MXPA00005228A - 4-arylpiperidine derivatives for the treatment of pruritus - Google Patents

Abstract

There is provided a compound of formula I, wherein R<1>, R<2>, R<3>and R<4>have meanings given in the description, which are useful in the prophylaxis and in the treatment of pruritus.

Description

NEW DERIVATIVES OF 4-ARILPIPERIDINES FOR THE TREATMENT OF PRURITE This invention relates to new 4-phenylpiperidine derivatives which have utility in the treatment of pruritic dermatosis and atopy in animals and humans, and processes for the preparation thereof as well as intermediates used in their preparation. Itching or pruritus is a common dermatological symptom that can lead to considerable distress in animals and humans. Pruritus is often associated with inflammatory skin disorders that can be caused by hypersensitivity reactions commonly, such as reactions to insect bites, for example flea bite, or environmental allergies such as house dust mite dust or pollen; or bacterial or fungal infections of the skin or ectoparasitic infections. Previous treatments for pruritus include the use of corticosteroids and antihistamines, although both have undesirable side effects. Other therapies include the use of dietary supplements of essential fatty acids that act slowly and offer only limited efficacy against allergic dermatitis. A variety of emollients such as light paraffin, glycerin and lanolin are also used but with limited success and with a continuing need for an effective remedy. Certain 1, 3,4-trisubstituted derivatives of 4-arylpiperidines are described in GB-A-1525584 as potent narcotic antagonists which also develop analgesic properties. These compounds are also claimed in EP-B-0287339 as opioid antagonists that block the effect of agonists on mu or kappa receptors, which have a potential utility in the treatment of a variety of disorders associated with these receptors such as eating disorders, opiate overdose, depression, smoking, alcoholism, sexual dysfunctions, shock, strokes, spinal cord injury and cephalic trauma; its usefulness as an appetite suppressant for weight loss has also been suggested. In addition, 1-N-substituted-4-arylpiperidines are described in EP-A-0506468 and EP-A-0506478. It suggests a potential utility in the prevention of unwanted effects of peripherally mediated opioids and in the relief of dioptotic symptoms of constipation and irritable bowel syndrome. In accordance with the present invention new 4-phenylpiperidines are provided which are potent and effective antipruritic agents. Thus, the present invention provides compounds of the formula I: wherein, Ri and R2 are each independently H or C-? - alkyl: R3 represents aryl (optionally substituted by one or more substituents selected from OH, nitro, halo, CN, CH2CN, CONH2, C? -4 alkyl, alkoxy C -? - 4, C? -5 alkanoyl (where any of the last three groups are optionally substituted by one or more halo atoms) and -N (R5a) (R5a), alkyl C? -? O, C3-? 0 alkenyl or C3-? Alkynyl or, said alkyl, alkenyl or alkynyl groups being optionally substituted and / or terminated by one or more substituents selected from OR5c, S (0) nR5d, CN, halo, C6-C6 alkoxy, C2-6 alkanoyl, C2-6 alkanoyloxy, C3-8 cycloalkyl, C4-9 cycloalkanoyl, N (R6a) S (0) R7, Het1, aryl, adamantyl (where either of the two Last groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH, C? - alkyl, C? - alkoxy, and C -? - alkanoyl (where any of the last three groups are optionally substituted by one or more halo atoms) or -W-A1-N (R6b) (R6c), n is 0, 1 or 2, W represents a single bond, C (O) or S (0) p; A1 represents a single bond or alkylene C? -10, so that when W and A1 represent single bonds, then the group -N (R6b) (R6c) is not directly bound to an unsaturated carbon atom, p is 0.1 or 2; R5a to R5d represe Each independently is H, Cryo alkyl, C3-10 alkenyl, C3-8 cycloalkyl, C? -phenyl alkyl, aryl (where any of the last six groups is optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C? -4 alkyl, C? -4 alkoxy, C? -5 alkanoyl (where any of the last three groups is optionally substituted by one or more halo atoms) or Het2; so that R5d does not represent H when n represents 1 or 2; R6a to R6c each independently represent H, C? -6 alkyl) C3-10 alkenyl, C3-? 0 alkynyl, C8-3 cycloalkyl C-? - alkyl aryl (where any of the last six groups are optionally substituted by one or more substituents selected from Oh, nitro, amino, halo, CN, CH2CN, CONH2, C? -4 alkyl, C?? - alkoxy, and C? -5 alkanoyl (where any of the last three groups is optionally substituted by one or more halo atoms), Het3, or R6 and R6c together represent unbranched C2_6 alkyl optionally interrupted by O, S and / or a group N (R8) and optionally substituted by one or more C? - alkyl groups; R7 represents alkyl C? _6, C3-8 cycloalkyl, C-? 4- alkyl phenyl or aryl, where the four groups are optionally substituted by one or more substituents selected from C? - alkyl, C? -4 alkoxy, OH, nitro, amino or halo; R8 represents H, C? -6 alkyl, C3-8 cycloalkyl, A2- (C3-8 cycloalkyl) or A2-aryl; A2 represents alkylene or C? -6; Het1, Het2 and Het3 independently represent 3 to 8 membered heterocyclic groups, containing at least one heteroatom selected from oxygen, sulfur and / or nitrogen, such groups being optionally fused to a benzene ring, and optionally substituted on the part of the heterocycle and / or the benzene ring condensed by one or more substituents selected from OH, = 0, nitro, amino, halo, CN, aryl, C? -4 alkyl, C? -4 alkoxy and C-alkanoyl ? -5 (where any of the last three groups is optionally substituted by one or more halo atoms); and R4 represents H, C? -5 alkyl, C-M2 alkanoyl, (pyridin-3-yl) carbonyl or (pyridin-4-yl) carbonyl (where any of the last three groups is optionally substituted in the form of N-oxidopyridine ); or its pharmaceutically or veterinarily acceptable derivatives; provided, when the group OR 4 is attached to the benzene ring in the meta position relative to the piperidine ring, the piperidine being not in the N-oxide form, then: (a) when R 1 and R 2 represent C 1-4 alkyl, then R 3 does not represent: C 8 -alkyl (optionally terminally substituted by C 8 cycloalkyl); unsubstituted C3-8 alkenyl; unsubstituted C 3-8 alkynyl; C? -3 alkyl, terminally substituted by phenyl, phenoxy, AS-phenyl, -N (H) phenyl or -N (C 1-4 alkyl) -phenyl, furan-2-yl or thiophen-2-yl; C -? - 4 alkyl, terminally substituted by an OH group and an additional group between phenyl, furan-2-yl and thiophen-2-yl; or C3-5 alkenyl, terminally substituted by phenyl, furan-2-yl or thiophen-2-yl; where the position of the unsaturation is in the carbon atoms which are in alpha, beta position with respect to the phenyl group, furan-2-yl or thiophen-2-yl; all phenyl, phenoxy and phenylthio groups are optionally substituted by one or two substituents selected from OH, C? -3 alkyl, C1-3 alkoxy, halo, nitro, amino and CF3; and all furanyl and thiophenyl groups are optionally substituted by a methyl group; and (b) when R1 represents methyl; and (i) R 2 represents C 4 -4 alkyl and R 4 represents H or C 4 -4 alkanoyl, then R 3 does not represent: unsubstituted C 3-8 alkyl; unsubstituted C4-8 alkenyl; C3-6 alkyl, substituted by an unsubstituted C4-8 cycloalkyl group, C2 alkyl, terminally substituted by a cycloalkanyl, an unsubstituted C2-6 alkanoyl group or an unsubstituted thiophenyl group; C-9 alkyl (optionally substituted in the 4-C to 9-C position by C-8 cycloalkyl) or C5-9 alkenyl, the alkyl and alkenyl groups being substituted in the 3-C position by OH, C? -6 alkoxy , oxyalkyl C? -3 phenyl or C2-5 alkanoyloxy (where the last three groups are unsubstituted), or C3 alkyl, terminally substituted by (1) OH, C? -6 alkoxy. oxyalkyl C? -3 phenyl or C2-5 alkanoyloxy (where the last three groups are not j-iÉ l * substituted and 2) C4-8 cycloalkyl, thiophenyl (the last two groups being unsubstituted); or (ii) R 2 represents H or C 1-4 alkyl and R 4 represents H or C 1 -C 5 alkyl, then (I) R 3 does not represent: -methyl; C2-2o alkyl or C4-? 0 alkenyl, both substituted in the 2-, 3- or 4-C positions by -W-A1-N (R6b) (R6c) and the alkyl group being also optionally also substituted in the positions 3- to 10-C, 4- to 10-C or 5- to 10-C (respectively) for an unsubstituted C 3-8 cycloalkyl or an unsubstituted phenyl; or alkyl C -? - 4, the alkyl group being terminally substituted by -W-A1-N (R6b) (R6c), and optionally also terminally substituted by unsubstituted C3-8 cycloalkyl or unsubstituted phenyl; wherein in both cases, W is a single bond, A1 is a single bond or alkylene C? -3, R6b or R6c is H or unsubstituted C? -? 0 alkyl and R6b or R6c (as appropriate) is H, C3-8 cycloalkyl, C-MO alkyl, C3-? O alkenyl, phenyl or C1-3 alkylphenyl (where the last five groups are unsubstituted); or (II) R3 does not represent: - C-MO alkyl or C3-? 0 alkenyl) both substituted at 1-C to 5-C (as appropriate) by unsubstituted C-? -6-alkoxycarbonyl or -W-A1-N (R6b) (R6c) and the alkyl or alkenyl groups also being optionally substituted in the 2- to 10-C, 3- to 10-C, 4- to 10-C or 5- to 10-C positions (respectively) by C3- cycloalkyl 8 unsubstituted or unsubstituted phenyl; or Cts alkyl which is terminally substituted by an unsubstituted C1-β-carbonyl alkoxy group or -W-A1-N (R6c) (R6c), and is optionally terminally substituted by an unsubstituted phenyl or by a C3-8 cycloalkyl not replaced; wherein in both cases, W is -C (O) -, A1 is a single bond, R6b or R6c is H or unsubstituted C? -3 alkyl and R6b or R6c is H or unsubstituted C1-3 alkyl and R6b or R6c (as appropriate) is H, or C3-10 alkyl, C3-8 cycloalkyl, phenyl, C3-alkyl phenyl (where the last five groups are unsubstituted), linear C? -4 alkyl (terminally substituted by amino), or R6b and R6c together represent unsubstituted C3-5 alkyl; (c) when R1 and R2 represent methyl and are mutually in the trans- configuration and R4 represents H or alkanoyl Cu, then R3 does not represent: unsubstituted C? -8 alkyl; unsubstituted C3-8 alkenyl; unsubstituted C 3-8 alkynyl; C 1-6 alkyl terminally substituted by an unsubstituted C 3 - cycloalkyl group; C3-alkyl, terminally substituted by a C3-8 cycloalkanoyl, C3-8 cycloalkoxy C3-8 cycloalkyl, naphthyl, thiophenyl, thiophenoxy, furanyl, furanoxy, tetrahydrofuranyl, pyridinyl or pyridinyloxy (where the last eleven groups are substituted), phenyl or phenoxy (wherein any of the last two groups is optionally substituted by one or more substituents selected from halo, C 1-4 alkyl and C 1-4 alkoxy); or C1-C4 alkyl, terminally substituted or an OH group and by one of the following groups: phenyl (optionally substituted by one or more substituents selected from halo, C4-4alkyl and C4-4alkoxy), C-alkyl ? -2 phenyl, C3-8 cycloalkyl, thiophenyl, furanyl or pyridinyl (where the last four groups are unsubstituted); under all these conditions the optionally substituted alkyl, alkenyl and alkynyl groups are not interrupted by one or more O and / or S atoms; these compounds will be collectively referred to as "the compounds of the invention" hereinafter. In the definitions used herein, alkyl, alkylene, alkoxy, alkoxycarbonyl, alkanoyl, alkanoyloxy, alkenyl, alkynyl and the alkyl portions of alkylphenyl and arylalkoxy groups may, when there is a sufficient number of carbon atoms, be linear or branched and / or optionally interrupted by one or more oxygen or sulfur atom (s), the term halo includes fluorine, chlorine, bromine or iodine. The term "aryl" includes optionally substituted phenyl, naphthyl and the like, and "aryloxy" includes optionally substituted phenoxy and naphthyloxy and the like. Unless otherwise indicated, the aryl and aryloxy groups are optionally substituted by one or more (for example one to three) substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C? - alkyl, C alco- alkoxy, C?-carbonyl alkoxy and alkanoyl (of which the last four groups are optionally substituted by one or more halo atoms). The heterocyclic rings representing Het1, Het2 and Het3 can be completely saturated, partially unsaturated and / or have completely or partially aromatic character. Specific rings that may be mentioned include: for Het1, dioxane, dioxolane, morpholine, piperidine, perhydroazepine, pyrazole, pyridine, triazole, tetrahydrofuran, tetrahydropyran, pyrrole, pyrrolidine or tetrazole; for Het2, tetrahydropyran. For the avoidance of doubt, when the Het groups (Het1, Het2 and Het3) are at least partially saturated, the possible substitution points include the atom (for example the carbon atom) at the Het group connection point to the rest of the molecule . The Het groups can also be linked to the rest of the molecule by a heteró-atom. The part of the piperidine in compounds of the formula I may be in the N-oxidized form. Sulfur atoms which can interrupt substituents (for example alkyl) in compounds of the formula I can be present in oxidized form (for example as sulfoxides or sulfones). The Het1 groups, Het2 and Het3 may also be in the N- or S-oxidized form. The term "pharmaceutically or veterinarily acceptable derivatives" includes non-toxic salts. Salts that may be mentioned include: acid addition salts, for example, salts formed with sulfuric, hydrochloric, hydrobromic, phosphoric, hydroiodic, sulfamic, organo-sulfonic, citric, carboxylic (eg, acetic, benzoic, etc.) , maleic, malic, succinic, tartaric, cinnamic, ascorbic and acid related; base addition salts; salts formed with bases, for example, the sodium, potassium and alkyl C? - ammonium salts.

