MXPA00005296A

MXPA00005296A - 4-arylpiperidine derivatives for the treatment of pruritus

Info

Publication number: MXPA00005296A
Application number: MXPA/A/2000/005296A
Authority: MX
Inventors: Paul Gibson Stephen; Scott Bronk Brian; Tommasini Ivan
Original assignee: Pfizer Limited
Priority date: 1999-05-28
Filing date: 2000-05-29
Publication date: 2001-11-21

Abstract

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

Description

NEW DERIVATIVES OF 4-ARILPIPERIDINE FOR THE TREATMENT OF PRURITE This invention relates to novel 4-phenylpiperidines which have utility in the treatment of pruritic dermatosis which includes allergic dermatitis and atopy in animals and humans, and to the processes for their preparation and to the intermediates used in the preparation of such compounds . Itching or itching is a common dermatological symptom that can cause considerable discomfort in both humans and animals. Pruritus is often associated with inflammatory skin disease that can commonly be caused by hypersensitivity reactions, such as reaction to insect bites, for example, flea bites, or environmental allergens such as house dust mites. or to pollen; or bacterial and fungal infections of the skin or infections of ectoparasites. 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 are slow in their performance and only offer limited efficacy against allergic dermatitis. Various emollients such as soft paraffin, glycerin and lanolin are also used, but with limited success and there is a continuing need for an effective remedy. Certain derivatives of 4-aryl-piperidine with three substitutions in , i 1, 3 and 4, are described in GB-A-1525584 as potent narcotic antagonists that also exhibit analgesic properties. These compounds are also claimed in EP-B-0287339 as opioid antagonists that block the effect of agonists at mu or kappa receptors that have potential utility in the treatment of a variety of disorders associated with these receptors such as disorders. in feeding, overdose of opiates, depression, smoking, alcoholism, sexual dysfunction, shock, cerebrovascular accident, spinal injury and brain trauma; It has also been suggested that it serves as an appetite suppressant to lose weight. EP-A-0 506 468 and EP-A-0 506 478 disclose additional 4-aryl-substituted piperidines in 1-N. A potential utility in the prevention of peripherally mediated unwanted opioid effects and in relieving the symptoms of idiopathic constipation and irritable bowel syndrome is suggested. According to the present invention, novel 4-phenylpiperidines are provided which are, and / or are prodrugs of, potent and effective antipruritic agents. Thus, the present invention provides compounds of formula I: wherein R and R are each independently H or C-M alkyl; R3 represents aryl (optionally substituted by one or more substituents selected from OH, nitro, halo, CN, CH2CN, CONH2, alkyl C? -4, C1-4 alkoxy, C? -5 alkanoyl (last three groups which are optionally substituted by one or more halo atoms) and -N (R4a) (R4b)), C1-10 alkyl, alkenyl C3-10 or C3-10 alkynyl wherein said alkyl, alkenyl or alkynyl groups are optionally substituted and / or terminated by one or more substituents selected from OR4c, S (O) nR4d, CN, halo, C1-6 alkoxycarbonyl, alkanoyl C2-6, C2-6 alkanoyloxy, C3-8 cycloalkyl, C4-9 cycloalkanoyl, N (R5a) S (O) 2R6, Het1, aryl, adamantyl (latter two groups which are optionally substituted by one or more substituents selected from OH , nitro, amino, halo, CN, CH2CN, CONH2, C1-4 alkyl, C1-4 alkoxy and C1-5 alkanoyl (last three groups which are optionally substituted by one or more halo atoms)), or -W-A1- N (R5b) (R5c); n is O, 1 or 2; W represents a simple bond, C (O) or S (O) p; A represents a single bond or C1-10 alkylene; provided that when both W and A represent simple 5b 5c bonds, then the -N (R) (R) group does not bind directly to an unsaturated carbon atom; p is 0, 1 or 2; R 4a to R 4d each