentrated and chromatographed on silica gel, eluting with acetone/hexane (1:3), which gives (S)-1-cyclopropylmethyl-3-(2,6-dimethylphenoxymethyl)piperidine as an oil.

(S)-1-cyclopropylmethyl-3-(2,6-dimethylphenoxymethyl)-piperidine was dissolved in dry ether (125 ml) and mixed with 1M hydrochloric acid in ether (18.9 ml). The white precipitate was collected and dried in vacuo to give (S)-1-cyclopropyl-methyl-3-(2,6-dimethylphenoxymethyl)piperidine hydrochloride, (3.6 g, 66%, mp 137.3-137, 5°C).

B. Similarly, by replacing (S)-3-(2,6-dimethylphenoxymethyl)-piperidine hydrochloride with other compounds of formula Ia, and optionally by replacing cyclopropylcarbonyl chloride with other acid chlorides and then by the procedure described in Example 4A above, the following compounds were produced formula I:

1-cyclopropylmethyl-3-(2,6-dimethylphenoxymethyl)-piperidine hydrochloride, melting point 147.5-148.0°C;

(R)-1-cyclopropylmethyl-3-(2,6-dimethylphenoxymethyl)-piperidine hydrochloride, melting point 137.2-138.1°C;

3-(2,6-dimethylphenoxymethyl)-1-ethylpiperidine hydrochloride, melting point 157.2-160.0°C;

3-phenoxymethyl-1-ethylpiperidine hydrochloride, mp 168, 3-169, 8°C; and

3-phenoxymethyl-1-cyclopropylmethylpiperidine hydrochloride, melting point 151.7-153.3°C.

Example 5

Alternative preparation of compounds of formula 1

Preparation of compounds of formula I in which R1 represents 2-dimethylaminoethyl, R2 and R6 represent methyl, and R3, R4 and R5 represent hydrogen

Chloroacetyl chloride (1.5 mL, 19 mmol) was added dropwise to a mixture of 3-(2,6-dimethylphenoxymethyl)piperidine hydrochloride (4.0 g, 16 mmol) in saturated aqueous sodium bicarbonate (70 mL) and ether (100 ml) which is previously cooled in an ice bath. After the addition is complete, the reaction mixture is stirred for 2 hours at room temperature. The ether layer was removed and concentrated, and the residue was taken up in dry methanol (100 ml) while cooling in an ice bath. Gaseous dimethylamine is slowly passed through the solution for 15 minutes and the mixture is stirred for 20 hours at room temperature. The solvent was evaporated and the residue was taken up in dry tetrahydrofuran (150 ml) under nitrogen and a 1M solution of lithium aluminum hydride in tetrahydrofuran (17.2 ml) was added. The reaction mixture is heated under reflux for 4 hours and stirred under reflux for 20 hours. Solid sodium sulfate decahydrate (25 g) is added slowly and the mixture is filtered. The solid was washed twice with ethyl acetate (100 mL) and the combined organic layers were concentrated. The residue was partitioned between 10% aqueous 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 give a solution of 3-(2,6-dimethylphenoxymethyl)-1-(2-dimethylaminoethyl)piperidine.

A solution of 3-(2,6-dimethylphenoxymethyl)-1-(2-dimethylamino-ethyl)piperidine was mixed with a 1M solution of hydrochloric acid in ether (17.2 ml). The resulting precipitate was isolated by filtration, then dried under high vacuum to give 3-(2,6-dimethylphenoxymethyl)-1-(2-dimethylaminoethyl)piperidine hydrochloride (4.0 g, 71%), mp 263, 2-263.5°C.

Example 6

Alternative preparation of the compound of formula I

Preparation of the compound of formula I in which R1 represents 3-methanesulfonamidopropyl, R2 and R6 represent methyl, and R3, R4 and R5 represent hydrogen

3-(2,6-Dimethylphenoxymethyl)piperidine hydrochloride (1.0 g, 3.9 mmol) was suspended in ethyl acetate (60 mL) and washed with 10% aqueous sodium hydroxide (50 mL). When the ethyl acetate layer was removed, dried and concentrated, 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 and then stirred for 20 hours at room temperature. , after which it was partitioned between ethyl acetate (100 ml) and water (100 ml).