The compounds of the invention can also be in the form of quaternary ammonium salts, for example in the part of the pyperidine, which salts can be formed by reaction with a variety of alkylating agents, such as an alkyl halide or an acid ester. sulfuric, or of an aromatic sulfonic acid. The compounds of the invention may present tautormerism. All tautomeric forms of the compounds of the formula I are included within the scope of this invention. The compounds of the invention contain one or more asymmetric centers and can therefore exist as enantiomers and diastereomers. The diastereoisomers can be separated using conventional techniques for example by fractional crystallization or by chromatography. The different stereoisomers can be isolated by separation of a racemic mixture or other mixture of the compounds using conventional techniques such as fractional crystallization or HPLC (high performance liquid chromatography). The desired optical isomers can be prepared by reaction of the appropriate optically active starting materials under conditions that do not cause racemization or epimerization. Alternatively, the desired optical isomers can be prepared by resolution, either by HPLC of the racemate using a suitable chiral support or, where appropriate, by fractional crystallization of the diastereoisomeric salts formed by reaction of the racemate with an acceptable optically active acid or base. The invention includes the use of the separated isomers as well as the mixtures of isomers. Also included within the scope of the invention are radioisotopically labeled derivatives of the compounds of formula I which are suitable for biological studies. According to a further aspect of the invention, there is provided a compound of formula I, as defined above, with the additional proviso that when OR 4 is OH, and it is attached to the benzene ring in the meta portion relative to the piperidine ring , which is not in the N-oxidized form, then R3 represents: optionally substituted aryl; optionally substituted C3-? 0 alkenyl or C3-? 0 alkynyl (the last two groups being interrupted by at least one oxygen and / or sulfur atom); C2-? or alkyl, interrupted by at least two oxygen atoms and / or at least one sulfur atom; C1-10 alkyl > C3-? 0 alkenyl or C3-? 0 alkynyl, which are optionally interrupted by one or more oxygen and / or sulfur atoms, and are substituted and / or terminated by one or more of: S (0, R5d, N (R6a ) S (O) 2R7, Het1 (substituted with one or more substituents selected from nitro, amino and C1-5 alkanoyl, (of which the latter group may be substituted by one or more halo atoms), aryl (substituted by one or more substituents selected from nitro, amino and halothanoyl C? -5) or adamantyl (the latter group being substituted by one or more of the corresponding substituents identified above), or OR5c, wherein R5c represents C1-7alkyl, C3alkenyl -10, C3-alkynyl or Het2 (the last four groups being optionally substituted by one or more of the corresponding substituents previously identified), or R5c represents C1-10 alkyl, C3-4 alkyl phenyl, C3-8 cycloalkyl or aryl (of which the last four groups are replaced by one om s corresponding substituents described above); -W-A1-N (R6b) (R6c), wherein R6b and / or R6c independently represent C alqu-phenyl alkyl, (the latter group being optionally substituted by one or more of the corresponding substituents described above), CMO alkyl , C3-10 alkenyl, C3- [alpha] 0 alkynyl, C3-8 cycloalkyl (the last four groups being substituted by one or more of the corresponding substituents described above), or aryl (substituted by one or more substituents selected from nitro, amino and haloalkanoyl C? _ ); Such compounds can also be referred to as "compounds of the invention". According to a further aspect of the invention, a compound of the formula I is provided, as defined above, with the additional proviso that when OR 4 is 0-C? - alkyl, and is attached to the benzene ring in the meta position relative to the piperidine ring, which does not is in the N-oxidized form, then R3 does not represent linear or branched C-MO alkyl (optionally substituted by one or more substituents selected from unsubstituted aryl or unsubstituted C3-8 cycloalkyl); such compounds may also be referred to as "compounds of the invention". Preferred compounds of the invention include those in which: The group OR 4 is attached to a benzene ring in the meta position relative to the piperidine group; R1 represents C? -2 alkyl; R2 represents H or C? -2 alkyl; R3 represents aryl (optionally substituted by one or more substituents selected from C? -2 alquilo alkyl, C? -2 alco alkoxy, halo, nitro and -N (R5a) (R5b)), C?-8 alkyl, C 3-8 alkenyl or C3-8 alkynyl wherein said alkyl, alkenyl or alkynyl groups are optionally interrupted by one or more oxygen atoms and / or are substituted and / or terminated by one or more substituents selected from OR5c, S (0) nR5d, CN, halo, C 1 -C 6 alkoxy, C 4-6 cycloalkyl, C 5-7 cycloalkanoyl, Het 1, aryl (the latter group being optionally substituted by one or more substituents selected from OH, C 1-2 alkyl, C 1-2 alkoxy or halo), or -W-A1-N (R6b) (R6c); W represents a single bond or C (O); A1 represents a single bond or alkylene C? -3; R5a to R5d each independently represent H, C? 6 alkyl, C3-6 alkenyl, C-8 cycloalkyl, C? -2 phenyl alkyl, aryl or Het2; R6b and R6C independently represent H, C? -2 alkyl, Het3, or R6b and R6c both represent unbranched C2-6alkylene, such alkylene group being optionally interrupted by O or S and is optionally substituted by one or more C? Alkyl groups? -2; Het1, Het2 and Het3 independently represent 5 to 7 membered heterocyclic groups, such groups contain at least one heteroatom selected from oxygen, sulfur, and / or nitrogen, these groups are optionally fused to a benzene ring, and such groups are optionally substituted at the part of the heterocyclic and / or benzene ring in part of the heterocyclic and / or benzene ring condensed by one or more substituents selected from OH, = 0 and C1-2 alkyl (the latter group optionally being substituted by one or more halo atoms); R4 represents H or C? -5 alkanoyl. The most preferred groups of the present invention include those in which: R 1 represents methyl; R 2 represents H or methyl; R3 represents phenyl (optionally substituted with one or more substituents selected from methyl, methoxy and -N (CH3) 2), linear C?-7 alkyl or C?-Linear alkenyl, such alkyl or alkenyl groups are optionally interrupted by one or more oxygen atoms and / or are optionally substituted and / or terminated by one or more selected substituents fe ^^^ between 0R5c, S (0) nR5d, C6-carbonyl alkoxy, C4-6 cycloalkyl, Het1 or -C (0) N (R6b) (R6c); R5C and R5d each independently represent H, alkyl C? -3, C3- alkenyl, C5- cycloalkyl, phenyl, naphthyl or Het2; R6b and R6c together represent unbranched C4-6alkylene, the alkylene group being optionally interrupted by O and optionally substituted by one or more alkyl groups C? -2. Particularly preferred compounds of the invention include those in which: R1 and R2 represent methyl groups mutually in the trans configuration; R4 represents H. Preferred compounds of the invention include the compounds of the examples described below. Thus, according to a further aspect of the invention, there is provided a compound of formula I, which, independently of any previous definition and condition, is: (±) -3-. { 1- [2- (cyclohexyloxy) ethyl] -'a-s-3,4-dimethylpiperidinyl} phenol; (±) -3-. { 1- [2- (1, 3-dioxan-2-yl) ethyl] -iraA7s-3,4-dimethylpiperidinyl} phenol; (±) -3- [1- (3-Hydroxypropyl) -frans-3,4-dimethyloxyperidyl] phenol; (±) -3-. { 1- [3- (allyloxy) propyl] -frans-3,4-dimethylpiperidinyl} phenol; (±) -3- [1 - (2-ethoxyethyl) -fraA? -3,4-dimethylpiperidinyl] phenol; (±) -3- [1- (3-tetrahydro-3-furanylpropyl) -lrans-3,4-dimethylpiperidinyljphenol; (±) -3-. { 1- [2- (2-methoxyethoxy) ethyl] -rrans-3,4-dimethylpiperidinyl} phenol; (±) -3- [1- (2-methoxyethyl) -irara-s-3,4-dimethylpiperidinyl] phenol; (±) -3-. { 1- [2- (Vinyloxy) ethyl] -rnes-3,4-dimethylpiperidinyl} phenol; (±) -3- (1- { 2- [2 (2-hydroxyethoxy) ethoxy] ethyl.} -. - trans-3,4-dimethylpiperidinyl) phenol; (±) -3-. { 1 - [3- (Tetrahydro-2H-pyran-2-yloxy) propyl] -i / -a / 7s-3,4-dimethylpiperidinyl} phenol; (±) -3- [1- (3-tetrahydro-2 / - / - pyran-2-ylpropyl] -irara? S-3,4-dimethylpiperidinyljphenol; (±) -3- { 1- [3- (1,3-dioxan-2-yl) propyl] -f-p-3,4-dimethylpiperidinyljphenol; (±) -3- [1- (3,3-d¡methoxypropyl) -f-ans-3 , 4-dimethylpiperidinyl] phenol, (±) -3- { 1- [2- (2-hydroxyethoxy) etl] -frans-3,4-dimethylpiperidinyl} phenol; (±) -3 - { 1- [2- (1, 3-dioxolan-2-yl) ethyl] -rnes-3,4-dimethylpiperidinyl} phenol; (±) -3- { 1- [4- ( 1,3-dioxolan-2-yl) butyl] -rans-3,4-dimethylpiperidinyl} phenol; (±) -3- { 1 - [2- (2,5,5-trimethyl-; 1,3-doxan-2-yl) ethylHrans-3,4-dimethylpiperidinyl} phenol; (±) -3- { 1- [2- (tetrahydro-2H-pyran-2-yloxy ) ethyl] -? tA-aA7s-3,4-dimethylpiperidinyljphenol; (±) -3- [1- (5-hydroxypentyl) -irap7s-3,4-dimethylpiperidinyl] phenol; (±) -3- [1- ( 3- (tetrahydro-2fy-pyran-4-ylpropyl) -fra? 7s-3,4-dimethylpiperidinyljphenol; (±) -3-. { 1- [2- (2-naphthyloxy) ethyl] -fra? S-3,4-dimethylpiperidinyl} phenol; (±) -3- [1- (2-isopropoxyethyl) -frans-3,4-dimethylpiperidinyl] phenol; 3- [1- (2-propoxyethyl) -rrans-3,4-dimethylpiperidinyl] phenol; (±) -3-. { 1- [2- (Cyclopentyloxy) ethyl] -rnes-3,4-dimethylpiperidinyl} phenol; (+) - 3- [1- (3-tetrahydro-2-furan-1-propyl) -iraA7S-3,4-dimethylpiperidinylphenol; (±) -3-. { 1- [2- (Cyclohexylsulfanyl) ethyl] -rnes-3,4-dimethylpiperidinyl} phenol; (±) -3-. { 1- [2- (Ethylsulfanyl) ethyl] -frans-3,4-dimethylpiperidinyl} phenol; (±) -3-. { 1- [2- (ethylene sulphonyl) ethyl] -irazyl-3,4-dimethylpiperidinyl} phenol; (±) -3-. { 1 - [2- (ethylene sulfonyl) ethyl] -frans-3,4-dimethylpiperidinyl} phenol; (+) - 3-. { 1 - [3- (1 H-1, 2,3,4-tetrazol-yl) propyl) -i? Ans-3,4-dimethylpiperidinyl} phenol; (±) -3-. { 1 - [3- (1 / -pyrazol-1-yl) propyl) -i "ans-3,4-dimethylpiperidinyl} phenol; (±) -3- { 1- [3- (4- pyridinyl) propyl) -i? a? s-3,4-dimethylpiperidinyl.} phenol; (+) - 3 { 1 - [3- (1 H-1, 2,4-triazol-1-yl) propyl) -rnes-3,4-dimethylpiperidinyl} phenol; (±) -3- { 1- [3- (7 / - -pyrrol-1-yl) propyl) -ira 7s-3 , 4-dimethylpiperidinyl, phenol, (±) -3- [IraA7s-3,4-dimethyl-4- (3-hydroxyphenyl) piperidinyl] -1- (4-morpholinyl) -1-propanone; {. 1- [3- (4-morpholinyl) propyl) -rans-3,4-dimethylpiperidinyl} phenol; 3 { 1 - [2- (1-acetyl) ethyl] -ira? s-3,4-dimethylpiperidinyl, phenol, 3- {1- [2- (4-morpholinyl) ethyl] -rnes-3,4-dimethylpiperidinyl} phenol; (±) -3-. { 1- [2- (1-piperidinyl) ethyl] -irans-3,4-dimethylpiperidinyl} phenol; 3-. { 1- [2- (1-pyrrolidinyl) ethyl] -iraA7s-3,4-dimethylpiperidinyl} phenol; 3-. { 1- [3- (1-piperidinyl) propyl] -rans-3,4-dimethylpiperidinyl} phenol; (±) -3- [1- (3-methoxyphenyl) -rnes-3,4-dimethylpiperidinyl] phenol; or (±) -3-. { 1- [4- (dimethylamino) phenyl] -frans-3,4-dimethylpiperidinyl} phenol; or (±) -methyl-3- [rans] -3,4-dimethyl-4- (3-hydroxyphenyl) piperidinyl] propionate, such compounds can also be referred to as "compounds of the invention". According to a further aspect of the invention, methods are provided for the preparation of compounds of the invention, as illustrated below. The following procedures are illustrative of the general synthetic procedures that can be adopted to carry out the preparation of the compounds of the invention. 1. Compounds of the formula I in which R3 represents Ci-alkyl optionally substituted with C3-8 cycloalkyl, Het1, aryl, adamantyl (the last two groups being optionally substituted by one or more substituents selected from OH, mitro, amino, halo , CN, CH2CN, CONH2, C? -4 alkyl, C -? Alco alkoxy and C C1-5 alca alkanoyl (the last three groups being optionally substituted by one or more atoms (halo)), or R3 represents C2- or alkyl, C3-10 alkenyl or C3-10 alkynyl (the three groups being optionally substituted by one or more of the corresponding substituents described above with respect to R3), wherein the alkyl, alkenyl or alkynyl groups are attached to the nitrogen atom of piperidine by a CH2 group, being Het1 as defined above, can be prepared by reduction of a corresponding compound of formula II, wherein R31 represents H, C3-8 cycloalkyl, Het1, aryl, adamantyl (where either of the last two groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH CN, CONH2, C? -4 alkyl, C? -4 alkoxy and C? -5 alkanoyl, (where any of the last three groups is optionally substituted by one or more halo atoms), C? -9 alkyl, C2-9 alkenyl or C2-9 alkynyl, such alkyl, alkenyl or alkynyl groups being optionally substituted and / or terminated by one or more substituents selected from OR5c, S (0) nR5d, CN, halo, C6-6 carbonyl alkoxy, C2-b alkoxy, C2-6 alkanoyloxy, C3-8 cycloalkyl, C -9 cycloalkanoyl, N (R6a) S (0) 2R7, Het1, aryl adamantyl (where either of the last two groups is optionally substituted with one or more substituents '«G ^? selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C? -4 alkyl, C? - alkoxy and C? -5 alkanoyl, (where any of the last three groups is optionally substituted by one or more halo atoms) )), or -W-A1-N (R6b) (R6c), and R1, R2, R3, R4, R5d, R6a to R6c, R7, Het1, n, W and A1 are as defined above, using an agent suitable reducing agent (for example lithium aluminum hydride or a borane derivative), for example as described above. The compounds of the formula II can be prepared by reaction of a corresponding compound of the formula III, wherein R1, R2 and R4 are as defined above with a compound of formula IV, R31C02H IV or a suitable derivative (for example a carboxylic acid) (for example an acid or anhydride halide) thereof, wherein R31 is as defined above, using coupling conditions known to those skilled in the art. The compounds of the formula III can be prepared from suitable precursors by analogy with other methods described herein that describe the preparation of compounds of the formula I. 2. The compounds of the formula I in which R1 represents alkanoyl C ? _? 2, (pyridin-3-yl) carbonyl or (pyridin-4-yl) carbonyl (where either of the last two groups is optionally substituted in the form of N-oxide of pyridine) can be prepared by reaction of a compound corresponding to the formula I in which R4 represents H with a compound of the formula V, R41-C02H V or a suitable derivative (for example carboxylic acid) (for example an acid or anhydride halide) thereof, in which R41 represents CMI alkyl, pyridin-3-yl or pyridin-4-yl (where either of the last two groups are optionally in the N-oxide form of pyridine), using coupling conditions well known to those skilled in the art. 3. The compounds of the formula I can also be prepared by reacting a corresponding compound of the formula III, as described above, with a compound of the formula VI, R3-L1 VI in which L1 represents a leaving group as halo, alkanesulfonate, perfluoroalkanesulfonate or arenesulfonate) and R3 is as defined above, under conditions that are well known to those skilled in the art, including, for example, alkylation at temperatures between room temperature and reflux temperature in the presence of an organic solvent inert to the reaction (for example N, Nd.methylformamide) and a suitable base (for example NaHCO3), and arylation at a temperature between room temperature and the reflux temperature in the presence of a suitable catalyst system ( for example, thirs (di-benzylidene ketone) -palladium (0) combined with tri-o-tolylphosphine), an appropriate strong base (for example sodium tert-butoxide) and a you inert to the reaction (for example toluene). 4. The compounds of the formula I in which R3 represents C-1 alkyl, which, instead of being optionally substituted by substituents as defined above, is optionally substituted by R31, where R31 is as defined above, can be prepared by reaction of a corresponding compound of formula III, as defined above, with a compound of formula VII. R31CHO R1 in which R31 is as defined above, for example in the presence of a suitable reducing agent (for example sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride) of a suitable solvent (for example methanol). 5. Compounds of the formula I in which R3 is a C-OM alkyl, C-? 0 alkenyl or C-? 0 alkynyl group which is completely saturated between carbon 1 and 3 (relative to the N atom of pyridine ), and the group R3 being substituted on carbon 2 (relative to the N atom of pyridine) by S (0) R5d, S (0) 2R5d, alkanoyl, cycloalkanoyl, alkoxycarbonyl, CN, -C (0) -A1- N (R6b) (R6c), -S (0) -A1-N (R6b) (R6c), or -S (0) 2-A -N (R6b) (R6c), wherein R5d, R6b, R6c and A1 are as defined above, they can be prepared by reacting a corresponding compound of formula III, as defined above, with a compound of formula VIII, R3a-Z VIII wherein R3a represents R3 as defined above except that it does not represent aryl, and that the chain R3a contains an additional carbon-carbon double bond in position alpha, beta with respect to the substituent Z, which represents S (0) R5d, alkanyl, cycloalkanoyl, alkoxycarbonyl, CN, -C (O) -A1-N (R6b) (R6c), -S (O) -A1-N (R6b) (R6c), or -S (O) 2- A1-N (R6b) (R6c), wherein R5d, R6b, R6c and A1 are as defined above, for example at a temperature between room temperature and the temperature of reflux in the presence of a solvent inert to the reaction (for example THF). The compounds of formulas IV to IX, and derivatives thereof, when not commercially available or not subsequently described, may be obtained analogously with the methods described herein, or by conventional synthetic procedures, in accordance with standard techniques. , from readily available starting materials using suitable reagents and reaction conditions (see for example, "Comprehensive Organic Transformations-A Guide to Functional Group Preparations," RC Larrock, VCH (1989), or "Advanced Organic Chemistry-Recations," Mechanism and Structure ", fourth edition, J. March, Wiley-lnterscience (1992)). For example, the compounds of the formula I in which R 4 represents H can be obtained according to or by analogy with the processes described in the aforementioned publications related to compounds based on 4-arylpiperidines. The substituents on alkyl, heterocyclic and aryl groups in the aforementioned compounds can be introduced, removed and interconverted using techniques that are well known to those skilled in the art. For example, the nitro group can be reduced to amino, CH can be alkylated to alkoxy, the alkoxy group can be hydrolyzed to OH, the alkenes can be hydrogenated to alkanes, the halo group can be hydrogenated to H, etc. The skilled person will also appreciate that other compounds of the formula I can be obtained with other standard interconversions between substituents or functional groups of certain compounds of the formula I. The compounds of the invention can be isolated from their reaction mixtures by conventional techniques. It will be appreciated by those skilled in the art throughout the performance of the methods described above, that the functional groups of the intermediates may need to be protected by protecting groups. The functional groups that one wishes to protect include oxo, OH, amino and carboxylic acid. Suitable protecting groups for oxo include acetals, ketals (for example ethylene ketals) and dithynes. Suitable protecting groups for OH include trialkylsilyl and diarylalkysilyl groups (for example, butyldimethylsilyl, urea-butyldiphenylsilyl or trimethylsilyl) and tetrahydropyranyl. Suitable protecting groups for amino include tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acid include C 1-6 alkyl or benzyl esters. Suitable groups for terminal alkynes include trialkylsilyl and diarylalkysilyl groups (for example ferc-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl). The protection and deprotection of the functional groups can take place before or after the reaction steps described above. The protecting groups are removed according to techniques well known to those skilled in the art. The use of protective groups is described in detail in "Protective Groups in Organic Chemistry", edited by JWF McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis", second edition, TW Greene & amp;; PGM Wutz, Wiley-lnterscience (1991). Those skilled in the art will appreciate that in order to obtain compounds of formula I as an alternative, and, in some cases, more conveniently, the steps of the aforementioned process can be carried out in different order, and / or individual reactions can carried out by the general route at different level (for example the substituents can be added to and / or the chemical transformations carried out in different intermediates to those mentioned above in conjunction with a given reaction). This will depend, inter alia, on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the group protection strategy (if any) to be adopted. Clearly, the type of chemistry involved will influence the choice of reagent used in the aforementioned synthetic stages, the need, and the type, of protective groups that are used, and the sequence for the achievement of the synthesis. The methods can be adapted as required by the reactants, reagents and other reaction parameters in such a way that it will be apparent to the person skilled in the art by reference to conventional textbooks and to the examples provided later in this document. It will be appreciated by those skilled in the art that certain protected derivatives of the compounds of formula I, which may be obtained prior to the final deprotection step, do not possess pharmacological activity as the former, but may, in certain cases, be administered orally or parenterally. and forming pharmacologically active compounds of the invention after metabolization in the body. Such derivatives can therefore be described as "prodrugs". In addition, certain compounds of the formula I can act as prodrugs of other compounds of the formula I. It will also be appreciated by those skilled in the art, that certain residues, known to those skilled in the art as "pro-residues", for example as described in "Design and Prodrugs" by H. Bungaard, Elsevier, 1985 (which is incorporated herein by reference), can be placed on suitable functionalities, when such functionalities are present in compounds of formula I. All protected derivatives, and prodrugs, of the compounds of formula I are included in the scope of the invention. The pharmaceutically acceptable acid addition salts of the compounds of the formula I containing a basic center can be prepared in a conventional manner. For example, a solution of free base may be treated with the appropriate acid, either neat or in the appropriate solvent, and the resulting salt is then isolated from the reaction solvent by filtration or by evaporation under vacuum. The pharmaceutically acceptable base addition salts can be obtained analogously by treating a solution of compound I with the appropriate base. Both types of salt can be formed or interconverted using techniques with ion exchange resins. The above procedures can be adapted as required by the particular reactants and groups involved and other variations for the specialist chemist are apparent from reference to conventional textbooks and examples provided below to facilitate the preparation of all compounds of the formula I. the invention are useful because they possess a pharmacological activity in animals, especially in mammals, including humans. Therefore they are indicated as drugs and, in particular, for use as medicines for animals. According to a further aspect of the invention there are provided compounds of the invention (optionally a compound of formula I as defined herein but without the conditions) for use as medicaments, such as drugs and medicaments for animals. The term "treatment" includes therapeutic treatment (curative) and prophylactic treatment. Specific, it has been found that the compounds of the invention are useful in the treatment of pruritus, and diseases characterized by pruritus as a symptom. Thus, according to a further aspect of the invention there is provided the use of the compounds of the invention (optionally a compound of the formula I as defined herein but without the conditions) in the production of a medicament for the treatment of pruritus. or a medical condition characterized by pruritus as a symptom. The compounds of the invention are expected, therefore, to be useful for the curative or prophylactic treatment of pruritic dermatosis including allergic dermatitis and atopy in animals and humans. Other diseases and conditions that may be mentioned include contact dermatitis, psoriasis, eczema and insect bites. In this way, the invention provides a method for the treatment or prevention of pruritus or medical condition characterized by pruritus as a symptom in an animal (e.g., a mammal), comprising administering a therapeutically effective amount of a compound of the invention. (optionally a compound of formula I as defined herein but without the conditions) to an animal in need of such treatment. The compounds of the invention will normally be administered orally or by any parenteral route, in the form of pharmacological preparations comprising the active ingredient, optionally in the form of an acid, base, non-toxic organic or inorganic addition salt in a form of pharmaceutically acceptable dosage. Depending on the disorder and the patient to be treated, as well as the route of administration, the compositions may be administered at varying doses (see below). While it is possible to administer a compound of the invention directly without any formulation, the compounds are preferably employed in the form of a pharmaceutical or veterinary formulation comprising a pharmaceutically or veterinarily acceptable carrier, diluent or excipient, and a compound of the invention. The vehicle, diluent or excipient may be selected according to the intended route of administration and to conventional pharmaceutical and / or veterinary practice. The pharmaceutical compositions comprising the compounds of the invention may contain from 0.1 weight percent to 90.0 weight percent of the active ingredient. The methods by which the compounds can be administered for veterinary use include oral administration by capsules, boluses, tablets or potions, topical administration as ointment, splash, drip, bath, spray, cream, shampoo, powder or necklace formulation, alternatively, they can be administered by injection (for example subcutaneously, intramuscularly or intravenously), or as an implant. Such formulations can be prepared in a conventional manner in accordance with conventional veterinary practice. The formulations will vary with respect to the weight of the active compound contained therein, depending on the animal species to be treated, the severity and type of the infection and the body weight of the animal. For parenteral, topical and oral administration, the typical dose ranges of the active ingredient are from 0.01 to 100 mg per kg of body weight of the animal. Preferably the range is from 0.1 to 10 mg per Kg. The compositions are preferably formulated in a unit dosage form, each dose containing from about 1 to about 500 mg, more usually from about 5 mg to about 300 mg of the active ingredient. The term "dosage unit form" refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined amount of the active material calculated to produce the desired therapeutic effect, together with a suitable pharmacological vehicle. In any case, the veterinarian or specialized person will be able to determine the practical dosage that will be the most appropriate for an individual patient, which may vary with the species, age, weight and response of the particular patient. The above dosages are examples of the average case; they can, of course, be given individual examples where a greater or lesser dosage range is allowed, such cases are within the scope of this invention. For veterinary use, the compounds of the invention are of particular value for the treatment of pruritus in domestic animals such as cats and dogs and in horses. As an alternative for the treatment of animals, the compounds can be administered with the animal feed and for this purpose a concentrated feed additive or premix can be prepared for mixing with the normal animal feed. For human use, the compounds are administered as a pharmaceutical formulation containing the active ingredient together with a pharmaceutically acceptable diluent or carrier. Such compositions include conventional tablets, capsules and ointment preparations which are formulated in accordance with conventional pharmaceutical practice. The compounds of the invention can also be administered alone or in combination with one or more agents used in the treatment or prophylaxis of a disease or in the reduction or suppression of symptoms. Examples of such agents (which are given by way of illustration and should not be construed as limiting) include antiparasitics, for example fipronil, lufenuron, im.dacloprid, avermectins (e.g., abamectin, ivermectin, doramectin), milbemycins, organophosphates, pyrethroids, antihistamines , for example chlorpheniramine, trimeprazine, diphenhydramine, doxylamine; antifungals, for example fluconazole, ketoconazole, itraconazole, griseofulvin, amphotericin B; antibacterials, for example enroflaxacin, marboflaxacin, ampicillin, amoxicillin; anti-inflammatories for example prednisolone, betamethasone, dexamethasone, carprofen, ketoprofen; dietary supplements, for example gamma-linoleic acid; and emollients. Thus, the invention further provides a product containing a compound of the invention and a compound from the foregoing list as a combined preparation for simultaneous, separate or sequential use in the treatment of pruritus. The skilled person will also appreciate that the compounds of the invention can be taken in a single dose on the basis of "as required" (eg as needed or desired). Thus, according to a further aspect of the invention there is provided a pharmaceutical or veterinary formulation comprising a compound of the invention (optionally a compound of the formula I as defined herein but without the conditions) in admixture with a pharmaceutically or veterinarily acceptable adjuvant, diluent or vehicle. The compounds of the invention may also have the advantage that in the treatment of human and / or animal patients, they may be more effective, be less toxic, have a broader spectrum of activity, be more potent, produce fewer side effects, be more rapidly absorbed, or have more useful pharmacological properties than compounds known in the prior art. The biological activity of the compounds of the present invention was determined by the following test procedure.