independently represent H, C 1-10 alkyl, C 3-10 alkenyl, C 3-10 alkynyl, C 3-8 cycloalkyl, C 1-4 alkylphenyl, aryl (last six groups which are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C? -4 alkyl, C?? 4 alkoxy and C? -s alkanoyl (last three groups which are optionally substituted by one or more halo atoms)) or Het; provided that R4d does not represent H when n represents 1 or 2; R5a to R5c each independently represent H, C1-10 alkyl, C3- or C3 alkenyl, C3-10 alkynyl, C3-8 cycloalkyl, alkylphenyl CM, aryl (last six groups which are optionally substituted by one or more substituents selected from OH , nitro, amino, halo, CN, CH2CN, CONH2, C1-4 alkyl, C1-4 alkoxy and C1-5 alkanoyl (last three groups which are optionally 3 5b 5c substituted by one or more halo atoms), Het, or R and R together represent unbranched C2-6 alkylene, alkylene group which is optionally interrupted by O, S and / or a group N (R7) and is optionally substituted by one or more C1-4 alkyl groups; R represents C 1-6 alkyl, C 3-8 cycloalkyl, alkylphenyl C-O aryl, four groups which are optionally substituted by one or more substituents selected from C 1-4 alkyl, C? - alkoxy, OH, nitro, amino or halo; R7 represents H, C1-6 alkyl, C3-8 cycloalkyl, A2-cycloalkyl CM) O A2-aryl; A2 represents C? -6 alkylene; Het1, Het2 and Het3 independently represent 3 to 8 membered heterocyclic groups, groups containing at least one heteroatom selected from oxygen, sulfur and / or nitrogen, groups which are optionally fused to a benzene ring, and groups which are optionally substituted the part of the heterocyclic ring and / or the benzene ring condensed by one or more substituents selected from OH, = O, nitro, amino, halo, CN, aryl, C- alkyl, Ci ^ alkoxy and d-5 alkanoyl (last three groups that are optionally substituted by one or more halo atoms); Y represents -C (= E) NR8R9, C (O) R10, C (O) OR10, C (O) CH (R10a) N (G) Ga, R11, CH (R12b) C (O) OR12a, CH ( R12b) OCO2R12a, C (O) C (R13a) = C (R13b) NH2, C (O) CH (R13a) CH (NH2) (R13b) or PO (OR14) 2; E represents O or S; R8 and R9 independently represent H, C1-10 alkyl, C3-? Alkenyl or (last two groups which are optionally substituted by one or more C4-7 aryl or cycloalkyl groups (two groups which are optionally substituted by one or more substituents selected from halo, C- alkyl, C- alkoxy, C 1-4 haloalkyl or haloalkoxy CM)), aryl, C- cycloalkyl (optionally substituted by one or more substituents selected from halo, C 1-4 alkyl and C- alkoxy (last two groups which are optionally substituted by one or more halo atoms), or R8 and R9, together with the N atom to which both bind, represent Het4; Het4 represents a 5- to 8-membered heterocyclic ring comprising at least one nitrogen atom and optionally one or more additional heteroatoms selected from oxygen and sulfur, heterocyclic ring which is optionally substituted by one or more C1- "alkyl groups; 'R10 represents H, Het5, C- cycloalkyl (optionally substituted by one or more Ci ^ alkyl groups), C1-11 alkyl (optionally substituted by one or more substituents selected from aryl (optionally substituted by one or more substituents selected from OH, halo, CM alkanoyl, C alca * alkanoyloxy, N (R8) (R9), C (O) N (R8) (R9), C? -4 alkyl, C? -4 alkoxy, Ci-4 haloalkyl and haloalkoxy C? -4) or C4-7 cycloalkyl (the latter group which is optionally substituted by one or more C-) -alkyl or aryl groups (optionally substituted by one or more substituents selected from OH, C? -4 alkanoyl halo, C alca alkanoyloxy) 4, N (R8) (R9), C (O) N (R8) (R9), C1- * alkyl and C1- * alkoxy (last two group which are optionally substituted by one or more halo atom groups)); R represents H, C4-7 cycloalkyl, C1-10 alkyl (optionally substituted by one or more substituents selected from aryl or cycloalkyl) C4-7), aryl or R (optionally, together with G) represents a naturally occurring amino acid substituent; G and Ga independently represent H, a protective