The aqueous phase is extracted with the addition of ethyl acetate (2 x 50 ml) and the combined ethyl acetate layers are washed with brine (60 ml), dried and concentrated. The residue was chromatographed on silica gel eluting with acetone/hexane (1:1) containing 1% triethylamine and concentrated to give 3-(2,6-dimethyl-phenoxymethyl)-1-(3-methanesulfonamido)propylpiperidine as a clear oil. .

3-(2,6-dimethylphenoxymethyl)-1-(3-methanesulfonamido)-propylpiperidine was dissolved in ether (30 ml) and mixed with 1M hydrochloric acid in ether (4.7 ml). The resulting white precipitate is isolated by filtration, which gives 3-(2,6-dimethylphenoxy-methyl)-1-(3-methanesulfonamido)propylpiperidine hydrochloride (650 mg, 43%, melting point, drawn, 51°C).

Example 7

Alternative preparation of the compound of formula I

Preparation of the compound of formula I in which R1, R2 and R3 represent methyl, R3 and R5 represent hydrogen, and R3 is hydroxy

A solution of 3-[4-(tert.butyldimethylsilyloxy)-2,6-dimethylphenoxymethyl]-1-methylpiperidine (3.2 g, 8.8 mmol) in tetrahydrofuran (50 ml) containing 20% acetic acid (5 .5 ml, 19 mmol) at 0°C, 1 M tetrabutylammonium fluoride in tetrahydrofuran (17.5 ml) was added. The mixture is stirred overnight from 0°C to room temperature and concentrated in a vacuum. The residue was partitioned between water and dichloromethane. The organic layer was dried and concentrated, and the residue was purified on silica gel by washing with 5% methanol in dichloromethane containing 0.25% ammonium hydroxide to give 3-(4-hydroxy-2,6-dimethylphenoxymethyl)-1 -methylpiperidine.

The product was converted to the hydrochloride salt and recrystallized from ethanol/tert.butyl methyl ether to give 3-(4-hydroxy-2,6-dimethylphenoxymethyl)-1-methyl-piperidine hydrochloride (1.46 g, 58%, m.p. 224.5-225.5°C).

Example 8

Conversion of compounds of formula I into other compounds of formula I

Preparation of a compound of formula I in which R1, R2 and R6 represent methyl, R3 and R5 represent hydrogen and R4 is 3-methoxyphenyl

To a solution of 3-(4-bromo-2,6-dimethylphenoxymethyl)-1-methyl-piperidine (531 mg, 1.70 mmol) in toluene (10 ml) was added 3-methoxyphenylboronic acid (319 mg, 2.10 mmol). ), tetrakis(triphenylphosphine)palladium(0) (0.58 mg, 0.05 mmol) and 2M sodium carbonate (1.7 ml, 3.4 mmol). The mixture is stirred overnight at 100°C and cooled to room temperature. The solution is partitioned between water and ethyl acetate. The organic layer is washed twice with water, with salt solution and dried. The solvent was removed and the residue was purified on silica gel eluting with 5% methanol in dichloromethane containing 0.25% ammonium hydroxide to give 3-[4-(3-methoxy-phenyl)-2,6-dimethylphenoxymethyl] -1-methylpiperidine.

The product was converted to the hydrochloride salt and crystallized from ethyl acetate to give 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 1 into other compounds of formula I

Preparation of compounds of formula I in which R1, R2 and R6 represent methyl, R3 and R5 represent hydrogen and R4 is 3-Aminophenyl

A mixture of 3-[2,6-dimethyl-4-(3-nitrophenyl)phenoxymethyl]-1-methylpiperidine (785 mg, 2.21 mmol), ethanol (10 ml) and ethyl acetate (5 ml) was hydrogenated under a pressure of 1 atmosphere of hydrogen overnight with platinum oxide (50 mg). The reaction mixture was purged with nitrogen and filtered through Celite. The solid was washed with methanol and ethyl acetate. The filtrate and eluates were concentrated to give 3-[4-(3-aminophenyl)-2,6-dimethylphenoxymethyl]-1-methylpiperidine as a yellow oil (735 mg, quantitative).