Biological assay The compounds of the invention are evaluated according to their activity as antipruritic agents by measuring their ability to inhibit the scratching behavior with the hind paw in rats by administration of a known pruritogen agent. These studies are based on the procedure described by Berendsen and Broekkamp in the European Journal of Pharmacology, 1991, 194, 201. The test is carried out as follows: Male Wistar rats (approximately 150 g body weight) are oculated with a pruritogen by subcutaneous injection into the cochote of 5-methoxytryptamine hydrochloride (4 mg / 3 ml / kg) dissolved in physiological saline. At this dose, a scratching response with the hind leg is constant and quantifiable after 90 minutes. The test compound is administered to the test animal by subcutaneous injection in an aqueous micelle formulation. The test compound is prepared in the following manner. The compound is dissolved in a vehicle (composition in v / v%: glycerol formal, 24, tween 80.17, benzyl alcohol, 1.5 and purified water to 100) then seven parts of purified water are added to three parts of the previous vehicle to give the aqueous micelle formulation. The compounds can be administered pre- or post-inoculation or can be administered at the same time as the pruritogenic inoculation. Once the pruritogenic inoculation is administered, scraping with the hind paw is scored for each animal by recording the presence or absence of it at each interval of 30 seconds, scoring 0 or 1 respectively. The qualification for each animal is totalized after minutes (maximum score 50). The effectiveness of the compounds is manifested by their ability to significantly reduce their rating in the treated groups compared to the control groups. The invention is illustrated by the following preparations and examples in which the following abbreviations are used: APCI = chemical ionization at atmospheric pressure br (in relation to NMR) = width DCM = dichloromethane DMF =? /,? / - dimethylformamide DMSO = dimethisulfoxide d (in relation to time) = day d (in relation to NMR) = doublet dd (in relation to NMR) = doublet of doublets EtOAc = ethyl acetate EtOH = ethanol h = hour (s) m (in relation to NMR) = multiplet MeOH = methanol min = minute h (in relation to NMR) = quadriplete rt = room temperature s (in relation to NMR) = singlet t (in relation to NMR) = triplet THF = tetrahydrofuran TSI = ionization by thermospray When talking of a chromatographic column in this context usually refers to a glass column filled with silica gel (40-63 microns). A pressure of 165 kPa is generally applied and the ratio of crude product: silica gel required for purification is typically 50: 1. Alternatively, an Isolute ™ SPE (solid phase extraction) column can be used at atmospheric pressure or a Waters Sep-Pak ™ cartridge filled with silica gel. The ratio of crude product to silica gel required for purification is typically 100: 1. The hydrochloride salts of the compounds of the examples can be obtained by methods well known to those skilled in the art of chemically synthesizing. For example, ethereal hydrochloric acid (1.0 M, 1.2 equivalents) can be added to a solution of free base in dichloromethane (1 g: 100 ml), the excess solvent is decanted and the remaining precipitate is washed three times with ether and dry to empty. A common starting material, (±) -3- (trans-3,4-dimethylpiperidinyl) phenol, can be prepared using the procedures described in: Zimmerman et al., J. Org. Chem., 1991, 56, 1660; b) Werner et al., J. Org. Chem., 1996, 61, 587-597. All starting materials are obtained from commercial sources unless otherwise specified. Nuclear magnetic resonance (NMR) spectra data were obtained using a Brucker AC3000 spectrometer, AM300 or AM400, the chemical displacements obtained (delta) were in accordance with the proposed structures. The 1 H-NMR data is measured in solution in CDCl 3 unless otherwise specified. The mass spectral (MS) data were obtained on a Finnigan Mat spectrometer. TSQ 7000 or Fisons Instruments Trio 1000. The observed and calculated ions quoted refer to the lower mass isotopic composition. HPLC means high performance liquid chromatography. Ambient temperature means from 20 ° C to 25 ° C.

EXAMPLES EXAMPLE 1 (+) - 3- (1-F2- (cyclohexyloxy) etiH-*? Trans-3,4-dimethyl-piperidinyl > phenol To a solution of 2- (cyclohexyloxy) ethyl-4-methylbenzenesulfonate (preparation 18, 226 mg, 0.76 mmol) in toluene (2.0 ml) at 0 ° C under nitrogen atmosphere was added pyridine (101 mg, 1.28 mmol) and ( ±) -3- (trans-3,4-d.methylpiperidinyl) phenol (155 mg, 0.76 mmol). The reaction was heated to reflux for 3 hours and then at room temperature for 48 hours. The mixture was concentrated in vacuo and the crude residue was partitioned between a saturated aqueous solution of sodium hydrogencarbonate (10 ml) and ethyl acetate (10 ml). The two layers were separated and the aqueous layer was extracted with dichloromethane (3 x 10 ml). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to yield a crude yellow oil. This was purified using a preparative silica plate, eluting with dichloromethane: methanol (95: 5), to give the title compound (79 mg, 31%) as a colorless oil. 1 H-NMR: 0.85 (d, 3H), 1.10-1.24 (m, 6H), 1.25 (s, 3H), 1.55 (m, 1 H), 1.60-1.68 (m, 2H), 1.71-1.95 (m, 2H), 2.05 (m, 1 H), 2.35 (m, 1 H), 2.60-2.92 (m, 5H), 3.05 (m, 1 H), 3.25 (m, 1 H), 3.68 (t, 2H) , 6.68 (d, 1 H), 6.78-6.83 (m, 2H), 7.11 (t, 1 H). MS (TSI +): m / z [MH +] 332.5; C21H33N02 + H needs 332.3.

EXAMPLE 2 (+) - 3-. { 1-r 2 - (1,3-dioxan-2-yl) ethyl-frans-3,4-dimethyl-piperidinyl) phenol To a solution of (±) -3- (trans-3,4-dimethylpiperidinyl) phenol (100 mg, 0.49 mmol) in? /,? / - dimethylformamide (2.0 ml) at room temperature under nitrogen atmosphere was added hydrogen carbonate sodium (54 mg, 0.54 mmol) and 2- (2-bromoethyl) -1, 3-dioxane (107 mg, 0.55 mmol). The solution was refluxed for 1 hour, cooled and then poured into saturated sodium hydrogencarbonate solution (10 ml) and extracted with diethyl ether (4 x 10 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to yield a brown oil. This was purified by silica gel column chromatography (10 g), eluting with a gradient of dichloromethane: ethanol: 0.88 ammonia (200: 8: 1 to 100: 8: 1), to yield the title compound (110 mg , 64%) in the form of a colorless oil. 1 H-NMR: 0.78 (d, 3 H), 1.28 (s, 3 H), 1.35 (m, 1 H), 1.60 (m, 1 H), 1.72-2.20 (m, 4 H), 2.25-2.60 (m, 6 H) ), 2.85 (m, 1 H), 3.68-3.78 (m, 2H), 4.02-4.12 (m, 2H), 4.60 (t, 1 H), 6.65 (m, 1H), 6.75 (m, 1 H) , 6.81 (d, 1 H), 7.15 (t, 1 H). MS (TSI +): m / z [MH +] 320.0; C19H29N03 + H needs 320.2.

EXAMPLE 3 (±) -3-ri- (3-hydroxypropyl) -frans-3,4-dimethyl-piperidine-phenol To a stirred solution of (±) -methyl 3- [rans-3,4-dimethyl-4- (3-hydroxy-phenyl) piperidinyl] propionate (example 45, 117 mg, 0.40 mmol) in terahydrofuran (1 ml) a 0 ° C was added lithium aluminum hydride (1.0 M solution in THF, 1.2 ml, 1.2 mmol). After 1 hour, the reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (3 x 20 ml). The combined extracts were washed with brine (20 ml), dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude product. This was purified by column chromatography on silica gel, eluting with a gradient of methanol: dichloromethane: 0.880 ammonia (10: 990: 1 to 30: 970: 3), to yield the title compound (32 mg, 12%) in the form of a pale yellow oil. 1 H-NMR (C6D6): 0.69 (d, 3H), 1.06 (s, 3H), 1.21-1.36 (m, 3H), 1. 63 (m, 1 H), 1.82 (m, 1 H), 2.05-2.20 (m, 4H), 2.36 (m, 1 H), 2.56 (m, 1 H), 3.71 (t, 2H), 6.59 ( m, 1 H), 6.82 (m, 1 H), 6.86 (m, 1 H), 7.05-7.10 (m, 1 H). MS (APCI +): m / z [MH +] 264.2; C16H25N02 + H needs 264.2.

EXAMPLE 4 (±) -3-. { 1-r3- (allyloxy) propiH frans-3,4-dimethyl-piperidipiphenol To a solution of (±) -3- (trans-3,4-dimethylpiperidinyl) phenol (60 mg, 0.29 mmol) in? /,? / - dimethylformamide (5.0 ml) at room temperature was added sodium hydrogen carbonate (27). mg, 0.32 mmol), sodium iodide (48 mg, 0.32 mmol) and 3-allyloxypropyl chloride (43 mg, 0.32 mmol). The solution was heated at 120 ° C for 1 hour, cooled and then water (10 ml) was added. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to yield a crude oil. This was purified by preparative HPLC (high performance liquid chromatography) on a Dynamax ™ column, 42 x 250 mm; flow of 8.0 ml / min using U.V. detection at 275 nm; acetonitrile eluent gradient: 0.05 M aqueous solution of ammonium acetate (90:10 to 10:90), to yield the title compound (50 mg, 66%) as its acetate salt. 1 H-NMR (data selected from the acetate salt): 0.78 (d, 3H), 1.28 (s, 3H), 1.60 (m, 1 H), 1.78-1.90 (m, 2H), 3.45 (t, 2H), 3.91 (m, 2H), 5.14 (t, 1 H), 5.23 (d, 1 H), 5.85 (m, 1 H), 6.61 (d, 1 H), 6.70-6.81 (m, 2H), 7.10 ( t, 1 H). MS (TSI +): m / z [MH +] 305.5; C? 9H29N02 + H needs 304.2.

EXAMPLE 5 (+) - 3-M - (ethoxyethyl) frans-3,4-dimethylpiperidine-phenol To a solution of (±) -3- (rrenes-3,4-dimethylpiperidinyl) phenol (60 mg, 0.29 mmoles) in? /, / V-dimethylformamide (5.0 ml) at room temperature was added sodium hydrogen carbonate (27 mg, 0.32 mmol), and 2-bromoethyl ethyl ether (50 mg, 0.32 mmol). The solution was heated at 120 ° C for 1 hour, cooled and then water (10 ml) was added. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to yield a crude oil. This was purified by preparative HPLC on a Dynamax ™ column, 42 x 250 mm; flow of 8.0 ml / min using U.V. detection at 275 nm; Acetonitrile eluent gradient: 0.05 M aqueous solution of ammonium acetate (90:10 to 10:90), to yield the title compound (31 mg, 39%) as its acetate salt. 1 H-NMR (data selected from the acetate salt): 0.82 (d, 3H), 1.18 (t, 3H), 1.30 (s, 3H), 1.70 (m, 1H), 2.01 (s, 3H), 2.05 (m , 1H), 2.38 (m, 1 H), 2.81-3.05 (m, 5H), 3.20 (m, 1 H), 3.42 (q, 2H), 3.68 (t, 2H), 6.65 (s, 1 H) , 6.72-6.80 (m, 2H), 7.12 (t, 1 H). MS (TSI +): m / z [MH +] 278.5, C17H27N02 + H needs 278.2.

EXAMPLE 6 (±) -3-f1- (3-Tetrahydro-3-furanylpropyl) -frans-3,4-dimethylpiperidininphenol To a stirred solution of (±) -1- [fra /? S-3,4-dimethyl-4- (3-hydroxyphenyl) -piperidinyl] -3- (tetrahydro-3-furanyl) -1-propanone (Preparation 2) , 150 mg, 0.47 mmol) in tetrahydrofuran (25 ml) at room temperature was added lithium aluminum hydride (2.2 ml, 1.0 M solution in diethyl ether): After 10 minutes, the reaction mixture was quenched with water and the precipitate The resultant was removed by filtration through a Cellite (R) layer, washing with diethyl ether. The filtrate was dried over sodium sulfate, filtered and concentrated in vacuo to yield the crude product (150 mg, 100%). 1 H-NMR: 0.77 (d, 3 H), 1.27 (s, 3 H), 1.32-1.61 (m, 6 H), 1.92-2.03 (m, 2 H), 2.18 (m, 1 H), 2.22-2.41 (m, 4H), 2.46-2.58 (m, 2H), 2.82 (m, 1 H), 3.30 (t, 1 H), 3.73 (m, 1 H), 3.81 (m, 1 H), 3.88 (t, 1 H) ), 6.59 (d, 1 H), 6.71 (s, 1 H), 6.80 (d, 1 H), 7.10 (t, 1 H). MS (TSI +): m / z [MH +] 318.5; C20H31NO2 + H needs 318.2.