group The amino acids, or G, together with R, represents a naturally occurring amino acid substituent; R represents H, C7 cycloalkyl (optionally substituted by one or more C1-4 alkyl groups), aryl (optionally substituted by one or more substituents selected from OH, halo, C1-4 alkanoyl, C1-4 alkanoyloxy, N ( R8) (R9), C (O) N (R8) (R9), C1-4 alkyl and C1-4 alkoxy (the last two groups which are optionally substituted by one or more halo atoms), C1-10 alkyl, alkenyl C3-10, alkyl or alkenyl group which is optionally substituted by jijUauaMMHa one or more substituents selected from C (O) NH2, Het, C4-7 cycloalkyl (optionally substituted by one or more C- alkyl groups), aryl, aryloxy or arylalkoxy d-4 (last three groups which are optionally substituted by one or more substituents selected from OH, halo, C 1-4 alkanoyl, C 1-4 alkanoyloxy, N (R 8) (R 9), C (O) N (R 8) (R 9), C 1-4 alkyl and C 1-4 alkoxy ( last two groups that are optionally substituted by one or more halo atoms) or R represents Het7; Het5 to Het7 independently represent 4- to 6-membered heterocyclic rings, rings containing at least one heteroatom selected from oxygen, sulfur and / or nitrogen, rings that are optionally fused to a benzene ring, and rings that are optionally substituted in the of the heterocyclic ring and / or the benzene ring condensed by one or more substituents selected from OH, = O, nitro, amino, halo, CN, aryl, C? -4 alquiloalkyl, C alco? alco alkoxy, C3-6 cycloalkyl and C?-C alca alkanoyl (last four groups which are optionally substituted by one or more halo atoms); R12a and R12b independently represent H, C4-7 cycloalkyl (optionally substituted by one or more CM alkyl groups), C1-10 alkyl (optionally substituted by one or more substituents selected from aryl or C4-7 cycloalkyl (latter group which is optionally substituted by one or more C? -4) alkyl or aryl groups (optionally substituted by one or more substituents selected from OH, halo, C- alkanoyl, C1-4 alkanoyloxy, CM alkyl and C- alkoxy (last two groups which are optionally substituted by one or more halo atoms)); pi3a and i3 represent independently H, cycloalkyl 4-7 (optionally substituted by one or more C- alkyl groups), CMO alkyl, C2-10 alkenyl (alkyl or alkenyl groups which are optionally substituted by one or more substituents selected from aryl or cycloalkyl C4-7 (last group which is optionally substituted by one or more C? -4 alkyl groups) or aryl (optionally substituted by one or more substituents selected from OH, halo, C- alkanoyl, C1-4 alkanoyloxy, d-4 alkyl) and C 1-4 alkoxy (last two groups which are optionally substituted by one or more halo atoms)): R 14 represents H, C 4-7 cycloalkyl (optionally substituted by one or more C- alkyl groups), C 1-6 alkyl ( optionally substituted by one or more substituents selected from aryl or C4-7 cycloalkyl (the latter group being optionally substituted by one or more C-) alkyl groups, or aryl (optionally substituted by one or more substituents selected s between OH, halo, d-4-alkanoyl, C-M-alkanoyloxy, d-4-alkyl and C 1-4 -alkoxy (last two groups which are optionally substituted by one or more halo atoms)); X represents one or more substituents on the benzene ring, substituents which are independently selected from halo, CN, nitro, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl (last three groups which are optionally substituted and / or terminated by one or more substituents selected from halo, CN, nitro, OH, C3-7 cycloalkyl, C1-6 alkoxy, C3-7 cycloalkoxy, C1-6 alkanoyl, C4-8 cycloalkanoyl, C2-6 alkoxycarbonyl, C2-6 alkanoyloxy or N (R15a) (R15)), C (O) R16a, C (O) OR16b, OC (O) R16c, S (O) rOR16d, S (O) tR17a, OR16e, N (R18a) (R18b), C (O) N (R18c) (R18d), OC (O) N (R18e) (R18f), N (R18g) C (O) R16f, N (R18h) C (O) OR19, N ( R18i) C (O) N (R18j) (R18k), N (R18m) S (O) 2R17b or B (OR15c) 2; R15a to R15c independently represent H, C1-6 alkyl or C3-7 cycloalkyl (latter two groups