A portion of the oil (175 mg) was mixed with 1N hydrochloric acid in ether and crystallized from methanol/ether to give 3-[4-(3-aminophenyl)-2,6-dimethylphenoxymethyl]-1-methylpiperidine hydrochloride (193 mg, melting point 272.3-273.9°C).

Example 10

Alternative conversion of compounds of formula 1 into other compounds of formula I

Preparation of a compound of formula I in which R1, R2 and R6 represent methyl, R3 and R5 represent hydrogen and R4 is 3-acetylaminophenyl

Pyridine (1.3 ml, 16 mmol) was added to a solution of 3-[4-(3-aminophenyl)-2,6-dimethylphenoxymethyl]-1-methylpiperidine (513 mg, 1.58 mmol) in dichloromethane at 0°C. and acetic anhydride (0.75 mL, 8.0 mmol). The mixture is stirred overnight at at a temperature ranging from 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 on silica gel eluting with 10% methanol/dichloromethane containing 0.25% ammonium hydroxide to give 3-[4-(3-acetylaminophenyl)-2,6-dimethylphenoxymethyl]-1-methylpiperidine (476 mg, 82%).

3-[4-(3-acetylaminophenyl)-2,6-dimethylphenoxymethyl]-1-methylpiperidine was mixed with 1N hydrochloric acid in ether and crystallized from methanol/tert.butyl methyl ether to give 3-[4-(3 -acetylaminophenyl)-2,6-dimethylphenoxymethyl]-1-methylpiperidine hydrochloride (melting point 231.0-231.9°C).

Example 11

Preparation of the N-oxide of the compound of formula I

Preparation of the N-oxide of the compound of formula I in which R1, R2 and R6 are methyl, R3 and R5 are hydrogen and R4 is bromine

A. (S)-3-(4-Bromo-2,6-dimethylphenoxymethyl)-1-methyl-piperidine hydrochloride (338 mg, 0.97 mmol) was partitioned between ether and aqueous ammonium hydroxide. The ether was dried and concentrated to give an oil which was dissolved in dichloromethane (10 ml). m-chloroperbenzoic acid (327 mg, 50-60%) was added to this solution. After 30 minutes, the reaction mixture is diluted with dichloromethane, then washed once with a 10% aqueous solution of sodium thiosulfate and three times with aqueous sodium bicarbonate. After drying, the solution in dichloromethane was concentrated and the residue was recrystallized from ethyl acetate to give (S)-3-(4-bromo-2,6-dimethylphenoxy-methyl)-1-methylpiperidine-N-oxide (90.1 mg, melting point 210.0-211.0°C).

B. It is similar, replacing (S)-3-(4-bromo-2,6-dimethylphenoxy-methyl)-1-methylpiperidine hydrochloride with (S)-3-(2,6-dimethyl-phenoxymethyl)-1-methylpiperidine hydrochloride and the procedure described in Example 11A above, produced (S)-3-(2,6-dimethylphenoxymethyl)-1-methylpiperidine-N-oxide (mp 203.5-204.8°C).

Example 12

This example shows the preparation of a typical pharmaceutical formulation for oral administration containing an active compound of formula I, eg (S)-3-(4-bromo-2,6-dimethyl-phenoxymethyl)-1-methylpiperidine hydrochloride.

Ingredients Quantity per tablet, mg

active compound 200

lactose, spray dried 148

magnesium stearate 2

The above ingredients are mixed and introduced into hard shell gelatin capsules.

For oral administration of the formulations of this example, one of the other compounds of formula I can be used as an active compound in the preparation.

Example 13

This example shows the preparation of another typical pharmaceutical formulation for oral administration containing an active compound of formula I, eg (S)-3-(4-bromo-2,6-dimethylphenoxymethyl)-1-methylpiperidine hydrochloride.

Ingredients Quantity per tablet, mg

active compound 400

corn starch 50

lactose 145

magnesium stearate 5

The above ingredients are thoroughly mixed and pressed into single scored tablets.