EXAMPLE 7 (±) -3-f1-r2- (2-methoxyethoxy) etin-frans-3,4-dimethylpiperidinyl > phenol To a solution of (±) -3- (rans-3,4-d-methylpiperidinyl) phenol (60 mg, 0.29 mmol) in α / γ / - dimethylformamide (5.0 ml) at room temperature was added water ( 10 ml). The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the crude oil. This was purified by preparative HPLC on a Dynamax ™ column, 42 x 250 mm; flow of 8.0 ml / min; using U.V. detection at 275 nm, gradient eluent of acetonitrile: aqueous solution 0.05 M ammonium acetate (90:10 to 10:90), to yield the title compound (71 mg, 80%) as its acetate salt. 1 H NMR (data for acetate salt): 0.82 (d, 3 H), 1.35 (s, 3 H), 1.72 (m, 1 H), 2.03-2.10 (m, 4 H), 2.38 (m, 1 H), 2.81-3.13 (m, 6H), 3.40 (s, 3H), 3.50-3.63 (m, 4H), 3.70-3.78 (m, 2H), 6.68 (m, 1 H), 6.81-6.82 (m, 2H) , 7.18 (t, 1 H). MS (TSI +): m / z [MH +] 308.3; C18H29N03 + H needs 308.2.

EXAMPLE 8 (±) -3-ri-f2-methoxyethyl) - * - rans-3,4-dimethylpiperidin-phenol To a solution of (±) -3- (trans-3,4-dimethylpiperidinyl) phenol (60 mg, 0.29 mmol) in?,? / - dimethylformamide (5.0 ml) at room temperature was added hydrogen carbonate sodium (27 mg, 0.32 mmol), and 1-bromo-2-methoxyethane (45 mg, 0.32 mmol). The solution was heated at 120 ° C for 1 hour, cooled and then water (10 ml) was added. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the crude oil. This was purified by preparative HPLC on a Dynamax ™ column, 42 x 250 mm; flow of 8.0 ml / min; using U.V. detection at 275 nm; acetonitrile eluent gradient: 0.05M aqueous solution of ammonium acetate (90:10 to 10:90), to yield the title compound (17 mg, 22%) as its acetate salt. 1 H NMR (data for acetate salt): 0.83 (d, 3H), 1.35 (s, 3H), 1. 72 (m, 1 H), 2.03-2.09 (m, 4H), 2.38 (m, 1 H), 2.70-3.18 (m, 6H), 3.38 (s, 3H), 3.58-3.65 (m, 2H), 6.68 (d, 1 H), 6.79-6.84 (m, 2H), 7.18 (t, 1 H). MS (TSI +): m / z [MH +] 264.2; C16H25N02 + H needs 264.2.

EXAMPLE 9 (±) -3-f1-r2- (vinyloxy) etin-frans-3,4-dimethylpiperidinyl} phenol To a solution of (±) -3- (rraA7s-3,4-dimethylpiperidinyl) phenol (60 mg, 0.29 mmol) in? /, / V-dimethylformamide (5.0 ml) at room temperature was added sodium hydrogen carbonate (27 mg. , 0.32 mmol), sodium iodide (48 mg, 0.32 mmol) and 2-chloroethyl vinyl ether (34 mg, 0.32 mmol). The solution was heated at 120 ° C for 1 hour, cooled and then water (10 ml) was added. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the crude oil. This was purified by preparative HPLC on a single Dynamax ™ column, 42 x 250 mm; acetonitrile eluent gradient: 0.05M aqueous solution of ammonium acetate (90:10 to 10:90), to yield the title compound (13 mg, 16%) as its acetate salt. 1 H-NMR (data for acetate salt): 0.82 (d, 3H), 1.38 (s, 3H), 1.62 (m, 1 H), 2.00-2.08 (m, 4H), 2.37 (m, 1 H), 2.56-3.05 (m, 6H), 3.80-3.92 (m, 2H), 4.02 (d, 1 H), 4.20 (d, 1 H), 6.47 (dd, 1 H), 6.65 (d, 1 H), 6.79 (s, 1 H), 6.85 (d, 1 H), 7.18 (t, 1 H). MS (TSI +): m / z [MH +] 276.3; C17H25N02 + needs 276.2.

EXAMPLE 10 (±) -3- (1- {2-r2- (2-hydroxyethoxy) ethoxyethyl) ->? - RAA? S-3,4-dinnetylpiperidinyl > phenol To a solution of (+) - 3 - (/ ra /? - 3,4-dimethylpiperidinyl) phenol (60 mg, 0.29 mmol) in? /,? / - dimethylformamide (5.0 ml) at room temperature was added hydrogen carbonate. sodium (27 mg, 0.29 mmol), sodium iodide (48 mg, 0.32 mmol) and 2-chloroethyl vinyl ether (34 mg, 0.32 mmol). The solution was heated at 120 ° C for 1 hour, cooled and then water (10 ml) was added. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the crude oil. This was purified by preparative HPLC on a Dynamax ™ column, 42 x 250 mm; flow of 8.0 ml / min; using U.V. detection at 275 nm; acetonitrile eluent gradient: 0.05M aqueous solution of ammonium acetate (90:10 to 10:90), to yield the title compound (13 mg, 16%) as its acetate salt. 1 H NMR (data for acetate salt): 0.85 (d, 3 H), 1.35 (s, 3 H), 1.70 (m, 1 H), 2.01-2.10 (m, 4 H), 2.32 (m, 1 H), 2.70-3.90 (m, 5H), 3.10 (m, 1 H), 3.58-3.70 (m, 6H), 3.71-3.79 (m, 4H), 6.68 (d, 1 H), 6.79-6.83 (m, 2H) ), 7.18 (t, 1 H) MS (TSI +): m / z [MH +] 276.3; C17H25N02 + H needs 276.2.

EXAMPLE 11 (±) -3-. { 1-r3-phthatrahydro-2-pyran-2-yloxy) propyn-frans-3,4-dimethylpiperidine D-phenol To a solution of (±) -3 - (? YaA7s-3,4-di-methylpiperidinyl) phenol (60 mg, 0.29 mmol) in? /,? / - dimethylformamide (5.0 ml) at room temperature At room temperature, sodium hydrogencarbonate (27 mg, 0.32 mmol) and 2- (3-bromopropoxy) tetrahydro-2H-p-ranose (71 mg, 0.32 mmol) were added. The solution was heated at 120 ° C for 1 hour, cooled and then water (10 ml) was added.

The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, and concentrated in vacuo to yield the crude oil. This was purified by preparative HPLC on a column Dynamax ™, 42 x 250 mm; flow of 8.0 ml / min; using U.V. detection to 275 nm; acetonitrile eluent gradient: 0.05 M aqueous solution of ammonium acetate (90:10 to 10:90), to yield the title compound (39 mg, 39%) as its acetate salt. 1 H NMR (data for acetate salt): 0.85 (d, 3H), 1.35 (s, 3H), 1.47-1.92 (m, 9H), 2.01-2.10 (m, 4H), 2.38 (m, 1 H) , 2.56-2.80 (m, 5H), 3.01 (m, 1 H), 3.40-3.56 (m, 2H), 3.78-3.90 (m, 2H), 4.58 (m, 1 H), 6.64 (d, 1 H ), 6.79-6.83 (m, 2H), 7.18 (t, 1 H). MS (TSI +): m / z [MH +] 348.2; C2? H33N03 + H needs 348.3.

EXAMPLE 12 (±) -3-ri- (3-Tetrahydro-2 / - / - p -ran-2-ylpropyl) -fraps-3,4-dimethyl-piperidine-phenol To a stirred solution of 1- [rraps-3,4-dimethyl-4- (3-hydroxyphenyl) -p -peridinyl] -3- (tetrahydro-2 / - / - pyran-2-yl) -1-propanone ( Preparation 3, 470 mg, 1.36 mmol) in diethyl ether (6.6 ml) at room temperature was added lithium aluminum hydride (1.0 M solution in diethyl ether, 2.72 ml, 2.72 mmol). After 2 hours, the reaction was quenched by adding 2N aqueous sodium hydroxide (0.2 ml), followed by water (0.3 ml) and then diethyl ether (15 ml). The solid precipitate was removed by filtration through a Cellite (R) layer, washing with ethyl acetate (5 x 50 ml). The filtrate was dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound (396 mg, 88%) as a pale yellow oil. 1 H-NMR (data selected): 0.78 (d, 3 H), 1.38 (s, 3 H), 1.80 (m, 1 H), 1.95 (m, 1 H), 2.20-2.70 (m, 5 H), 2.78-2.90 (m, 1 H), 3.25 (m, 1 H), 3.41 (m, 1 H), 3.98 (m, 1 H), 6.65 (d, 1 H), 6.75 (s, 1 H), 6.82 (d) , 1 H), 7.18 (t, 1 H). MS (TSI +): m / z [MH +] 332.1; C21H33N02 + H needs 332.3.

EXAMPLE 13 (±) -3-f1-r3- (1,3-dioxan-2-yl) propin-frans-3,4-dimethylpiperidinyl) phenol To a solution of (±) -3- (frans-3,4-dimethylpiperidinyl) phenol (150 mg, 0.29 mmol) in? /, / V-dimethylformamide (4.0 ml) at room temperature was added sodium hydrogen carbonate (84 mg. , 1.00 mmole) and 2- (3-bromopropyl) -1, 3-dioxane (Preparation 4, 209 mg, 1.00 mmole). The solution was heated at 100 ° C for 2 hours, cooled, and then added to a mixture of saturated aqueous sodium hydrogencarbonate solution and diethyl ether (100 ml of 1: 1). The aqueous layer was extracted with diethyl ether (2 x 50 ml) and the combined organic layers were washed with water (100 ml), dried over sodium sulfate, filtered and concentrated in vacuo to yield a crude oil. This was purified by silica gel column chromatography (10 g), eluting with CH 2 Cl 2: ethanol: 0.88 ammonia (100: 8: 1), to yield the title compound (70 mg, 28%) as a foam white 1 H-NMR: 0.78 (d, 3H), 1.35-1.70 (m, 9H), 1.90-2.18 (m, 2H), 2.23-2.64 (m, 6H), 2.85 (m, 1 H), 3.68-3.79 ( m, 2H), 4.02-4.18 (m, 2H), 4.52-4.57 (m, 1 H), 6.61 (d, 1 H), 6.70-6.80 (m, 2H), 7.15 (t, 1 H).

EXAMPLE 14 (±) -3-f1- (3,3-dimethoxypropyl) -frans-3,4-dimethylpiperidininophenol To a solution of (±) -3- (ε ?Aa7s-3,4-dimethylpiperidinyl) phenol (60 mg, 0.29 mmol) in / /, / / - dimethylformamide (2.5 ml) at room temperature was added sodium hydrogen carbonate ( 27 mg, 0.32 mmol), sodium iodide (48 mg, 0.32 mmol) and 3-chloro-1,1-dimethoxypropane (53 mg, 0.32 mmol) in N, N-dimethylformamide (2.0 ml). The mixture was heated at 120 ° C for 1.5 hours, cooled and then water (30 ml) and ethyl acetate (10 ml) were added sequentially. The two layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 10 ml) and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield a crude oil. This was purified by preprarativa HLPC in column Dynamax ™, 42 x 250 mm; flow of 8.0 ml / min; using U.V. detection at 275 nm; Acetonitrile eluent gradient: 0.05 M aqueous solution of ammonium acetate (10:90), to yield the title compound as its acetate salt. 1 H-NMR (data selected for the acetate salt). 0.78 (d, 3H), 1.18-1.28 (m, 6H), 1.29 (s, 3H), 3.45-3.70 (m, 4H), 4.60 (t, 1 H), 6.62 (dd, 1 H), 6.72 ( s, 1 H), 6.82 (d, 1 H), 7.18 (t, 1 H). MS (APCI +): m / z [MH +] 336.2; C20H33NO3 + H needs 336.2.

EXAMPLE 15 (±) -3-. { 1-r2-f2-hydroxyethoxy) etin-frans-3,4-dimethylpiperidinyl > phenol To a solution of (±) -3- (zVans-3,4-dimethylperidyl) phenol (60 mg, 0.29 mmol) in? /,? / - dimethylformamide (2.5 ml) at room temperature Sodium hydrogen carbonate (27 mg, 0.32 mmol), sodium iodide (48 mg, 0.32 mmol) and 2- (2-chloroethoxy) -1-ethanol (53 mg, 0.32 mmol) in N, N-dimethylformamide ( 2.0 ml). The mixture was heated at 120 ° C for 1.5 hours, cooled and then water (30 ml) and ethyl acetate (10 ml) were added. The two layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 10 ml) and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield a crude oil.

This was purified by preparative HPLC on Dynamax ™ column, 42 x 250 mm; flow of 8.0 ml / min; using U.V. detection at 275 nm; acetonitrile eluent gradient: 0.05M aqueous solution of ammonium acetate (90:10), to yield the title compound as its acetate salt. 1 H-NMR (data selected for the acetate salt): 0.82 (d, 3 H), 1.31 (s, 3 H), 1.70 (m, 1 H), 2.02 (s, 3 H), 2.04 (m, 1 H), 2.32 (m, 1 H), 2.62-2.90 (m, 5H), 3.05 (m, 1 H), 3.52-3.80 (m, 6H), 6.66 (dd, 1 H), 6.72-6.80 (m, 2H), 7.15 (t, 1 H). MS (APCf): m / z [MH +] 294.1; C17H27N03 + H needs 294.2.

EXAMPLE 16 (±) -3-. { 1-F2- (1,3-dioxolan-2-yl) etn-frans-3,4-dimethylpiperidinyl > phenol To a solution of (±) -3- (frans-3,4-dimethylpiperidinyl) phenol (60 mg, 0.29 mmol) in N, N-dimethylformamide (2.5 ml) at room temperature was added sodium hydrogen carbonate (27 mg, 0.32 g). mmoles), and 2- (2-bromoethyl) -1,3-dioxolane (60 mg, 0.32 mmol) in? /,? / - dimethylformamide (2.0 ml). The mixture was heated at 120 ° C for 1.5 hours, cooled and then water (30 ml) and ethyl acetate (10 ml) were added. The two layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 10 ml) and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield a crude oil. This was purified by preparative HPLC on Dynamax ™ column, 42 x 250 mm; flow of 8.0 ml / min; using U.V. detection at 275 nm; acetonitrile eluent gradient: aqueous solution 0-05 M ammonium acetate (90:10 to 10:90), to produce the title compound in the form of its acetate salt. 1 H-NMR (data selected for the acetate salt). 0.80 (d, 3H), 1.30 (s, 3H), 1.65 (m, 1 H), 1.90-1.97 (m, 2H), 2.02 (m, 1 H), 2.35 (m, 1 H), 2.43-2.70 (m, 5H), 2.90 (m, 1 H), 3.80-3.98 (m, 4H), 4. 93 (m, 1 H), 6.66 (dd, 1 H), 6.72-6.82 (m, 2H), 7.15 (t, 1 H). MS (APCI +): m / z [MH +] 306.3; C? 8H27N03 + H needs 306.2.

EXAMPLE 17 (±) -3- 1 -r4- (1,3-d.oxolan-2-yl) butin-frans-3,4-dimethylpiperidinyl > phenol To a solution of (±) -3- (rrans-3,4-dimethylpiperidinyl) phenol (60 mg, 0.29 mmol) in N, N-dimethylformamide (2.5 ml) at room temperature was added sodium hydrogen carbonate (27 mg, 0.32 g). mmoles), and sodium iodide (27 mg, 0.32 mmol), sodium iodide (48 mg, 0.32 mmol) and 2- (4-chlorobutyl) -1, 3-dioxolane (53 mg, 0.32 mmol) in? /, ? / - dimethylformamide (2.0 ml). The mixture was heated at 120 ° C for 1.5 hours, cooled and then water (30 ml) and ethyl acetate (10 ml) were added. The two layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 10 ml) and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield a crude oil. This was purified by preparative HPLC on Dynamax ™ column, 42 x 250 mm; flow of 8.0 ml / min; using U.V. detection at 275 nm; Acetonitrile eluent gradient: 0.05M aqueous solution of ammonium acetate (90:10 to 10:90), to yield the title compound in the form of its acetate salt. H-NMR (data selected for acetate salt). 0.81 (d, 3H), 1.38-1.70 (m, 7H), 2.03 (m, 1 H), 2.36 (m, 1 H), 2.43-278 (m, 5H), 2.98 (m, 1 H), 3.80 -3.98 (m, 4H), 4.93 (m, 1 H), 6.66 (dd, 1 H), 6.72-6.82 (m, 2H), 7.15 (t, 1 H). MS (APCI +): m / z [MH +] 334.1; C20H3? NO3 + H needs 334.2.

EXAMPLE 18 (±) -3- (1-r2- (2,5,5-Trimethyl-1,3-d-oxan-2-yl) etin-frans-3,4-dimethylpiperidinyl.} Phenol To a solution of (±) -3- (rraps-3,4-dimethylpiperidinyl) phenol (60 mg, 0.29 mmol) in N, N-dimethylformamide (2.5 ml) at room temperature was added sodium hydrogen carbonate (27 mg, 0.32 g). mmoles), and 2- (2-bromoethyl) -2,5,5-trimethyl-1,3-dioxane (76 mg, 0.32 mmol) in N, N-dimethylformamide (2.0 ml). The mixture was heated at 120 ° C for 1.5 hours, cooled and then water (30 ml) and ethyl acetate (10 ml) were added. The two layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 10 ml) and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield a crude oil. This was purified by preparative HPLC on Dynamax ™ column, 42 x 250 mm; flow of 8.0 ml / min; using U.V. detection at 275 nm; acetonitrile eluent gradient: 0.05 M aqueous solution of ammonium acetate (90:10 to 10:90), to yield the title compound as its acetate salt. 1 H-NMR (data selected for the acetate salt). 0.70 (s, 3H), 0.81 (d, 3H), 1.18 (s, 3H), 1.30 (s, 3H), 1.58-1.60 (m, 5H), 3.40 (d, 2H), 3.60 (d, 3H) , 6.65 (m, 1 H), 6.72-6.82 (m, 2H), 7.15 (t, 1 H). MS (APCf): m / z [MH +] 362.2; C22H35N03 + H needs 362.3.