which are optionally substituted by one or more halo atoms); R16a to R16f independently represent H, C-MO alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl (last four groups which are optionally substituted by one or more substituents selected from halo, nitro, OH, C alkyl? -4 or C 4 -4 alkoxy) or Het 8; R17a and R17b independently represent CMO alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl (last four groups which are optionally substituted by one or more substituents selected from halo, nitro, OH, C4-4 alkyl or alkoxy C1-4), Het9 or N (R20a) (R20b); provided that R17a does not represent N (R20a) (R20b) when t is 1; R18a to R18 independently represent H, d.io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl (last four groups which are optionally substituted by one or more substituents selected from 10 1 fii 1 ñk halo, nitro , OH, C? -4 alkyl or C? -4 alkoxy) Het, or R 'and R together represent unbranched C3-6 alkylene, alkylene group which is optionally interrupted by oxygen, sulfur or an NR group; R19 represents C? -α- or C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl (last four groups which are optionally substituted by one or more substituents selected from halo, nitro, OH, C1-4alkyl or alkoxy) d-4) or Het11; 20s 20c R a R independently represent H, C 1-4 alkyl or C 3-7 cycloalkyl (last two groups which are optionally substituted by one or more halo atoms); r is 1 or 2; t is 0, 1 or 2; Het8 to Het11 represent 4- to 7-membered heterocyclic rings, rings containing at least one heteroatom selected from oxygen, sulfur and / or nitrogen, and rings that are optionally substituted by one or more substituents selected from OH, = O, nitro, amino , halo, CN, aplo, d-4 alkyl, C 1-4 alkoxy, d-6 cycloalkyl and C 1-5 alkanoyl (last four groups which are optionally substituted by one or more halo atoms); or pharmaceutically or veterinarily acceptable derivatives thereof; compounds collectively referred to hereafter as "the compounds of the invention" In the definitions used herein, alkyl, alkylene, alkoxy, alkoxycarbonyl, alkanoyl, alkanoyloxy, alkenyl, alkynyl and the alkyl portions of the alkylphenyl and aryl alkoxy groups may be , when there is a sufficient number of carbon atoms, straight or branched chains and / or optionally interrupted by one or more oxygen (s) and / or sulfur atom (s). The term "halo" includes fluoro, chloro, bromo or iodo. The term "aryl" includes optionally substituted phenyl, naphthyl and the like, and "aryloxy" includes phenoxy and naphthyloxy and the like optionally substituted. Unless otherwise specified, the aryl and aryloxy groups are optionally substituted by one or more (eg, one to three) substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-4alkyl , C 1-4 alkoxy C 1-4 alkoxycarbonyl and alkanoyl d-5 (last four groups which are optionally substituted by one or more halo atoms). The heterocyclic rings representing Het1, Het2, Het3, Het4, Het5, Het6, Het7, Het8, Het9, Het10 and Het11 can be completely saturated, partially unsaturated and / or completely or partially aromatic in character. Specific rings that may be mentioned include: for Het5, pyridine or pyridine- / V-oxide. For the avoidance of doubt, when the Het groups (Het1, Het2, Het3, Het4, Het, Het, Het, Het, Het, Het and Het) are at least partially saturated, the possible substitution points include the atom (for example the carbon atom) at the point of attachment of the Het group to the rest of the molecule. Het groups can also be linked to the rest of the molecule by a heteroatom. The piperidine moiety in the compounds of formula I may be in the N-oxidized form. The sulfur atoms that can interrupt the substituents (for example, alkyl) in the compounds of formula I may be present in oxidized form (eg, as sulfoxides or sulfones). All the groups Het1, Het2, Het3, Het4, Het5, Het6, Het7, Het8, Het9, Het10 and Het11 can also be in N- or S-oxidized forms. The