For oral administration of the formulations of this example, one of the other compounds of formula I can be used as an active compound in the preparation.

Example 14

This example shows the preparation of a typical pharmaceutical formulation containing an active compound of formula I, eg (S)-3-(4-bromo-2,6-dimethylphenoxymethyl)-1-methyl-piperidine hydrochloride.

An oral suspension with the following composition was produced:

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

Seasoning 0.035 ml

Dye 0.5 mg

distilled water q.s up to 100 ml

For oral administration of the formulations of this example, one of the other compounds of formula I can be used as an active compound in the preparation.

Example 15

This example shows the preparation of a typical pharmaceutical formulation for oral administration containing an active compound of formula I, eg (S)-3-(4-bromo-2,6-dimethyl-phenoxymethyl)-1-methylpiperidine hydrochloride.

A preparation, buffered at pH 4, with the following composition was produced:

Ingredients

active compound 0.2 g

sodium acetate buffer solution (0.4M) 2.0 ml

HCl (1N) q.s. to pH 4

distilled water q. with up to 20 ml

To prepare the injection formulations of this example, one of the other compounds of formula I can be used as an active compound in the preparation.

Example 16

This example shows the preparation of a typical pharmaceutical formulation for topical administration containing an active compound of formula I, eg (S)-3-(4-bromo-2,6-dimethyl-phenoxymethyl)-1-methylpiperidine hydrochloride.

Ingredients grams

active compound 0.2-10

Span 60 2

Tween 60 2

mineral oil 5

petrolatum 10

methyl paraben 0.15

propyl paraben 0.05

BHA (butylated hydroxy anisole) 0.01

Water g.s up to 100

All the above ingredients, except water, are mixed and heated to 60°C while stirring. Then, with vigorous stirring at 60°C, add the amount of water sufficient to emulsify the ingredients and then add water q.s. up to 100 g.

For the surface formulations of this example, one of the other compounds of formula I can be used as an active compound in the preparation.

Example 17

This example shows the preparation of a typical pharmaceutical formulation containing an active compound of formula I, eg (S)-3-(4-bromo-2,6-dimethylphenoxymethyl)-1-methyl-piperidine hydrochloride.

A suppository with a total weight of 2.5 grams and the following composition was produced:

Ingredients

active compound 500 mg

Witepsol H-15* residue; (*Triglycerides of saturated vegetable fatty acids; product of Riches-Nelson, Inc., New York, N.Y.)

For suppository formulations of this example, one of the other compounds of formula I can be used as an active compound in the preparation.

Example 18

Examination of sodium channel blockade in vitro

This test determines the effectiveness of compounds of formula Ia as sodium channel blockers in an in vitro model by the compound's inhibitory effect on possible propagation in isolated nerve preparations.

The sodium channel assay was performed as described by Kourtney and Stricharz in Local Anesthetics, Springer-Verlag, New York, 1987. Briefly, the vagus nerve was harvested from a rat, with constant perfusion with control solutions or test compound solutions. Electric shocks were applied to the nerve to stimulate the propagation of nerve impulses. The amplitude of the synchronous effect of the action potential was measured; it was reduced when sodium channels permeated with compounds were blocked.

These tests lead to the conclusion that the compounds of formula I, tested by this method, are, depending on the use, strong blockers of sodium channels, especially at higher frequencies.

Example 19

Mechanical allodynia test in vivo This test determines the effectiveness of compounds of formula I in alleviating symptoms in a model of neuropathic pain in vivo produced by spinal nerve ligation, namely mechanical allodynia.

Sensory allodynia was induced in rats using the procedure described by Kim and Chung, Pain 1992, 50:355-363. Briefly, rats were anesthetized with an intraperitoneal dose of pentobarbital sodium (65 mg/kg) with an additional dose of anesthetic given as needed. Each animal was then placed prone, a 3 cm lateral incision was made, and the left paraspinal muscle was separated from the spinous process at the L4-S2 level. The L6 transverse process was then removed to visually identify the L4-L6 spinal nerves. Then the spinal nerves L5 and L6 are individually isolated and tightly connected with a silk sheath. The wound is then closed in layers using silk sutures. With these procedures, rats were obtained that develop a significant increase in sensitivity to mechanical stimulation, which does not cause a reaction in normal rats.