EXAMPLE 19 (±) -3- f1-r2- (Tetrehydro-2 H -pyran-2-ioxyinetin-frans-3,4-dimethylpiperidine D phenol To a solution of (±) -3- (fra /? S-3,4-dimethylpiperidinyl) phenol (60 mg, 0.29 mmol) in N, N-dimethylformamide (2.5 ml) at room temperature was added sodium hydrogen carbonate (27 mg, 0.32 mmol), sodium iodide (48 mg, 0.32 mmol) and 2-chloroethyl-tetrahydro-2H-pyran-2-yl ether (52 mg, 0.32 mmol) in? /,? / - dimethylformamide (2.0 ml. ). The mixture was heated at 120 ° C for 1.5 hours, cooled and then water (30 ml) and ethyl acetate (10 ml) were added. The two layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 10 ml) and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield a crude oil. This was purified by preparative HPLC on Dynamax ™ column, 42 x 250 mm; flow of 8.0 ml / min; using U.V. detection at 275 nm; Acetonitrile eluent gradient: 0.05M aqueous solution of ammonium acetate (90:10 to 10:90), to yield the title compound in the form of its acetate salt. 1 H-NMR (data selected for the acetate salt). 0.81 (d, 3H), 1.30 (s, 3H), 1.40-1.92 (m, 7H), 2.01-2.10 (m, 1 H), 2.35 (m, 1 H), 2.50-2.82 (m, 5H), 2.98 (m, 1 H), 3.42-3.62 (m, 2H), 3.82-3.95 (m, 2H), 4.60 (m, 1 H), 6.64 (d, 1 H), 6.70-6.83 (m, 2H) , 7.15 (t, 1 H). MS (APCf): m / z [MH +] 334.4; C20H3? NO3 + H needs 334.2.

EXAMPLE 20 (±) -3-H - (5-Hydroxypentyl) -fra / 7s-3,4-dimethylpiperidininophenol To a solution of (±) -3- (ε-ans-3,4-dimethylpiperidinyl) phenol (60 mg, 0.29 mmol) in N, N-dimethylformamide (2.5 ml) at room temperature was added sodium hydrogen carbonate (27 mg , 0.32 mmol), sodium iodide (48 mg, 0.32 mmol) and 5-chloro-1-pentanol (40 mg, 0.32 mmol) in? /,? / - dimethylformamide (2.0 ml). The mixture was heated at 120 ° C for 1.5 hours, cooled and then water (30 ml) and ethyl acetate (10 ml) were added. The two layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 10 ml) and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield a crude oil. This was purified by preparative HPLC on Dynamax ™ column, 42 x 250 mm; flow of 8.0 ml / min; using U.V. detection at 275 nm; Acetonitrile eluent gradient: 0.05M aqueous solution of ammonium acetate (90:10 to 10:90), to yield the title compound in the form of its acetate salt. 1 H-NMR (data selected for acetate salt) 0.78 (d, 3 H), 1.31 (s, 3 H), 1.38-1.70 (m, 7 H), 2.84 (m, 1 H), 3.65 (t, 2 H), 6.61 (d, 1 H), 6.75 (s, 1 H), 6.83 (d, 1 H), 7.15 (t, 1 H). MS (APCI +): m / z [MH +] 291.9; C? 8H29N02 + H needs 292.2.

EXAMPLE 21 (±) -3-f1- (3-tetrahydro-2H-pyrn-4-ylpropyl) -fra / 7S-3,4-dimethylpiperidinyl-1-phenol To a solution of (±) -1- [rans-3,4-dimethyl-4-3-hydroxyphenyl) -piperidinyl] -3- (tetrahydro-2H-pyran-4-yl) -1-propanone (Preparation 5, 500 mg, 1.45 mmol) in tetrahydrofuran (6 ml) at room temperature was added lithium aluminum hydride (1.0 M solution in diethyl ester, 2.72 mmol). After 1 hour, the reaction was quenched first with 2N aqueous sodium hydroxide (0.2 ml and then with water (0.3 ml) and diluted with diethyl ether 25 ml). The solid precipitate was then removed by filtration through a pad of Celite (R), washed with ethyl acetate (5 x 50 ml). The filtrate was dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (253 mg, 53%) as a white foam. 1 H-NMR (CD3OD, data selected for the acetate salt). 0.82 (d, 3H), 1.45 (s, 3H), 3.90-3.99 (m, 2H), 6.65 (d, 1 H), 6.72 (s, 1 H), 6.73 (d, 1 H), 7.18 (t , 1 HOUR). MS (TSI ++): m / z [MH +] 331.9; C21H33N02 + H needs 332.3.

EXAMPLE 22 (±) -3-. { 1-r2-f2-naphthyloxy) etin-frans-3,4-dimethylpiperidinyl > phenol To a solution of (±) -3- (rans-3,4-dimethylpiperidinyl) phenol (82 mg, 0.40 mmol) in N, N-dimethylformamide (2.0 ml) at room temperature was added sodium hydrogen carbonate (35 mg, 0.42 mmole) and 2- (2-iodoethoxy) naphthalene (Preparation 11, 120 mg, 0.40 mmole). The mixture was heated at 150 ° C for 2 hours, and then at room temperature for 16 hours. The solution was then partitioned between water (5 ml) and diethyl ether (10 ml). The two layers were separated and the aqueous layer was extracted with diethyl ether (1 x 10 ml) and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield a crude oil. This was purified using a Waters Sep-Pak ™ cartridge filled with silica gel eluting with a gradient of CH 2 Cl 2: EtOH: 0.88 ammonia (100: 0: 0 to 500: 20: 1), to yield the title compound (64 mg , 43%) in the form of a brown solid. 1 H-NMR: 0.82 (d, 3 H), 1.38 (s, 3 H), 1.62 (m, 1 H), 2.02 (m, 1 H), 2.37 (m, 1 H), 2.50-3.10 (m, 6 H) , 4.20-4.30 (m, 2H), 6.64 (d, 1 H), 6.78 (s, 1 H), 6.85 (d, 1 H), 7.10-7.22 (m, 3H), 7.36 (t, 1 H) , 7.45 (t, 1 H), 7.70-7.80 (m, 3H). MS (TSI +): m / z [MH +] 3763.7; C25H29N02 + H needs 376.2 EXAMPLE 23 (+) - 3-H - (2-isopropoxyethyl) - * - rans-3, 4-dimethylpiperrindinin phenol To a solution of (+ -3- (trans-3,4-dimethylpiperid) phenol (82 mg, 0.40 mmol) in? /,? / - dimethylformamide (2.0 ml) at room temperature was added sodium hydrogen carbonate (35 mg, 0.42 mmol) and 2- (2-iodoethoxy) propane (preparation 13, 86 mg, 0.40 mmol), the mixture was heated at 150 ° C for 2 hours, and then at room temperature for 16 hours, the reaction mixture was partitioned between water (20 ml) and diethyl ether (20 ml), the two layers were separated and the aqueous layer was extracted with diethyl ether (1 x 20 ml) and the combined organic layers were extracted over sodium sulfate, filtered and concentrated under vacuum to produce a crude oil, this was purified using a Waters Sep-Pak ™ cartridge filled with silica gel eluting with a gradient of CH02Cl2: EtOH: ammonia 0.88 (100: 0: 0 to 500: 20: 1), produce the title compound (59 mg, 51%) as a brown solid.1H-NMR: 0.80 (d, 3H), 1.18 (d, 6H), 1.35 (s, 3h), 1.60 (m, 1 H) ), 2. 02 (m, 1 H), 2.37 (m, 1 H), 2.40-2.90 (m, 6H), 3.55-3.65 (m, 3H), 6.64 (d, 1 H), 6.78 (s, 1 H) ), 6.85 (d, 1 H), 7.18 (t, 1 H). MS (TSI +): m / z [MH +] 292.3; C18H29N02 + H needs 292.2.

EXAMPLE 24 3-F1 - (2-Propoxyethyl) -frans-3,4-dimethylpylerid) phenol To a solution of (^ S-itrans-Z, 4-dimethylpiperid) phenol (82 mg, 0.40 mmole) in N,? / - dimethylformamide (2.0 ml) at room temperature was added sodium hydrogen carbonate (35 mg, 0.42 mmol) and 1- (2-iodoethoxy) propane (preparation 15.86 mg, 0.40 mmol), the mixture was heated at 150 ° C for 2 hours, and then at room temperature for 16 hours, the reaction mixture was partitioned between water (20 ml ) and diethyl ether (20 ml), the two layers were separated and the aqueous layer was extracted with diethyl ether (1 x 20 ml) and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to produce a crude oil, this was purified using a Waters Sep-Paktm cartridge filled with silica gel (10 g) eluting with dichloromethane: ethanol: 0.88 ammonia (500: 20: 1), to yield the title compound (43 mg, 37 mg). %) in the form of a brown solid. 1 H-NMR (data selected): 0.88-0.95 (m, 3H), 0.95 (t, 3H), 1.32 (s, 3H), 3.41 (t, 2H), 3.50-3.64 (m, 2H), 6.66 (d , 1 H), 6.78 (s, 1 H), 6.85 (d, 1 H), 7.18 (t, 1 H). MS (APCI +): m / z [MH +] 292.0; C18H29N02 + H needs 292.2 EXAMPLE 25 (^ -S-fl-r? -fc-cyclopentyloxetip-frans-S. 4-dimethylpiperid) phenol To a solution of ^^ - (trans-S ^ -dimethylpiperidini phenol (21 mg, 0.10 mmol) in? /,? / - dimethylformamide (2.0 ml) at room temperature was added sodium hydrogen carbonate (10 mg, 0.12 mmol) and 1- (2-iodoethoxy) cyclopentane (preparation 17.15 mg, 0.06 mmol), the mixture was heated at 150 ° C for 2 hours, and then at room temperature for 16 hours.The reaction mixture was partitioned between water (8 ml) diethyl ether (15 ml), the two layers were separated and the aqueous layer was extracted with diethyl ether (1 x 15 ml) and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield an oil crude, this was purified using a Waters Sep-Pak ™ cartridge filled with silica oil (5 g) eluting with a gradient of CH 2 Cl 2: EtOH: 0.88 ammonia (100: 0: 0 to 500: 20: 1), to produce the compound of the title (15 mg, 47%) as a brown solid.1H-NMR: 0.78 (d, 3H), 1.30 (s, 3H), 1.40-1.80 (m, 9H) 1.98 (m, 1 H), 2.35 (m, 1 H), 2.42-2.50 (m, 5H), 2.86 (m, 1 H), 3.56 (t, 2H), 3.90 (m, 1 H), 6.64 (d, 1 H) , 6.78 (s, 1 H), 6.83 (d, 1 H), 7.18 (t, 1 H). MS (TSI +): m / z [MH +] 3.18.1; C20 H31NO2 + H needs 318.2 EXAMPLE 26 ñ-S-FI-ÍS-tetrahydro ^ -furanylpropiD-fra / is-S ^ dimethylpiperidphenol To a stirred solution of (±) - '\ - [trans-3,4-d-rret \\ - 4- (3-hydroxyphenyl) -piperind] -3- (tetrahydro-2-furanyl) -1-proponone (preparation 6.270 mg, 0.82 mmol) in tetrahydrofuran (25 ml) at room temperature was added lithium aluminum hydride (1.0 M solution in diethyl ether, 4.0 ml, 4.0 mmol). After 10 minutes at room temperature, the reaction was quenched with water, the aqueous layer was extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated in vacuo to yield the title compound (170 mg, 67% ) in the form of a brown oil. 1 H-NMR: 0.80 (d, 3H), 1.30 (s, 3H), 1.40-2.05 (m, 10H), 2.25-2.70 (m, 6H), 2.85 (m, 1 H), 3.65-3.90 (m, 3H), 6.64 (d, 1 H), 6.78 (s, 1 H), 6.83 (d, 1 H), 7.18 (t, 1 H). MS (TSI +): 77 / z [MH +] 318.3; C20H31NO2 + H needs 318.2 EXAMPLE 27 rVS-fl ^ -cyclohexyl-sulfonyl-Quethill-frans-S, 4-dimethylpiperidinyl) phenol To a solution of (±) -3- (trans-3,4-dylmethylpiperidinyl) phenol (150 mg, 0.29 mmol) in? /,? / -dimetelformamide (10 ml) at room temperature was added sodium hydrogen carbonate ( 70 mg, 0.80 mmol), sodium iodide (120 mg, 0.80 mmol) and 1 - [(2-chloroethyl) sulfanyl] cyclohexane (140 mg, 0.80 mmol), the mixture was heated to reflux for 1 hour, cooled and then water and ethyl acetate were added, the two layers were separated and the aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to yield a crude oil, it was purified by preparative HPLC on Dynamax ™ column, 42 x 250 mm; flow of 8.0 ml / min; using U.V detection at 275 nm, eluent gradient of acetonitrile: aqueous solution 0.05 M ammonium acetate (90:10 to 10:90), to produce the title compound in the form of its acetate salt. 1 H-NMR (data for the free base): 0.79 (d, 3H), 1.20-1.40 (m, 9H), 1.60-2.00 (m, 6H), 2.24-2.95 (m, 10H), 6.60 (d, 1 H), 6.70 (s, 1 H), 6.80 (d, 1 H), 7.12 (t, 1 H). MS (TSI +): m / z [MH +] 348.2; C21H33NOS + H needs 348.2.

EXAMPLE 28 ñ-S-l ^ -fetylsulfaniDetin-fra / is-S ^ -dimethylpiperidinylIphenol To a solution of (^ -S- ^ rans-S ^ -dimethylpiperidinylJphenol (100 mg, 0.49 mmol) in? /,? / - dimethylformamide (2 ml) at room temperature was added sodium hydrogen carbonate (47 mg, 0.56 mmole) , sodium iodide (7 mg, 0.05 mmol) and 2-chloroethylethyl sulfide (70 microliters, 0.56 mmol), the mixture was heated at 140 ° C for 1 hour, cooled, and then concentrated in vacuo to yield an oil crude, this was purified by silica gel column chromatography (10 g), eluting with dichloromethane: ethanol: 0.86 ammonia (500: 8: 1 to 300: 8.1), to yield the title compound (120 mg, 33% ) in the form of orange oil, 1 H-NMR: 0.77 (d, 3 H), 1.20 (t, 3 H), 1.26 (s, 3 H), 1.57 (m, 1 H), 1.95 (m, 1 H), 2.26 ( m, 1 H), 2.38 (m, 1H), 2.50-2.68 (m, 8H), 2.81 (m, 1 H), 6.59 (d, 1 H), 6.71 (s, 1 H), 6.81 (d, 1 H), 7.12 (t, 1 H), MS (APCI +): m / z [MH +] 294.4, C17H27NOS + H needs 294.2.

EXAMPLE 29 (±) -3-ri- (2- (ethylsulfinyl) etiH-frans-3,4-dimethylpiperidinyl) phenol To a solution of (^^ - (trans, 4-dimethylpiperidinyl) phenol (100 mg, 0.49 mmol) in N, N-dimethylformamide (2 ml) at room temperature was added sodium hydrogen carbonate (7 mg, 0.05 mmol) and sulfoxide. of 2-chloroethylethyl (preparation 7.76 mg, 0.54 mmol), the mixture was heated to reflux for 1.5 hours, cooled, and then concentrated in vacuo to yield a crude oil, this was purified by silica gel column chromatography ( 10 g), eluting with dichloromethane: ethanol: 0.88 ammonia (200: 8: 1), to yield the title compound (43 mg, 28%) as a brown solid.1H-NMR: 0.70-0.80 (m, 3H), 1.26 (s, 3H), 1.28-1.38 (m, 3H), 1.58 (m, 1 H), 1.95 (m, 1 H), 2.18-2.90 (m, 11 H), 6.61 (d, 1 H), 6.71-6.80 (m, 2H), 7.12 (t, 1 H), MS (APCI +) m / z [MH +] 310.5, C17H27N02S + H needs 310.2.

EXAMPLE 30 (±) -3- (1- (ethylsulphonyl) ethyl-frans-3,4-dimethylpiperidinyl} phenol To a solution of (4 -S-iorap-S ^ -dimethylpiperidinylJphenol (100 mg, 0.49 mmole) in? /,? / - dimethylformamide (2 ml) at room temperature was added sodium hydrogen carbonate (47 mg, 0.56 mmole), sodium iodide (7 mg, 0.05 mmol) and 2-chloroethylethylsulfone (preparation 8.88 mg, 0.56 mmol), the mixture was heated at 140 ° C for 1 hour, cooled and then concentrated in vacuo to produce a crude oil, this it was purified with a silica gel chromatography column (10 g) eluting with CH 2 Cl 2: EtOH: 0.88 ammonia (500: 8: 1), to yield the title compound (155 mg, 97%) as an orange oil . 1 H-NMR: 0.70 (m, 3 H), 1.27 (s, 3 H), 1.35 (t, 3 H), 1.35 (t, 3 H), 1.59 (m, 1 H), 1.96 (m, 1 H), 2.22 ( m, 1 H), 2.38 (m, 1 H), 2.47-2.63 (m, 2H), 2.79-2.85 (m, 3H), 2.99-3.18 (m, 4H), 6.61 (d, 1 H), 6.72 (s, 1 H), 6.80 (d, 1 H), 7.15 (t, 1 H). MS (APCI +): m / z [MH +] 326.4; C17H270NO3S + H needs 326.2.