skilled person will understand that the term "amino protecting group", as used herein, includes those mentioned in "Protective Groups in Organic Synthesis", 2nd edition, TW Greene &hox ; PGM Wutz, Wiley-Interscience (1991), in particular those indicated on pages 218 to 222 of this reference, description in the document that is incorporated herein by reference. Thus, specific examples of amino protecting groups include carbamate groups (e.g., methyl, cyclopropylmethyl, 1-methyl-1-cyclopropylmethyl, diisopropylmethyl, 9-fluorenylmethyl, 9- (2-sulfo) fluorenylmethyl, 2-furanylmethyl, 2.2 groups. , 2-trichloroethyl, 2-haloethyl, 2-trimethylsilylethyl, 2-methylthioethyl, 2-methylsulfonylethyl, 2 (p-toluenesulfonyl) ethyl, 2-phosphononoethyl, 1, 1-dimethylpropynyl, 1, 1-dimethyl-3 - (? ,? / - dimethylcarboxamido) propyl, 1,1-dimethyl-3 - (? /, / V-diethylamino) propyl, 1-methyl-1- (l-adamantyl) ethyl, 1-methyl-1-phenylethyl, 1-methyl-1 - (3,5-dimetphenyl) ethyl, 1-methyl-1- (4-biphenylyl) ethyl, 1-methyl-1- (p-phenylazophenyl) ethyl, 1,1-dimethyl-2-haloethyl , 1,1-dimethyl-2,2,2-trichloroethyl, 1,1-dimethyl-2-cyanoethyl, isobutyl, isobutyl, f-amyl, cyclobutyl, 1-methylcyclobutyl, cyclopentyl, cyclohexyl, 1- methyl-cyclohexyl, 1 -admantyl, isobornyl, vinyl, allyl, cinnamyl, phenyl, 2,4,6-tri-1-butylphenyl, A77-nitrophenyl, S-phenyl, 8-quinolinyl,? / - hydro xipperidinyl, 4- (1,4-dimethylpiperidinyl), 4,5-diphenyl-3-oxazolin-2-one, benzyl, 2,4,6-trimethylbenzyl, p-metbenzyl, 3,5-dimetbenzyl, p- decyloxybenzyl, p-nitrobenzyl, o-nitrobenzyl, 3,4-dimet-6-nitrobenzyl, p-bromobenzyl, chlorobenzyl, 2,4-dichlorobenzyl, p-cyanobenzyl, or - (? /,? / - dimethylcarboxamidobenzyl) benzyl, - chloro-p-acyloxybenzyl, p- (dihydroxyboronyl) benzyl, p- (phenylazo) -benzyl, p-. { p'-metphenylazo) benzyl, 5-benzisoxazolyl-methyl, 9-anthrylmethyl, diphenylmethyl, phenyl (o-nitrophenyl) methyl, di (2-pyridyl) methyl, 1-methyl-1- (4-pyridyl) ethyl, isonicotinyl or S-benzyl carbamate), amide groups (e.g.,? / -formyl, N-acetyl,? / -chloroacetyl,? / -dichloroacetyl,? / -trichloroacetyl, A / -trifluoroacetyl, Nitrophenylacetyl,? / - groups o-Nitrophenoxyacetyl,? / -acetoacetyl,? / - acetylpyridinium,? / -3-phenylpropionyl,? / -3- (p-hydroxyphenyl) propionyl,? / -3- (o-nitrophenyl) propionyl,? / - 2- methyl-2- (o-nitrophenoxy) propionyl,? / - 2-methyl-2- (o-phenylazophenoxy) propionyl,? / - 4-chlorobutyryl,? / - isobutyryl,? / - o -nitrocinnamoyl,? / -picolinoyl,? / - (? / '- acetylmethionyl),? / - (? /' - benzoylphenylalanyl),? / - benzoyl,? / - p-phenylbenzoyl, Np-metbenzoyl,? / - o -nitrobenzoyl or ? / - o- (benzoyloxymethyl) benzoyl amide), alkyl groups (e.g.,? / -alyl groups,? / - phenacyl,? / -3-acetoxypropyl,? / - (4-nitro-1-cyclohexyl-2- oxo-pyrrolin-3-yl),? / - metmethyl,? / - chloroet methyl, N-benzyloxymethyl,? / - pivaloyloxymethyl,? / - 2-tetrahydropyranyl,? / - 2,4-dinitrophenyl, N-benzyl,? / - 3,4-dimetbenzyl,? / - o -nitrobenzyl,? / - di (p-metphenyl) methyl, N-triphenylmethyl,? / - (p-metphenyl) diphenylmethyl,? / - diphenyl-4-pyridylmethyl,? / - 2-picolyl N'-oxide or? / - dibenzosuberyl), phosphinyl groups and phosphoryl (for example, N-diphenylphosphinyl,? / - dimethylthiophosphinyl,? / - diphenylthiophosphinyl,? / - diethylphosphoryl, N-dibenzylphosphoryl or? / - phenylphosphoryl groups), sulfenyl groups (eg, N-benzenesulfenyl groups,? / - o-nitrobenzenesulfenyl,? / - 2,4-dinitrobenzenesulfenyl, N-pentachlorobenzenesulfenyl,? / - 2-nitro-4-metbenzenesulfenyl or N-triphenylmethylsulfenyl), sulfonyl groups (eg,? / - benzenesulfonyl, Np-metbenzenesulfonyl,? / -2,4,6-trimethylbenzenesulfonyl,? -toluenesulfonyl, N- benzylsulfonyl,? / - p -methylbenzylsulfonyl,? / - trifluoromethylsulfonyl or N-phenacylsulfonyl) or the? / -trimethylsilyl group. The term "naturally occurring amino acid" as used herein includes the amino acids glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, histidine, serine, threonine, methionine, cysteine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, arginine and proline. The term "pharmaceutically or veterinarily acceptable derivatives" includes non-toxic salts. Salts which may be mentioned include: acid addition salts, for example, salts formed with sufuric, hydrochloric, hydrobromic, phosphoric, hydroiodic, sulfamic, organosulfonic, citric, carboxylic (eg, acetic, benzoic, etc.), maleic, acids. malic, succinic, tartaric, cinnamic, ascorbic and related acids; basic addition salts; salts formed with bases, for example, the sodium, potassium and alkyl C 1-4 ammonium salts. The compounds of the invention may also be in the form of quaternary ammonium salts, for example, in the piperidine moiety, salts which may be formed by reaction with various alkylating agents, such as an alkyl halide or a sulfuric ester, or an aromatic sulfonic acid. The compounds of the invention may exhibit tautomerism. All tautomeric forms of the compounds of formula I are included within the scope of the invention.

The compounds of the invention contain one or more asymmetric centers and can thus exist as enantiomers and diastereomers. The diastereoisomers can be separated using conventional techniques, for example, by fractional crystallization or chromatography. The various stereoisomers can be isolated by the separation of a racemic or other mixture of the compounds using conventional techniques, for example, fractional crystallization or HPLC. The desired optical isomers can be prepared by reacting the appropriate optically active starting materials under conditions that will 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 diastereomeric salts formed by reaction of the racemate with a suitable optically active acid or base. The invention includes the use of both separate individual isomers and mixtures of isomers. Radiolabeled derivatives of the compounds of formula I which are suitable for biological studies are also included within the scope of the invention. According to a further aspect of the invention, there is provided a compound of formula I, as defined above, provided that when Y is H or 2-methyl-2-propionamide, OY is attached to a benzene ring at the relative meta position. to the piperidine ring (ring that is not in the N-oxidized form), and X is one or two substituents independently selected from halo, C? -4 alkyl or C 1-4 alkoxy (last two groups which are optionally substituted by one or more halo atoms, but otherwise not substituted), then R3 represents: optionally substituted aryl; C3-? o alkenyl or C3-? alkynyl or optionally substituted (two groups which are both interrupted by at least one oxygen and / or sulfur atom); C2-10 alkyl, interrupted by at least two oxygen atoms and / or at least one sulfur atom; C-MO alkyl, C3-10 alkenyl or C3-10 alkynyl, groups which are all optionally interrupted by one or more oxygen and / or sulfur atoms, and are substituted and / or terminated by one or more of: S (O ) nR4d, N (R5a) S (O) 2R6, Het1 (substituted by one or more substituents selected from nitro, amino and C1-5 alkanoyl (the latter group being optionally substituted by one or more halo atoms)), aryl (substituted by one or more substituents selected from nitro, amino and haloalkanoyl Ci-s) or adamantyl (the latter group being substituted by one or more of the relevant substituents identified above); or OR4c, wherein R4c represents C7-10 alkyl, C3-10 alkenyl, C3-10 alkynyl or Het2 (last four groups which are optionally substituted by one or more of the relevant substituents identified above), or R4c represents alkyl d. -io, C1-4 alkylphenyl, C3-cycloalkyl aryl (last four groups which are all substituted by one or more of the relevant substituents identified above); -W-A1-N (R5b) (R5c), wherein R5b and / or R5c independently represent alkylphenyl Cu (the latter group being optionally substituted by one or more of the relevant substituents identified above), C-MO alkyl, alkenyl C3-? O, C3-10 alkynyl, C3-8 cycloalkyl (last four groups which are all substituted by one or more of the relevant substituents identified above), or aryl (substituted by one or more substituents selected from nitro, amino and haloalkanoyl) ds); compounds which may also be referred to as "compounds of the invention". 