Mechanical sensitivity was tested by the procedure described by Chaplan et al., J. Neurosci. Methods 1994, 53:55-63. Briefly, an array of eight Von Frey fibers of varying stiffness was placed on the flat surface of the hindpaw ipsilateral to the ligatures with a force just sufficient to stretch the fibers. The fibers are held in this position for no longer than three seconds, or until the rat shows a positive allodynic response. A positive allodynic response consists in raising the injured paw immediately after striking or shaking the paw. The sequence and frequency with which the individual fibers were placed was determined by applying Dixon's up-down method. The test was started with the middle hair of the row with subsequent fibers placed in series, either ascending or descending, depending on whether a negative or positive response was obtained with the initial fiber.

The results show that one hour after oral administration the compounds of formula I had a minimum effective dose of less than 300 mg/kg. In general, the compounds of the proposed invention, tested by this method, were found to be effective in reversing mechanical symptoms similar to allodynia.

Example 20

In vivo test of cold allodynia

This test determines the effectiveness of the compounds in alleviating one of the symptoms of neuropathic pain caused by unilateral mononeuropathy, namely cold allodynia.

Unilateral mononeuropathy was induced in rats using the Chronic Constriction Injury model, which was performed essentially as described by Bennet and Xie, Pain, 1988, 33:87-107. Briefly, rats were anesthetized with an intraperitoneal dose of pentobarbital sodium (65 mg/kg). The lateral side of the limbus of each hind paw of the rat was shaved and rubbed with Novasan.

Using an aseptic procedure, an incision was made on the side of the limbus of the paw at the level of the middle grip. The biceps femoris was briefly dissected to reveal the sciatic nerve. On the right hind limb of each rat, four loosely wound ligatures were made around the sciatic nerve at a distance of approximately 1-2 mm. An identical dissection was performed on the left side of each rat except that the sciatic nerve was not ligated. The muscle is closed with a continuous suture and the skin is closed with wound clips.

Rats exhibiting unilateral mononeuropathy were tested for sensitivity to acute and chronic cold allodynia. Briefly, each rat was placed individually in a Plexiglas chamber with a metal plate 6 cm from the bottom. This chamber was filled with ice water to a depth of 2.5 cm above the metal plate, while the temperature of the bath was maintained at 0°C during the experiment. The clock was started and the rat's reaction latency was measured to the nearest tenth of a second. A "reaction" is defined as a rapid complete withdrawal of the right tied hindpaw from the water, as the animal is immobile and unable to turn. Increased limping while the animal was walking was not counted as a reaction. The maximum dipping time was 20 seconds with 20 minute intervals between two trials. The test criteria were 1) that the average value of the two trials was less than or equal to 13 seconds, and 2) that there was consistency of the summation results in the two trials. animals were examined for cold hypersensitivity 4 to 10 days after surgery, and were selected for inclusion in the dose-response study based on the criteria described above. The values of the pre-dose test were taken as the baseline results of the cold allodynic animal.

For acute studies, animals received oral injections and were tested for cold allodynia 1, 3, and sometimes 5 hours after dosing. Doses were based on the free form of the compounds of formula I. When tested in the acute cold allodynia test, the compounds of formula I generally showed anti-allodynic activity at a dose of 100 mg/kg. At higher doses (above 600 mg/kg), the inhibition of the effects of cold allodynia lasts up to 5 hours after the dose.