EXAMPLE 31 (±) -3- (1-3r3- (1H-1,2,3,4-tetrazol-1-yl) propin-frans-3,4-dimethylpiperidinyl > phenol To a solution of (^ Sp-hydroxypropylJfrans-S, 4-dimethyl-piperidinyl] phenol (example 3, 155 mg, 0.59 mmole), 1 H-tetrazole (42 mg, 0.60 mmole) and triphenylphofin (155 mg, 0.59 mmole) in dichloromethane (2 ml) at 0 ° C diethyl azodicarboxylate (103 mg, 0.59 mmol) was added dropwise by syringe, the reaction was stirred at room temperature for 16 hours, and then treated with more triphenylphosphine (75 mg, 0.29 mmol) and diethyl azodicarboxylate (51 mg, 0.29 mmol) After stirring at room temperature for more than 16 hours, the reaction was concentrated in vacuo to give a crude residue, this was purified on silica gel column chromatography ( 20 g) eluting with a gradient of dichloromethane: ethanol: 0.88 ammonia (300: 8: 1 to 200: 8: 1), to yield the title compound (53 mg, 29%) as an oil. 1 H-NMR: 0.80 (m, 3 H), 1.32 (s, 3 H), 1.59 (m, 1 H), 2.00 (m, 1 H), 2.15-2.60 (m, 8 H), 2.81 (m, 1 H) , 4.75 (T, 2H), 6.65 (dd, 1 H), 6.76 (s, 1 H), 6.85 (d, 1 H), 7.18 (t, 1 H), 8.50 (s, 1 H) EM (APCI + ): m / z [MH +] 316.5; C? 7H25N50 + H needs 316.2 EXAMPLE 32 (+) - 3- (1-F3- (1 H -pyrazol-1-yl) propyl-frans-3,4-dimethylpiperidinyl > phenol To a stirred solution of (±) -1- [Irans-3,4-dimethyl-4- (3-hydroxyphenyl) -piperidinyl] -3- (1 H -pyrazol-1-yl) -1-propanone (preparation 9.71) mg, 0.22 mmole) in tetrahydrofuran (3 ml) at room temperature was added lithium aluminum hydride (1.0 M solution in diethyl ether, 0.4 ml, 0.4 mmol). After 10 minutes at room temperature, the reaction was quenched and diluted with ethyl acetate. The solid precipitate was removed by filtration and through a Cellite® layer, and brine was added to the filtrate. The two layers were separated and the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to yield the title compound (49 mg, 71%) as an oil. 1 H-NMR (CD 3 OD, data selected): 0.80 (d, 3 H), 1.38 (s, 3 H), 6.32 (s, 1 H), 6.61 (d, 1 H), 6.68 (s, 1 H), 6.72 ( d, 1 H), 7.15 (t, 1 H), 7.58 (s, 1 H), 7.70 (s, 1 H). MS (TSI +): m / z [MH +] 314.3; C? 9H27N30 + H needs 314.2.

EXAMPLE 33 (±) -3-. { 1-r3- (4-Pyridinyl) propyl-fra / 7s-3,4-dimethylpiperidinyl) phenol To a solution of 4-pyridinepropanol (1.0 g, 7.29 mmol) in dichloromethane (25 ml) at 0 ° C was added methanesulfonyl chloride (0.90 mg, 7.90 mmol). The mixture was stirred at room temperature for 1 hour, and then concentrated in vacuo. This crude oil was dissolved in 1,2-dimethoxyethane (10 ml), and then added to a solution of (±) -3-. { trans-3,4-dimethylpiper? dyl) phenol (300 mg, 1.46 mmol) and sodium hydrogen carbonate (1.0 g, 11.9 mmol). The mixture was refluxed for 16 hours, cooled and then filtered. The filtrate was concentrated in vacuo to yield a crude residue which was purified on silica gel column chromatography eluting with a gradient of dichloromethane: methanol (98: 2 to 0: 100). This produced the title compound as a brown solid. 1 H-NMR (D 20, data selected for the HCl salt): 0.70 (d, 3H), 1.30 (s, 3H), 6.70 (d, 1 H), 6.78 (s, 1 H), 6.88 (d, 1 H), 7.20 (t, 1 H), 7.22-7.25 (m, 2H) , 8.29-8.35 (m, 2H). MS (TSI +): m / z [MH +] 325.5; C21H28N20 + H needs 325.2.

EXAMPLE 34 (±) -3-f 1 -l "3- (1 H-1,2,4-triazol-1-yl) propin-frans-3,4-dimethylpiperidinyl) phenol To a solution of (±) -3- (íraps-3,4-dimethylpiperidinyl) phenol (150 mg, 0.73 mmol) in? /,? / - dimethylformamide (6 ml) at room temperature was added sodium hydrogen carbonate (62 mg. , 0.80 mmoles) and 1- (3-bromopropyl) -1 H-1, 2,4-triazole (prepared as described in the document DE 4115433 A1: 152 mg, 0.80 mmol). The mixture was refluxed for 1.5 hours, and then at room temperature for 16 hours. The solution was then poured into water (100 ml) and alkalized (pH 9) with aqueous 2N sodium hydroxide solution. The aqueous layer was extracted with diethyl ether (2 x 100 ml) and the combined organic layers were dried over magnesium sulfate., they were filtered and concentrated in vacuo to produce a crude oil. This was purified using a Waters Sep-Pak ™ cartridge filled with silica gel (10 g) eluting with dichloromethane: ethanol: 0.88 ammonia (200: 8: 1), to yield the title compound (130 mg, 57%) in shape of a yellow oil. 1 H-NMR: 0.80 (m, 3 H), 1.30 (s, 3 H), 1.59 (m, 1 H), 1.95-2.38 (m, 7 H), 2.48-2.58 (m, 2 H), 2.78 (m, 1 H ), 4.26 (t, 2H), 6.62 (m, 1 H), 6.78 (m, 1 H), 6.84 (d, 1 H), 7.15 (t, 1 H), 7.95 (s, 1 H), 8.05 (s, 1 H). MS (TSI +): m / z [MH +] 315.6; C18H26N40 + H needs 315.2.

EXAMPLE 35 (±) -3-f 1 -F3- (1 H -pyrrol-1 -yl) propylHrans-3,4-d-methyl-piperidinyl) phenol To a solution of (±) -3- (frans-3,4-dimethylpiperidinyl) phenol (60 mg, 0.29 mmol) in acetonitrile (2.5 ml) at room temperature was added sodium hydrogen carbonate (27 mg, 0.32 mmol) and 1 g. - (3-bromopropyl) -1 H -pyrrole (43 mg, 0.32 mmol) in acetonitrile (2.5 ml). The solution was heated to reflux for 3 hours, cooled, and then water was added. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over magnesium sulfate, ered, and concentrated in vacuo to yield the title compound as an oil. 1 H-NMR (data selected): 0.81 (d, 3H), 1.28 (s, 3H), 3.98 (t, 3H), 6.05-6.15 (m, 2H), 6.60-6.69 (m, 3H), 6.78 (s) , 1 H), 6.85 (d, 1 H), 7.18 (t, 1 H). MS (APCI +): m / z [H +] 313.1; C20H28N2O + H needs 313.2.

EXAMPLE 36 (±) -3-Ffra /? S-3,4-dimethyl-4- (3-hydroxyphenyl) -piperidinin-1- (4-morpholinyl) -1-propanone To a solution of 4-acryloylmorpholine (152 mg, 1.08 mmol) in tetrahydrofuran (4 ml) at room temperature was added (±) -3- (trans-3,4-dimethylpiperidinyl) phenol (200 mg, 0.97 mmol). The mixture was refluxed for 16 hours and then cooled. The solvent was removed in vacuo to yield a pale yellow oil. This was purified with a chromatographic column eluting with a gradient of CH 2 Cl 2: EtOH: 0.88 ammonia (300: 8: 1 to 100: 8: 1), to afford the title compound (327 mg, 97%) as a solid White. 1 H-NMR: 0.72 (d, 3 H), 1.27 (s, 3 H), 1.58 (m, 1 H), 1.95 (m, 1 H), 2.20-2.85 (m, 9 H), 3.42-3.48 (m, 2 H) ), 3.52-3.62 (m, 6H), 6.60 (m, 1 H), 6.73 (s, 1 H), 6.79 (d, 1 H), 7.12 (t, 1 H). MS (TSI +): m / z [MH +] 347.4; C20H30N2O3 + H needs 347.2.

EXAMPLE 37 3- (1-f3- (4-morpholinyl) propin-*? Trans-3,4-dimethylpiperidinyl) phenol To a stirred solution of (±) -3- [rans-3,4-dimethyl-4- (3-hydroxyphenyl) -piperidinyl] -1- (4-morpholinyl) -1-propanone (example 36, 150 mg, 0.43 mmoles) in tetrahydrofuran (3 ml) at 0 ° C was added lithium aluminum hydride (1.0 M solution in diethyl ether, 0.47 ml, 0.47 mmole). After 15 minutes at 0 ° C the mixture was warmed to room temperature and stirred at room temperature for 16 hours. The reaction was quenched with a saturated solution of ammonium chloride (5 ml) and water (5 ml). The aqueous layer was extracted with ethyl acetate (4 x 10 ml) and the combined organic layers were dried over sodium sulfate, ered and concentrated in vacuo to yield a yellow oil. This was purified by column chromatography on silica gel (7.5 g) eluting with dichloromethane: ethanol: 0.88 ammonia (100: 8: 1), to yield the title compound (124 mg, 87%) as a yellow oil pale. 1 H-NMR: 0.75 (d, 3 H), 1.26 (s, 3 H), 1.57 (m, 1 H), 1.62-1.70 (m, 2 H), 1.98 (m, 1 H), 2.25-2.59 (m, 12 H) ), 2.80 (m, 1 H), 3.67-3.71 (m, 4H), 6.59 (m, 1 H), 6.72 (s, 1 H), 6.78 (d, 1 H), 7.12 (t, 1 H) . MS (APCI +): m / z [MH +] 333.1; C20H32N2O2 + H needs 333.3.

EXAMPLE 38 3-f 1 -f 2 - (1-azepanyl) etn-frans-3,4-dimethylpiperidinyl} phenol To a solution of (±) -3- (frans-3,4-dimethylpiperidinyl) phenol (60 mg, 0.29 mmol) in acetonitrile (2.5 ml) at room temperature was added sodium hydrogen carbonate (27 mg, 0.32 mmol), iodide sodium (48 mg, 0.32 mmol) and a mixture of 1- (2-chloroethyl) azepane hydrochloride (64 mg, 0.32 mmol) and triethylamine (32 mg, 0.32 mmol) in acetonitrile (2.5 ml). The solution was heated to reflux for 3 hours, cooled and then water was added. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over magnesium sulfate, ered and concentrated in vacuo to yield the title compound as an oil. 1 H-NMR: 0.78 (d, 3H), 1.28 (s, 3H), 1.56-1.78 (m, 9H), 1.97 (m, 1 H), 2.20-2.43 (m, 2H), 2.56-2.98 (m, 11 H), 6.67 (m, 1 H), 6.72-6.81 (m, 2H), 7.15 (t, 1 H). MS (APCI +): m / z [MH +] 331.1; C21H34N20 + H needs 331.3.

EXAMPLE 39 3-. { 1-F2- (4-morpholinyl) etin-frans-3,4-dimethylpiperidinyl} phenol To a solution of (±) -3- (r? Aps-3,4-dimethylpiperidinyl) phenol (60 mg, 0.29 mmol) in acetonitrile (2.5 ml) at room temperature was added sodium hydrogen carbonate (27 mg, 0.32 g). mmoles), sodium iodide (48 mg, 0.32 mmol) and a mixture of 4- (2-chloroethyl) morpholine hydrochloride (60 mg, 0.32 mmol) and triethylamine (32 mg, 0.32 mmol) in acetonitrile (2.5 ml). The solution was heated to reflux for 3 hours, cooled and then water was added. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to yield the title compound as an oil. 1 H-NMR: 0.82 (d, 3 H), 1.35 (s, 3 H), 1.72 (m, 1 H), 2.10 (m, 1 H), 2.33-2.86 (m, 12 H), 2.98 (m, 1 H) , 3.68-3.77 (m, 4H), 6.67 (m, 1 H), 6.78 (s, 1 H), 6.84 (d, 1 H), 7.15 (t, 1 H). MS (APCI +): m / z [MH +] 319.2; C19H30N2O2 + H needs 319.2.

EXAMPLE 40 3-f1-F2- (1-piperidinyl) -etip-frans-3,4-dimethylpiperidine-phenol To a solution of (±) -3- (fra 7S-3,4-dimethylpiperidinyl) phenol (60 mg, 0.29 mmol) in acetonitrile (2.5 ml) at room temperature was added sodium hydrogen carbonate (27 mg, 0.32 mmol), sodium iodide (48 mg, 0.32 mmol) and a mixture of 1- (2-chloroethyl) piperidine hydrochloride (59 mg, 0.32 mmol) and triethylamine (32 mg, 0.32 mmol) in acetonitrile (2.5 ml). The solution was heated to reflux for 3 hours, cooled and then water was added. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to yield the title compound as an oil. 1 H-NMR: 0.79 (d, 3 H), 1.29 (s, 3 H), 1.40-1.80 (m, 7 H), 2.01 (m, 1 H), 2.20-2.90 (m, 13 H), 6.65 (m, 1 H ), 6.75 (s, 1H), 6.80 (d, 1 H), 7.15 (t, 1H). MS (APCI +): m / z [MH +] 317.1; C20H32N2O + H needs 317.3.

EXAMPLE 41 3-f1-f2- (1-pyrrolidinyl) ethyl-1-frans-3,4-dimethylpiperidinyl) phenol To a solution of (±) -3- (íraps-3,4-dimethylpiperidinyl) phenol (60 mg, 0.29 mmol) in acetonitrile (2.5 ml) at room temperature was added sodium hydrogen carbonate (27 mg, 0.32 mmol), iodide sodium (48 mg, 0.32 mmol) and a mixture of 1- (2-chloroethyl) pyrrolidine hydrochloride (54 mg, 0.32 mmol) and triethylamine (32 mg, 0.32 mmol) in acetonitrile (2.5 ml). The solution was heated to reflux for 3 hours, cooled and then water was added. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to yield the title compound as an oil. 1 H-NMR: 0.79 (d, 3 H), 1.29 (s, 3 H), 1.58 (m, 1 H), 1.67-1.90 (m, 4 H), 2.01 (m, 1 H), 2.20-2.90 (m, 13 H) ), 6.65 (m, 1 H), 6.70 (s, 1 H), 6.81 (d, 1 H), 7.15 (t, 1 H). MS (APCI +): m / z [MH +] 303.1; C19H30N2O + H needs 303.2.

EXAMPLE 42 3-. { 1-f3- (1-piperidinyl) propin-frans-3,4-dimethylpiperidinyl > phenol To a solution of (±) -3- (f? Ans-3,4-dimethyl piperidin) phenol (60 mg, 0.29 mmol) in acetonitrile (2.5 ml) at room temperature was added sodium hydrogen carbonate ( 27 mg, 0.32 mmol) sodium iodide (48 mg, 0.32 mmol) and a mixture of 1- (3-chloropropyl) piperidine hydrochloride (63 mg, 0.32 mmol) and triethylamine (32 mg, 0.32 mmol) in acetonitrile (2.5 ml). The solution was heated to reflux for 3 hours, cooled and then water was added. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to yield the title compound as an oil. 1 H-NMR: 0.80 (d, 3H), 1.25-2.01 (m, 13H), 2.20-2.95 (m, 13H), 6.65 (m, 1 H), 6.72-6.81 (m, 2H), 7.15 (t, 1 HOUR). MS (APCI +): m / z [MH +] 331.2; C21H34N20 + H needs 331.3.

EXAMPLE 43 (+) - 3-F1 (3-methoxyphenyl) -fra /? S-314-dimethylpiperidinyl > phenol To a solution of (±) -3- (íraps-3,4-dimethylpiperidinyl) phenol (82 mg, 0.40 mmol), 3-bromoanisole (56 microliters, 0.44 mmol) and tri-o-tolylphosphine (5 mg, 0.04 mmol) in toluene (2 ml) was added sodium tert-butoxide (54 mg, 0.56 mmol) and tris. (dibenzyl dacetone) -palladium (0) (8 mg, 0.02 mmol) and the reaction mixture was heated to reflux for 6 hours. After cooling, the reaction mixture was concentrated in vacuo to yield the crude product, which was purified on silica gel column chromatography, eluting with gradient methanol: dichloromethane: 0.880 ammonia (10: 990: 1 to 30: 970 : 3), to produce the title compound (36 mg), 29%) as a yellow oil. 1 H-NMR (C 6 D 6): 0.78 (d, 3 H), 1.08 (s, 3 H), 1.25 (m, 1 H), 1.72 (m, 1 H), 2.10 (m, 1 H), 2.70 (m, 1 H), 2.95 (m, 1 H), 3.15 (m, 1 H), 3.32 (m, 1 H), 3.39 (s, 3H) , 4.01 (s br, 1 H), 6.34-6.40 (m, 2H), 6.52-6.55 (m, 2H), 6.64 -6.40 (m, 2H), 6.52-6.55 (m, 2H), 6.64 (m, 1 H), 6.67 (m, 1 H), 7.01 (t, 1 H), 7.15 (t, 1 H).

MS (APCI): m / z [MH "] 312.1; C20H25NO2 + H needs 312.2.

EXAMPLE 44 (±) -3-. { 1-F4- (dimethylamino) phenan-fraps-3,4-dimethylpiperidinyl > phenol To a stirred solution of (±) -4- (3-hydroxyphenyl) -trans-3,4-dimethylpiperidine (82 mg, 0.40 mmol),? /,? / - dimethyl-4-bromoaniline (112 mg, 0.56 mmol) and tri-o-tolylphosphine (5 mg, 2.04 mmol) in toluene (2 ml) was added sodium tert-butoxide 54 mg, 0.56 mmol) and tris (dibenzylideneacetone) -palladium (0) (8 mg, 0.02 mmol) and the reaction mixture was heated to reflux for 48 hours. After cooling, the reaction mixture was diluted with water (20 ml) and extracted with dichloromethane (3 x 20 ml). The combined extracts were washed with brine (20 ml), dried over sodium sulfate, filtered and concentrated in vacuo to yield the crude product. This was purified on silica gel column chromatography, eluting with methanol: dichloromethane: ammonia gradient 0.88 (10: 990: 1 to 20: 980: 1), to yield the title compound (23 mg, 18%) in shape of a yellow oil. 1 H-NMR (C 6 D 6): 091 (d, 3 H), 1.16 (s, 3 H), (m, 1 H), 1.74 (m, 1 H), 2.12 (m, 1 H), 2.44-2.58 (m, 6H), 2.75 (m, 1 H), 3.03 (m, 2H), 3.21 (m, 1 H), 6.57 (m, 1 H), 6.69 (m, 1 H), 6.71-6.76 (m, 3H) , 6.83-6.92 (m, 2H), 7.07 (t, 1 H). EM APCI +): m / z [MH +] 325.2; C21H28N20 + H needs 325.2.