For chronic studies, animals received injections of vehicle (deionized water; 10 ml/kg) or compounds of formula 1 (10 or 20 mg/kg), twice daily for 4 days and once on the fifth day. Animals were tested for allodynia on the first day at 1, 3, and five hours after the 8th morning dose, and 5 hours after the 8th morning dose on the third and fifth days. Two days later (day 7) the animals were tested for cold allodynia, to check whether washout of the test drug had occurred. Following this cold allodynia test, animals received oral injections of vehicle or compounds of formula I at a dose previously found to actually produce significant anti-allodynia effects (300 mg/kg). One hour after this dosing, the animals were again tested for cold allodynia. For chronic studies, compounds of formula I given orally at a subthreshold dose can produce as strong an anti-allodynic effect as a 15-fold acute dose (compare 20 mg/kg chronic vs. 300 mg/kg acute) on the fifth day of dosing. After a 48 hour washout period on the seventh day, the animals were re-examined and found to have returned to their baseline allodynia score, leading to the conclusion that the relaxation obtained with the compounds of formula I was sympathotic without altering the disease effect on the underlying pathophysiology of the neuropathy. Importantly, acutely active doses of compounds of formula I (300 mg/kg) given at the end of the chronic study (ie, day seven) produced significant anti-allodynic effects, demonstrating that no tolerance to the effects of chronic administration occurs.

The long-term administration and efficacy observed in this trial provide strong support for the use of the compounds of the present invention in the treatment of neuropathic pain.

Example 21

Examination of mechanical hyperalgesia In vivo

This trial demonstrates the effectiveness of the compounds in relieving one of the symptoms of neuropathic pain caused by unilateral mononeuropathy, namely mechanical hyperalgesia.

Chronic constriction injury was induced by light ligation 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 processed to create mimic conditions.

Rats with chronic constriction injury were tested for mechanical hyperalgesia to spike stimulation as described by Koch et al., Analgesia 1996, 2(3), 157-164. Briefly, rats were placed in separate compartments of Plexiglas chambers with a heated, perforated metal floor. The duration of hindpaw withdrawal was measured after a slight prick on the plantar surface of the tied (right) and untied (left) paw.

Compounds of the proposed invention, tested by this method, produce long-term tolerance (5 hours) to mechanical hyperalgesia induced by a stimulatory spike in rats with a conical constriction injury.

Example 22

Hyperalgesia test in vivo

This test determines the effectiveness of the compounds in relieving one of the symptoms of neuropathic pain caused by unilateral mononeuropathy, namely thermal hyperalgesia.

Rats operated on as described in Example 21A were tested for thermal hyperalgesic sensitivity at least 10 days after surgery. Briefly, rats were placed under an inverted Plexiglas cage on an elevated glass platform and a radiant heat source under the glass was directed toward the sole of the hind paw. The duration of time before the hind paw was withdrawn from the floor was measured to the nearest tenth of a second. The interruption time of the thermal excitation was 20 seconds, and the light was calibrated so that the duration of the excitation did not burn or cause bubbles to appear on the skin. Four latency measurements were performed for each hindpaw in each group, alternating left and right paws, with 5 min intervals between trials. The mean latency values of each side were determined and the difference value was calculated. Among the 12 days previously operated rats, randomly selected rats were assigned to receive an injection of drug or vehicle.

Oral administration of the compounds of the proposed invention produces strong and effective anti-hyperalgesic effects in rats with unilateral mononeuropathy. Doses up to 300 mg/kg were tested without adverse effects. When tested by this method, the potency and efficacy of the compounds of formula I in inhibiting thermal hyperalgesia in rats with unilateral mononeuropathy, taken together with their clean safety profile after oral administration, suggest that the compounds of the present invention will be therapeutically effective in the treatment of neuropathic pain with a low probability harmful consequences.

Since the proposed invention has been described with respect to specific embodiments thereof, one skilled in the art must understand that various changes may be made and equivalents may be substituted without departing from the true spirit and purpose of the invention. In addition, many modifications can be made according to the object of the sense and purpose of the proposed invention, to adapt to a particular situation, material, composition of matter, process, stage or stages of the process. All such modifications are considered to be within the scope of the patent claims appended hereto.