EXAMPLE 45 (±) -3-ffrans-3,4-dmethyl-4- (3-hydroxyphenyl) piperidine-methylpropionate r To a stirred solution of (±) -3- (rans-3,4-dimethylpiperidinyl) phenol (82 mg, 0.40 mmol) in methanol (3 ml) at room temperature was added methyl acrylate (54 microliters, 0.6 mmol) . After 2 hours at room temperature the reaction mixture was concentrated in vacuo to yield the crude product. This was purified by column chromatography on silica gel, eluting with a gradient of methanol: dichloromethane: 0.880 ammonia (10: 990: 1 to 30: 970), to afford the title compound (60 mg, 51%) as a pale yellow oil.1H-NMR (C6D6, data for free base): 0.82 (d, 3H), 1.13 (s, 3H), 1.32 (m, 1 H), 1.73 (m, 1 H), 2.09 (m, 1 H), 2.17-2.35 (m, 5H), 2.46-2.59 (m, 3H), 3.29 (s, 3H), 5.90 (s br, 1 H), 6.63 (dd, 1 H), 6.69 (d, 1 H), 6.76 (m, 1 H), 7.06 (m, 1 H) . EM APCI +): m / z [MH +] 292.3; C17H25N03 + H needs 292.2.

EXAMPLE 46 The compounds according to the present invention, for example, the compound of Example 5, were found to exhibit anti-pruritic activity when tested according to the above procedure.

Preparation of starting materials Preparation 1: 3- (Tetrahydro-3-furanyl) propionic acid To a solution of trans-3-furanacrylic acid (10 g, 72.4 mmol) in industrial methylated spirits (50 ml) was added 10% palladium on carbon ( 1.0 g) at room temperature. The reaction vessel was charged with hydrogen gas under pressure of 345 KPa and stirred at room temperature for 16 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give the title compound as a colorless oil. 1 H-NMR: 1.44-1.58 (m, 1 H), 1.61-1.82 (m, 2H), 1.99-2.12 (m, 2H), 2.15-2.48 (m, 3H), 3.38 (t, 1 H), 3.62 -3.98 (m, 3H).

Preparation 2j (±) -1 - | Yrans-3,4-dimethyl-4- (3-hydroxy-phenyl) pperidin-3- (tetrahydro-3-furan-1) -propanone A a solution of 3- (tetrahydro-3-furanyl) propionic acid (preparation 1, 202 mg 1.40 mmol) in? /,? / - dimethylformamide (40 ml) at room temperature was added 1- (3-dimethylaminopropyl) hydrochloride 3-ethylcarbodiimide (320 mg, 1.70 mmol) and 1-hydroxybenzotriazole (204 mg, 1.51 mmol). After the mixture had become homogeneous, (±) -3- (rraps-3,4-dimethylpiperidinyl) phenol (300 mg, 1.46 mmol) was added in one portion. The mixture was stirred at room temperature for 16 hours and then water was added. The organic layer was extracted with diethyl ether and the combined organic layers were dried over sodium sulfate., filtered and concentrated in vacuo to yield a clear crude residue. This was purified on silica gel column chromatography, eluting with ethyl acetate to yield the title compound (150 mg, 30%) as a colorless oil. 1 H-NMR: (5: 4 rotamers mixture): 0.56-0.61 (m, 3H), 1.28- 1.35 (m, 3H), 1.40-1.76 (m, 4H), 1.95-2.45 (m, 6H), 2.85 (m, 0.56H), 3.10 (m, 44H), 3.28-3.90 (m, 6H), 4.30 (m, 0.44H), 4.61 (m, 0.56H), 6.60-6.77 (m, 3H), 7.10 ( m, 1 H).

Preparation 3 (±) -1- [fraA7s-3,4-dimethyl-4- (3-hydroxyphenylpiperidinyl-3- (tetrahydro-2H-pyran-2-yl) -1-propanone A a solution of 3- (tetrahydropyran-2-yl) propionic acid (prepared as described in Chem. Ber, 1990, 123, 153: 243 mg, 1.54 mmole) in? /,? / - dimethylformamide (55 ml) at room temperature At room temperature, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (420 mg, 2.19 mmol) and 1-hydroxybenzotriazole (223 mg, 1.65 mmol) were added.After the mixture had become homogeneous, it was added ( ±) -3-trans-3,4-dimethylpiperidinyl) phenol (338 mg, 1.65 mmol) in one portion. The mixture was stirred at room temperature for 48 hours and then water (50 ml) was added. The aqueous layer was extracted with diethyl ether (2x150 ml) and the combined organic layers were washed with brine (50 ml), dried over sodium sulfate, filtered, and concentrated in vacuo to yield a clear residue. This was purified by column chromatography on silica gel, eluting with a gradient of ethyl acetate: hexane (66:44 to 75:25), to yield the title compound (473 mg, 90%) as a colorless oil. . 1 H-NMR (data selected from the rotamer mixture (approximately 1: 1)): 0.59-0.68 (m, 3H), 1.38-1.41 (m, 3H), 2.87 (m, 0.5H), 3.15 (m, 0.5 H), 3.50-3.70 (m, 1 H), 4.35 (m, 0.5H), 4.70 (m, 0.5H), 6.68 (d, 1 H), 6.72-6.80 (m, 2H), 7.18 (t, 1 HOUR). MS (TSI +): m / z [MH +] 346.3; C21H31N03 + H needs 346.2.

Preparation 4: 2- (3-bromopropyl) -1,3-dioxane To a solution of 4-bromobutanal (prepared as described in J. Org Chem., 1979, 44, 3230-3238: 450 mg, 2.98 mmol) in tetrahydrofuran (10 ml) at room temperature, 1,3-propanediol (1.0 ml, 13.7 mmol) and p-toluenesulfonic acid monohydrate (50 mg, 0.26 mmol) were added. The mixture was refluxed for 2 hours, cooled and suspended in a mixture of water and diethyl ether (200 ml of 1: 1). The two layers were separated and the organic layer was dried over magnesium sulfate, cooled and then concentrated in vacuo to yield the title compound as a clear oil. 1 H-NMR: 1.25-2.20 (m, 6H), 3.43 (t, 2H), 3.75 (m, 2H), 4.10 (dd, 2H), 4.58 (t, 1 H).

Preparation 5 (±) -1-rfraA7s-3,4-di? ~ Netyl-4- (3-hydroxyphenyl) p.peridinyl-3- (tetrahydro-2H-pyran-4-yl) -1- propanone To a solution of 3- (tetrahydropyran-4-yl) propionic acid (prepared as described in Justus Leibigs Ann. Chem., 1937, 532, 83: 320 mg, 2.02 mmol) in? /,? / - dimethylformamide ( 70 ml) at room temperature was added dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (552 mg, 2.88 mmol) and 1-hydroxybenzotriazole (293 mg, 2.17 mmol). After the mixture had become homogeneous, (±) -3-trans-3,4-dimethylpiperidinyl) phenol (338 mg, 1.65 mmol) was added in one portion. The mixture was stirred at room temperature for 16 hours and then water (50 ml) was added. The aqueous layer was extracted with diethyl ether 12 x 150 ml) and the combined organic layers were washed with brine (50 ml), dried over sodium sulfate, filtered, and concentrated in vacuo to yield a clear residue. This was purified by column chromatography on silica gel, eluting with a gradient of ethyl acetate: hexane (66:44 to 75:25), to yield the title compound (500 mg, 72%) as a colorless oil. . 1 H-NMR (data selected from a 4: 3 rotamer mixture): 0. 60-0.68 (m, 3H), 1.38-1.40 (m, 3H), 4.38 (m, 0.43H), 4.70 (m, 2.57H), 6.68 (d, 1 H), 6.72-6.80 (m, 2H), 7.18 (t, 1 H). MS (TSI +): m / z [MH +] 346.1; C21 H31 N03 + H needs 346.2.

Preparation 6 (±) -1-frrans-3,4-dimethyl-4- (3-hydroxypheniOpiperdinedin1-3- (tetrahydro-2-furanyl) -1-propanone To a solution of 3- ( tetrahydro-2-furanyl) propionic prepared as described in J. Amer. Chem. Soc, 1923, 45, 3042: 202 mg, 1.40 mmol) in? /,? / - dimethylformamide (50 ml) at room temperature was added hydrochloride of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (320 mg, 2. 00 mmoles) and 1-hydroxybenzotriazole (204mg, 1.50 mmoles). After the mixture had become homogeneous, (±) -1-frans-3,4-dimethylpiperidinyl) phenol (300 mmoles) was added in one portion. The mixture was stirred at room temperature for 16 hours and then water was added. The aqueous layer was extracted with diethyl ether and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to yield a clear residue. This was purified by column chromatography on silica gel, eluting with a gradient of ethyl acetate: dichloromethane (0: 100 to 100: 0) to yield the title compound (270 mg, 58%) as a colorless gum. 1 H-NMR (4: 3 rotamers mixture): 0.58-0.63 (m, 3H), 1.35-1.38 (m, 3H), 1.40-2.60 (m, 11 H), 2.82-3.90 (m, 6H), 4.35 (m, 0.43H), 4.68 (m, 0.57H), 6.64 (d, 1 H), 6.72-6.78 (m, 2H), 7.15 (t, 1 H).

Preparation 7: 2-C Oroethy Ethyl Sulfoxide To a solution of 3-chloroperoxybenzoic acid (2.95 mg, 8.55 mmol) in dichloromethane (25 mL) at 0 ° C was added 2-chloroethyl ethyl sulfide (1.0 mL, 8.58 mmol). After 10 minutes at 0 ° C the cooling bath was removed and the mixture was stirred at room temperature for 48 hours. The reaction mixture was diluted with dichloromethane (75 ml) and then poured into a saturated aqueous solution of sodium hydrogencarbonate (100 ml). The two layers were separated and the aqueous layer was extracted with dichloromethane (2 x 50 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to yield an oil. This was purified by column chromatography on silica gel (50 g), eluting with ethyl acetate to yield the title compound (740 mg, 61%) as a yellow oil. 1 H-NMR: 1.33 (t, 3H), 2.70-2.81 (m, 2H), 2.92-3.05 (m, 2H), 3.85-3.96 (m, 2H). MS (TSI +): m / z [MNH4 +] 157.9; C4H9C10S + NH1 needs 158.0.

Preparation 8: 2-C-Oroethyldyl sulfone To a solution of 2-chloroethyl ethyl sulfide (1.1 mg, 8.58 mmol) in dichloromethane (25 ml) at room temperature was added 3-chloroperoxybenzoic acid (5.9 ml, 17.0 mmol) in portions . The reaction was exothermic and needed to be cooled in an ice bath to complete the addition. A thick white suspension formed and more dichloromethane (25 ml) was added. The mixture was stirred at room temperature for 16 hours and then filtered by washing with dichloromethane. The filtrate was washed with a saturated aqueous solution of sodium hydrogencarbonate (200 ml). The two layers were separated and the aqueous layer was extracted with dichloromethane (2 x 100 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to yield a colorless oil. This was purified by column chromatography on silica gel (50 g), eluting with ethyl acetate: hexane (1: 3) to give the title compound (1.2 g, 90%) as a colorless oil. 1 H-NMR: 1.40 (t, 3H), 3.08 (q, 2H), 3.35 (t, 2H), 3.90 (t, 2H). MS (TSI +): m / z [MNH4 +] 173.8; C4H9CI02S + NH4 needs 174.0.

Preparation 9: (±) -1-ffrans-3,4-dimethyl-4- (3-hydroxyphenylDp) peridn -n-3- (1 H -pyrazole-1-yl) -1 -propanone To a solution of (3- (pyrazol-1-yl) propionic acid (prepared as described in Synlett, 1997, 1013-1034: 225 mg, 1.60 mmol) in N, N-dimethylformamide (50 ml) at temperature At room temperature, 1- (3-dimethylamidopropyl) -3-ethylcarbodiimide hydrochloride (418 mg, 2.18 mmol) and 1-hydroxybenzotriazole (216 mg, 1.60 mmol) were added.After 15 minutes at room temperature the solution had become homogeneous and (±) -3- (trans-3,4-dimethylpipeidinyl) phenol (293 mg, 1.43 mmol) was added in portions, the mixture was stirred at room temperature for 16 hours and then poured into water. with diethyl ether (1 x 20 ml) and made alkaline with 2N aqueous sodium hydroxide solution (to pH 10), and then extracted with diethyl ether The combined organic layers were washed with brine, dried over magnesium sulfate, they filtered, and were concentrated in vacuo to yield the title compound (71 mg, 14%) as an oil. This was used in the next stage without further purification. MS (APCI +): m / z [MH +] 328.0; C19H25N302 + H needs 328.2.

Preparation 10: 4-bromobenzenesu 2- (2-naphtyloxy) ethyl fonate To a solution of 2- (2-naphthyloxy) -1-ethanol (1.5 g, 7.97 mmole) and triethylamine (1.21 g, 11.95 mmole) in dichloromethane ( 20 ml) at 0 ° C was added 4-bromobenzenesulfonyl chloride (2.12 g, 8.36 mmole) in dichloromethane (10 ml) in drops for 30 minutes. The reaction was then warmed to room temperature and stirred for 16 hours before adding more 4-bromobenzenesulfonyl chloride (0.20 g, 0.80 mmol) and stirring was continued for 2 hours. The mixture was then poured into water (50 ml) and acidified with 2N aqueous hydrochloric acid (15 ml). The aqueous layer was extracted with dichloromethane and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to yield a crude residue.

This was purified by column chromatography on silica gel (50 g), eluting with hexane: ethyl acetate (9: 2) to give the title compound (0.56 g, 17%) as a white crystalline solid. 1 H-NMR: 4.25-4.31 (m, 2H), 4.45-4.55 (m, 2H), 6.92-7.02 (m, 2H), 7.36 (t, 1 H), 7.45 (t, 1 H), 7.62-7.85 (m, 7H). MS (TSI +): m / z [MNH + 4] 424.0; C18H15Br04S + NH4 needs 424.0.

Preparation 11: 2- (2-Vethoxy) naphthalene To a solution of 2- (2-naphthyloxy) ethyl 4-bromobenzenesulfonate (preparation 10, 380 mg, 0.93 mmole) in acetone (5 ml) at room temperature was added iodide sodium (1.0 g, 6.66 mmol). The mixture was heated at 35 ° C for 16 hours and then cooled. The residual precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was partitioned between diethyl ether (20 ml) and water (20 ml). The two layers were separated and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the title compound (200 mg, 72%) as a pale yellow oil. 1 H-NMR: 3.50 (t, 2H), 4.39 (t, 2H), 7.10-7.20 (m, 2H), 7.30-7.50 (m, 2H), 7.65-7.84 (m, 3H).

Preparation 12: 2-isopropoxyethyl 4-bromobenzenesulfonate To a solution of 2-isopropoxy-1-ethanol (1.5 g, 14.4 mmol) and triethylamine (2.2 g, 21.6 mmol) in dichloromethane (20 ml) at 0 ° C was added chloride of 4-bromobenzenesulfonyl (2.12 g, 8.36 mmol) in dichloromethane (10 ml) in droplets for more than 30 minutes. The reaction was then warmed to room temperature and stirred for 16 hours. The mixture was then poured into water (50 ml) and acidified with 2N aqueous hydrochloric acid (15 ml). The aqueous layer was extracted with dichloromethane and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to yield a crude residue. This was purified by column chromatography on silica gel (50 g), eluting with hexane: ethyl acetate (9: 3) to give the title compound (4.0 mg, 86%) as a colorless oil. 1 H-NMR: 1.08 (d, 6H), 3.52 (m, 1 H), 3.60 (t, 2H), 4.19 (t, 2H), 7.70 (d, 2H), 7.80 (d, 2H).

Preparation 13: 2- (2-Vethoxy) propane To a solution of 2-α-propoxyethyl 4-bromobenzenesulfonate (preparation 12, 1.0 g, 3.08 mmol) in acetone (5 ml) at room temperature was added sodium iodide (1.0 g). , 6.66 mmoles). The mixture was heated at 35 ° C for 16 hours and then cooled. The residual precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was partitioned between diethyl ether (20 ml). The two layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound (180 mg, 27%) as a pale brown oil. 1 H-NMR (1.19 (d, 6H), 3.22 (t, 2H), 3.60-3.72 (m, 3H).

Preparation 14: 4-bromobenzenesu fonate of 2-propoxieti or To a solution of 2-propoxy-1-ethanol (1.5 g, 14.4 mmoles) and triethylamine (2.2 g, 21.6 mmoles) in dichloromethane (20 ml) at 0 ° C 4-bromobenzenesulfonyl chloride (3.86 g, 15.1 mmol) in dichloromethane (10 ml) was added dropwise for more than 30 minutes. The reaction was then warmed to room temperature and stirred for 16 hours. The mixture was then poured into water (50 ml) and acidified with 2N aqueous hydrochloric acid (15 ml). The aqueous layer was extracted with dichloromethane and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to yield a crude residue. This was purified by column chromatography on silica gel (50 g), eluting with hexane: ethyl acetate (9: 3) to give the title compound (2.2 g, 48%) as a colorless oil. 1 H-NMR (0.86 (t, 3H), 1.52 (m, 2H), 3.36 (t, 2H), 3.62 (t, 2H), 4.2 (t, 2H), 7.70 (d, 2H), 7.80 (d, 2H) .MS (TS +): m / z [MNH + 4] 323.0; CnH15Br04S + NH4 needs 323. 0 Preparation 15: 1- (2-vodoethoxy) propane To a solution of 2-propoxyethyl 4-bromobenzenesulfonate (preparation 14), 1.0 g, 3.08 mmol) in acetone (5 ml) at room temperature was added sodium iodide (1.0 g, 6.66 mmol). The mixture was heated at 35 ° C for 16 hours and then cooled. The residual precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was partitioned between diethyl ether (20 ml) and water (20 ml). The two layers were separated and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the title compound (400 mg, 61%) as a pale yellow oil. 1 H-NMR: 0.92 (t, 3H), 1.60 (m, 2H), 3.24 (t, 2H), 3.42 (t, 2H), 3.70 (t \ 2H).

Preparation 16: 2- (Cyclopentyloxyethyl) To a solution of 2- (cyclopentyloxy) -1-ethanol (prepared as described in J. Orq. Chem. 1968, 33, 2271-2284: 127 mg, 0.97 mmol. ) and triethylamine (101 mg, 0.1 mmol) in dichloromethane (3 ml) at 0 ° C was added 4-bromobenzenesulfonyl chloride (255 mg, 0.1 mmol) in dichloromethane (3 ml) at 0 ° C in drops for more than 5 minutes. The reaction was then warmed to room temperature and stirred for 16 hours. The mixture was then poured into water (3 ml) and the two layers separated. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield a crude residue. This was purified by column chromatography on silica gel (50 g), eluting with a gradient of dichloromethane: hexane (50:50 a). 0: 100), to yield the title compound (200 mg, 59%) as a colorless oil. 1 H-NMR: 1.40-1.78 (m, 8H), 3.57 (t, 2H), 3.80-3.90 (m, 1 H), 4.20 (t, 2H), 7.67 (d, 2H), 7.78 (d, 2H). MS (TSI +): m / z [MHN + 4] 366.0; C? 3H2? Br04S + NH4 needs 366.0.