Claims (19)

1. Compound of formula I: [image] indicated by that R1 represents hydrogen, (C1-4)alkyl, -(CH2)mcycloalkyl, -(CH2)mNR7R8, or -(CH2)mNR7SO2R9; m is 1 to 3; R7 and R8 independently represent hydrogen or (C1-4)alkyl; and R 9 is (C 1-4 )alkyl; R 2 , R 3 , R 5 and R 6 independently represent hydrogen, (C 1-4 )-alkyl, or halogen; R4 is hydrogen, (C1-4)alkyl, hydroxy, alkyloxy, fluoroalkyloxy, halogen, or phenyl or mono- or di-substituted phenyl, wherein the substituents are selected from alkyloxy, amino, nitro or acetylamino; provided that if R 1 represents hydrogen, at least two of R 2 , R 3 , R 4 , R 5 and R 6 are other than hydrogen; and further provided that if R 1 represents methyl and R 2 , R 3 , R 5 and R 6 represent hydrogen, then R 4 is other than fluoro; or a pharmaceutically acceptable salt or N-oxide thereof, as a single isomer or as a racemic or non-racemic mixture of isomers. 2. Compound according to claim 1, characterized in that R1 represents hydrogen, (C1-4)alkyl or - (CH2)mcycloalkyl. 3. Compound according to claim 2, characterized in that R1 represents hydrogen, methyl, ethyl or -(CH2)mcycloalkyl. 4. Compound according to claim 3, characterized in that R2, R3, R5 and R6 independently represent hydrogen or (C1-4)alkyl. 5. Compound according to claim 4, characterized in that R2, R3, R5 and R6 independently represent hydrogen, methyl or ethyl. 6. Compound according to claim 5, characterized in that R4 represents hydrogen or halogen. 7. Compound according to claim 6, characterized in that R4 represents hydrogen, bromine or chlorine. 8. Compound according to claim 1, characterized in that R1, R3 and R5 represent hydrogen, R2 and R6 represent methyl, and R4 is bromine. 9. Compound according to claim 1, characterized in that R1, R2 and R6 represent methyl, R3 and R5 represent hydrogen, and R4 is bromine. 10. Compound according to claim 1, characterized in that R1, R2 and R6 represent methyl, R3, R4 and R5 represent hydrogen. 11. The compound according to claim 1, characterized in that the individual isomer is the (S)-isomer. 12. The compound according to claim 1, characterized in that its pharmaceutically acceptable salt is hydrochloride. 13. A compound, indicated by the fact that it is selected from the group consisting of: 3-(4-bromo-2,6-dimethylphenoxymethyl)-1-methylpiperidine; 3-(4-bromo-2,6-dimethylphenoxymethyl)-1-methylpiperidine-N-oxide; (S)-3-(4-bromo-2,6-dimethylphenoxymethyl)-1-methyl-piperidine; 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)-1-methylpiperidine. 14. Medicine, characterized in that it contains one or more compounds according to any one of claims 1-13 or its pharmaceutically acceptable salt or its N-oxide and at least one pharmaceutical auxiliary agent, for the treatment of diseases. 15. The drug according to claim 14, characterized in that it is used for the suppression or treatment of diseases based on the therapeutic indications of sodium channel blockers, which include the suppression or treatment of neuropathic pain conditions. 16. A process for preparing a compound of formula 1 as defined in claim 1, characterized in that it includes: a) the reaction of the compound of the formula [image] with the compound formula [image] wherein R1, R6 are as defined above and Y is hydrogen or -OY represents a leaving group, or b) deprotection of the compound of the formula [image] wherein R represents an amino protecting group and R -R are as defined above, or c) alkylation or acylation of a compound of the formula [image] in which R2-R6 are as described above, thereby obtaining a compound of formula I, in which R1 represents (C1-4)alkyl, -(CH2)mcycloalkyl, -(CH2)mNR7R8 or -(CH2)mNR7SO2R9, d) oxidation of the compound of formula I, which gives the N-oxide, or e) separation of the racemic mixture into its enantiomeric components, i f) optionally, converting the compound of formula 1 into a pharmaceutically acceptable salt. 17. A compound according to any one of claims 1-13, characterized in that it is produced by the process according to claim 16 or an equivalent method. 18. The use of a compound according to any one of claims 1-13, characterized in that it is used for the suppression or treatment of diseases based on the therapeutic indications of sodium channel blockers, which include neuropathic pain conditions, or for the production of a drug containing such a compound. 19. An invention, characterized in that it is in accordance with the above description.