Preparation 17: 1- (2-vodoethoxy) c! C! Opentane To a solution of 2- (cyclopentyloxy) ethyl 4-bromobenzenesulfonate (preparation 16, 60 mg, 0.17 mmol) in acetone (5 ml) at room temperature. added sodium iodide (200 mg, 1.3 mmol). The mixture was heated at 35 ° C for 16 hours and then cooled. The residual precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was partitioned between diethyl ether (10 ml) and water (10 ml). The two layers were separated and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the title compound (15 mg, 37%) as a brown oil. 1 H-NMR: 1.42-1.80 (m, 8H), 3.22 (t, 2H), 3.67 (t, 2H), 3.93-4.01 (m, 1 H).

Preparation 18: 2- (cyclohexyloxy) ethyl 4-methylbenzenesulfonate To a solution of 2- (cyclohexyloxy) -1-ethanol (200 mg, 1.39 mmol) in pyridine (10 ml) at 0 ° C was added p-toluenesulfonyl chloride (292 mg, 1.53 mmol) in portions followed by - (dimethylamino) pyridine (a few crystals) and the mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo to yield a crude residue that was partitioned between dichloromethane and 2N aqueous hydrochloric acid. The two layers were separated and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield a yellow oil. This was purified by column chromatography on silica gel, eluting with dichloromethane to yield the title compound (226 mg, 54%) as a yellow oil. MS (TSI +): m / z [MH +] 299.3; C? 5H22S04 + NH4 needs 299.1.

Claims (19)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound of the formula I, wherein, R1 and R2 are each independently H or C? - alkyl; R3 represents aryl (optionally substituted by one or more substituents selected from OH, nitro, halo, CN, CH2CN, CONH, C? - alkyl, C? - alkoxy, C? -5 alkanoyl (where any of the last three groups are optionally substituted by one or more halo atom) and -N (R5a) (R5b)), C? -? alkyl, C3-10 alkenyl or C3-? 0 alkynyl, said alkyl, alkenyl or alkynyl groups being optionally substituted and / or terminated by one or more substituents selected from OR5C, S (0) nR5d, CN, haloalkoxy C6-6 carbonyl, C2-6 alkanoyl, C2-6 alkanoyloxy, C3-8 cycloalkyl, cycloalkanoyl * C -9, * S ( 0) nR5d, CN, halo, alkoxy, * C3-8, carbonyl, C2.6 alkanoyl, C2-6 alkanoyloxy, cycloalkyl * C3-8, cycloalkanoyl * C4-9, N (R6a) S (0) 2R7, aryl, adamantyl (where any of the last two groups is optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C-? - alkyl, C? -4 alkoxy, C? alkanoyl? -5 (where any of the last three groups are optionally substituted by one or more halo atom)) or -W-A'-N (R6b) (R6c); n is 0, 1 or 2; W represents a simple bond, C (O) or S (0) p; A1 represents a single bond or CMO alkylene; so that when W and A1 represent single bonds, then the group -N (R6b) (R6c) is not directly bonded to an unsaturated carbon atom; p is 0, 1 or 2; R5a to R5d each independently represent H, CMO alkyl, C3-? 0 alkenyl, C3-? 0 alkynyl, C3-8 cycloankynyl, C? Alkyl-phenyl, aryl (where any of the last six groups is optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C? - alkyl, C? - alkoxy, C1-5 alkanoyl (where any of the last three groups are optionally substituted by one or more halo atoms) or Het2, so that R5d represents H when n represents 1 or 2, R6a to R6c represent each independently H, C1-10 alkyl, C3-? al alkenyl, C3-? al alkynyl, C3-8 cycloankynyl, alkylphenyl C ? -4, aryl (where any of the last six groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C-? -4 alkyl, C? - alkoxy, alkanoyl C? -5 (where any of the last three groups are optionally substituted by one or more halo atoms ) or CONH2, C? -4 alkyl, C? -4 alkoxy, C? -5 alkanoyl (where any of the last three groups are optionally substituted by one or more halo atoms) or Het3, or R6b and R6c together represent C2 alkylene -6 unbranched optionally interrupted by O, S and / or a group N (R8) and optionally substituted by one or more alkyl groups d-4; R7 represents C? -6 alkyl, C3-8 cycloalkyl, C?? 4 alkyl, phenyl or aryl, where the four groups are optionally substituted by one or more substituents selected from C 1-4 alkyl, C? - alkoxy, OH, nitro, amino, halo; R 8 represents H, C 1 -C 6 alkyl, C 3-8 cycloalkyl, A2 (C 3-8 cycloalkyl) or A2-aryl; A2 represents alkylene * C? -6; Het1, Het2 and Het3 independently represent 3 to 8 membered heterocyclic groups, containing at least one heteroatom selected from oxygen, sulfur and / or nitrogen, being in such groups optionally fused with a substituted benzene ring in the heterocycle part and / or of the benzene ring condensed by one or more substituents selected from OH, = 0, nitro, amino, halo, CN, aryl, C 4 alkyl, and C 5 alkanoyl (where any of the last three groups is optionally substituted by one or more halo atoms); and R4 represents H, C? -5 alkyl, C? -? 2 alkanoyl, (pyridin-3-yl) carbonyl or (pyridin-4-yl) carbonyl (where any of the last three groups is optionally substituted in the N-form) -oxidopyridine); or its pharmaceutically or veterinarily acceptable derivatives; as long as; when the group OR 4 is attached to a benzene ring in the meta position relative to the piperidine ring, not being in the N-oxide form, then: (a) when R 1 and R 2 represent C 1 - alkyl, then R 3 does not represent: C -? - 8 (optionally terminally substituted by C-8 cycloalkyl); unsubstituted C3-8 alkenyl; unsubstituted C3-8 alkynyl; C? -3 alkyl, terminally substituted by phenyl, phenoxy, -S-phenyl, -N (H) -phenyl or -N (C? -) alkyl-phenyl, furan-2-yl or thiophen-2-yl; C1-4 alkyl, terminally substituted by an OH group and an additional group selected from phenyl furan-2-yl and thiophen-2-yl; or C3-5 alkenyl, terminally substituted by phenyl. furan-2-yl or thiophen-2-yl, where the position of the unsaturation is in the carbon atoms that are in alpha, beta position, relative to the phenyl group, furan-2-yl or thiophen-2-yl; all of the phenyl, phenoxy, and phenylthio groups are optionally substituted by one or more substituents selected from OH, C -? - 3 alkyl, C? -3 alkoxy, halo, nitro, amino and CF3; and all the furanyl and thiophenyl groups are optionally substituted by a methyl group; and (b) when R1 represents methyl, and: (i) R2 represents C? -4 alkyl and R4 represents H or C- alkanoyl, then R3 does not represent: unsubstituted C3-8 alkyl; unsubstituted C3-8 alkenyl; C3-6 alkyl substituted by an unsubstituted C4-8 cycloalkyl group; C2-alkyl substituted by an unsubstituted C-9 cycloalkanoyl, a C2-β alkanoyl group not substituted by an unsubstituted thiophenyl group; C4-9 alkyl (optionally substituted in the 4- to 9-C position by C4-8 cycloalkyl) or C5-9 alkylene with the alkyl and alkenyl groups being substituted at the 3-C position by OH, C? -6 alkoxy, oxyalkyl C? -3 phenyl or C2-5 alkanoyloxy (where the last three groups are unsubstituted), or C3 alkyl, terminally substituted by (1) OH, C? -6 alkoxy, C3-phenyl oxyalkyl or C2- alkanoyloxy? s (where the last three groups are unsubstituted) and (2) C-8 cycloalkyl, thiophenyl (in which the last two groups are unsubstituted); or (ii) R 2 represents H or C 1 -C 4 alkyl and R 4 represents H or C 1 alkyl. 5 then (I) R3 does not represent: - methyl; C2-2o alkyl or C4-? alkenyl or both substituted in the 2-, 3-, or 4-C positions by -WAN (R6b) (R6c) and the alkyl group being also optionally also substituted in the 3- to 10-positions -C, 4- to 10-C or 5- to 10-C (respectively) for an unsubstituted C 3-8 cycloalkyl or an unsubstituted phenyl; or C 1 - alkyl, the alkyl group being terminally substituted by -W-A'-N (R 6b) (R 6c), and optionally also terminally substituted by unsubstituted C 3-8 cycloalkyl or unsubstituted phenyl; in which both cases, W is a single bond, A1 is a single bond or alkylene C? -3, R6b or R6c is H or unsubstituted C1-10 alkyl and R6b or R6c (as appropriate) is H, C3 cycloalkyl -8, C-MO alkyl, C3-? O alkenyl, phenyl or C3-alkylphenyl (where the last five groups are unsubstituted); or (II) R3 does not represent: - C-MO alkyl or C3-10 alkenyl, both substituted at 1-C to 5-C (as appropriate) by unsubstituted C?-6 alkoxycarbonyl or -W-A1-N (R6b) (R6c) and the alkyl or alkenyl groups also being optionally substituted in the 2- to 10-C, 3- to 10-C, 4- to 10-C or 5- to 10-C positions (respectively) by unsubstituted C3.8 cycloalkyl or unsubstituted phenyl; or C -? - 5 alkyl, which is terminally substituted by an unsubstituted C? -8 carbonyl alkoxy group or -W-A'-N (R6b) (R6c), and is optionally terminally substituted by an unsubstituted phenyl or by an unsubstituted C3-8 cycloalkyl; wherein both cases, W is -C (O) -, A1 is a single bond, R6b or R6c is H or unsubstituted C? -3 alkyl, and R6b or R6c (as appropriate) is H or C- alkyl MO, C3-10 alkenyl) C3- [alpha] cycloalkyl, or phenyl, alkyl C-? -3 phenyl (where the last five groups are unsubstituted), C? -4 alkyl linearly (terminally) substituted by an amino), or R6b or R6c together represent unsubstituted C3-5 alkylene; (c) when R1 and R2 represent methyl and are mutually in the trans- configuration and R4 represents H or C? -4 alkanoyl, then R3 does not represent: unsubstituted C? -8 alkyl; unsubstituted C3-8 alkenyl; unsubstituted C 3-8 alkynyl; C -? - 6 alkyl, terminally substituted by an unsubstituted C3-8 cycloalkyl group; C? -3 alkyl, terminally substituted by a C3-8 cycloalkanoyl, C3-8 cycloalkoxy, C3-8 cycloalkyl, naphthyl, thiophenyl, thiophenoxy, furanyl, furanoxy, tetrahydrofuranyl, pyridinyl or pyridinyloxy (where the last eleven groups are substituted) , phenyl or phenoxy (wherein either of the latter two is optionally substituted by one or more substituents selected from halo, C? -4 alkyl and C? -4 alkoxy); or alkyl * c; or alkyl C? -, Terminally substituted by an OH group and by one of the following groups: phenyl (optionally substituted by one or more substituents selected from halo, C? -4 alkyl and C? - alkoxy), C? 2 alkyl phenyl, C3 cycloalkyl 8 thiophenyl, furanyl or pyridinyl (where the last four groups are unsubstituted); in all these conditions the optionally substituted alkyl groups, Alkenyl, and alkynyl are not interrupted by one or more O and / or S atoms.
2. 2. A compound according to claim 1, wherein the OR4 group is attached to the benzene ring in the meta position relative to the group. piperidine.
3. 3. A compound according to claim 1 or 2, wherein R1 represents C1-2 alkyl.
4. 4. A compound as claimed in any of claims 1 to 3, wherein R2 represents H or C? Alkyl? , 5. - A compound according to any of claims 1 to 4, wherein R3 represents aryl, (optionally substituted by one or more substituents selected from C alquilo -2 alquilo) halo, nitro and "N (R5a) (R5b)) , alkyl C? -8, C3-8 alkenyl or C3-8 alkynyl, said alkyl, alkenyl or alkynyl groups being optionally interrupted by one or more oxygen atoms and / or being substituted and / or terminated by one or more selected substituents between OR5c, S (0) nR5d, CN, halo, C?-carbonyl alkoxy, C-6 cycloalkyl, C5-7 cycloalkanoyl, Het1 'aryl (where the latter group is optionally substituted by one or more substituents selected from OH, alkyl C1-2, C1-2 alkoxy or halo), or -W-A1-N (R6b) (R6c) 6.- A compound according to any of claims 1 to 5, wherein W represents a single bond or C (O) 7. A compound according to any of claims 1 to 6, wherein A1 represents a single bond or C-3 cyano. 8. A compound according to any of claims 1 to 7, wherein R5a to R5b independently represent H, C? -6 alkyl, C3-6 alkenyl, C3-6 alkynyl, C4-8 cycloalkyl, C? Alkyl? -2 phenyl, aryl or Het2. 9. A compound according to any of claims 1 to 8, wherein R6b to R6c independently represent H, C? -2 alkyl, Het3, or R6b and R6c together represent unbranched C2-6 alkylene optionally interrupted by O or S and which is optionally substituted by one or more C -? - alkyl groups. 10. A compound according to any of claims 1 to 9, wherein Het1, Het2 and Het3 independently represent 5- to 7-membered heterocyclic groups, containing at least one heteroatom selected from oxygen, sulfur and / or nitrogen , with large groups optionally condensed with a benzene ring, and optionally substituted on the heterocyclic part and / or on the benzene ring part condensed by one or more substituents selected from OH, = 0 and C? -2 alkyl (where the last group is optionally substituted by one or more halo atoms). 11. A compound according to any of claims 1 to 10, wherein R4 represents H or alkanoyl C? -5. 12. A compound as defined in any of claims 1 to 11, for use as a medicament. 13. A compound as defined in any of claims 1 to 11, for use as an animal medicament. 14. A formulation comprising a compound as defined in any of claims 1 to 11, in admixture with a pharmaceutically or veterinarily acceptable adjuvant, diluent or vehicle. 15. A formulation according to claim 14, which is a veterinary formulation. 16. The use of a compound as defined in any of claims 1 to 11, in the manufacture of a medicament for the curative or prophylactic treatment of pruritus in a patient. 17. A process for the preparation of a compound as defined in claim 1, comprising: a) for compounds of the formula I wherein R3 represents alkyl d optionally substituted by C3-8 cycloalkyl, Het1, aryl, adamantyl (where either of the last two groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C? -4 alkyl, C? and alkanoyl C -? - 5 (where any of the last three groups is optionally substituted by one or more halo atoms), or R3 represents C2-? alkyl, C3-? o alkenyl or C3-? 0 alkynyl (where all three groups are optionally substituted by one or more of the substituents identified in claim 1 relative to R3), such alkyl, alkenyl and alkynyl groups being attached to the nitrogen atom of the piperidine by a CH2 group, with Het1 being as defined in claim 1, the reduction of a corresponding compound of formula II, wherein R31 represents H, C3-8 cycloalkyl, Het1, aryl, adamantyl (where either of the last two groups is optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, alkyl C? -4, C? - alkoxy and C? - alkyl, C? -4 alkoxy and C? _5 alkanoyl (where any of the last three groups are optionally substituted by one or more halo atoms), C? -9 alkyl , C2-9 alkenyl or C2-9 alkynyl, such alkyl, alkenyl or alkynyl groups being optionally substituted and / or terminated by one or more substituents selected from OR5C? S (O) nR5d, CN, halo, C6-6 alkoxycarbonyl, C2-6 alkanoyl, C6 alkanoyloxy, C3-8 cycloalkyl, C4-9 cycloalkanoyl, N (R6a) S (O) 2R7, Het1, aryl adamantyl (wherein any of the last two groups is optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C? - alkyl, C? - alkoxy, and C1-5 alkanoyl wherein any of the last three groups is optionally substituted by one or more halo atoms), or -W-A1-N (R6b) (R6c), and R1, R2, R4, R5c, R5d, R6a to R6c, R7, Het1, n , w and A1 are as defined in claim 1; b) for compounds of the formula I in which R4 represents alkanoyl C? -? 2, (pyridin-3-yl) carbonyl or, (pyridin-4-yl) carbonyl (where either of the last two groups is optionally in the N-oxide form of pyridine), the reaction of a corresponding compound of the formula I in which R4 represents H with a compound of the formula V, R41-C02H V or a suitable derivative thereof, wherein R41 represents alkyl Ci.-n, pyridin-3-yl or pyridin-4-yl (the last two optional groups being substituted in the N-oxide form of pyridine); c) the reaction of a corresponding compound of the formula III wherein R1, R2 and R4 are as defined in claim 1, with a compound of the formula VI, R3-L1 VI wherein L1 represents a leaving group and R3 is as defined in claim 1; d) for compounds of formula I wherein R3 represents Ci-alkyl, which, instead of being optionally substituted by the substituents defined in claim 1, is optionally substituted by R31, where R31 is as defined above, the reaction of a corresponding compound of the formula III, as defined above, with a compound of the formula VII, wherein R31 is as defined above, in the presence of a suitable reducing partner; e) for compounds of the formula I in which R3 is a C-0 alkenyl C-0 alkyl or C4-0 alkynyl group completely saturated between the carbons 1 and 3 (relative to the N atom of the piperidine), and group R3 is substituted on carbon 2 (relative to the N atom of piperidine) by ¿^ ^ G g am am am am S (O) R5b, alkanoyl, cycloalkanoyl, alkoxycarbonyl, CN, -C (0) -A1-N (R6b) (R6c), -S (0) -A1-N (R6b) (R6c), or -S (0) 2-A1-N (R6b) (R6c), wherein R5d, R6b, R6c and A1 are as defined in claim 1, the reaction of a corresponding compound of formula III, as defined above, with a compound of formula VIII, R3a-Z VIII wherein R3a represents R3 as defined in claim 1 except that it does not represent aryl, and that the R3a chain contains a double bond additional carbon-carbon at position a, β with respect to the substituent Z, and Z represents S (0) R5d, S (O) 2R5d, alkanoyl, cycloalkanoyl, alkoxycarbonyl, CN, -C (0) -A1-N (R6b) ( R6b), -S (0) -A1-N (R6b) (R6b), or -S (0) -A1-N (R6b) (R6b), wherein R5b, R6, R6c and A1 are as defined in claim 1; f) the conversion of a functional group on an alkyl, heterocyclic or aryl group of a compound of formula I into another. 18. A compound of formula II, as defined in claim 17. 19. A compound of formula III, as defined in claim 17.