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 OY represents O-alkyl d-4, OY is attached to the benzene ring at the relative meta position to the piperidine ring (ring that is not in the A / -oxidated form), and X is one or two substituents independently selected from halo, C 1-4 alkyl or C 1-4 alkoxy (last two groups which are optionally substituted by one or more halo atoms, but which are otherwise not substituted), then R3 does not represent: - straight or branched C1-10 alkyl chain (optionally substituted by one or more substituents selected from unsubstituted aryl or unsubstituted C3-β cycloalkyl);compounds which may also be referred to as "compounds of the invention". Preferred compounds of the invention include those in which: The group OY is attached to the benzene ring in the meta position relative to the piperidine group; the substituent (s) X is (are) bonded to the benzene ring at the position (s) which are ortho- and / or para- relative to the piperidine group; R1 represents C? -2 alkyl; R2 represents H or C? -2 alkyl; R3 represents C-i-β alkyl, C3-8 alkenyl or C3-8 alkynyl wherein said alkyl, alkenyl or alkynyl groups are optionally substituted and / or terminated by one or more substituents selected from C3-8 cycloalkyl, OR 4c, CN, Het 1 or aryl (last group which is optionally substituted by one or more substituents selected from OH, d-2 alkyl, C 2 -2 alkoxy or halo); R4c represents H, C? -6 alkyl, C4-6 cycloalkyl, aryl or Het2; Het and Het independently represent 5 to 7 membered heterocyclic groups, groups containing at least one heteroatom selected from oxygen, sulfur and / or nitrogen, and groups which are optionally substituted by one or more C1-2 alkyl groups (alkyl groups which are optionally substituted by one or more halo atoms); Y represents C (= E) NR8R9, C (O) R10 or R11; R8 and R9 independently represent H or C-M alkyl; R10 represents β-alkyl (substituted by one or more phenyl groups) or aryl (optionally substituted by one or more substituents selected from OH, halo, C? -2 alca alkanoyloxy, NH 2, C (O) NH 2 and C C1-2 alquilo alkyl (latter group that is optionally substituted by one or more halo atoms)); R11 represents H, C1-10 alkyl or C3-? Alkenyl, or latter two groups which are optionally substituted by one or more substituents selected from Het and phenyl; Het represents a 5-6 membered heterocyclic ring, ring containing at least one heteroatom selected from oxygen, sulfur and / or nitrogen, ring that is optionally fused to a benzene ring, and ring that is optionally substituted on the ring part heterocyclic and / or benzene ring condensed by one or more substituents selected from OH, = O and C- alkyl); Het is in the S-rusty form; X represents one to three substituents selected from halo, nitro, C 2-6 alkenyl, C 1-6 alkyl (alkyl group which is optionally substituted and / or terminated by a substituent selected from OH, C 1-4 alkoxy or N (R 15a) (R15b)), C (O) R16a, C (O) OR16b, S (O) tR17a, N (R18a) (R18b), C (O) N (R18c) (R18d), N (R18g) C (O ) R16f, N (R18h) C (O) OR19, N (R18I) C (O) N (R18j) (R18k) or N (R18m) S (O) 2R17b; 15b R and R independently represent H or Ci ^ alkyl; Ri6a g pi6f independently represent H or alkyl d-6 (latter group which is optionally substituted by one or more halo atoms); R17a and R17 independently represent C? -4 alkyl (optionally substituted by one or more halo atoms) or N (R) (R); R18a to R18m independently represent H, alkyl d-6, or R18j 18k and R together represent unbranched C3-6alkylene optionally interrupted by oxygen; R19 represents C- alkyl; R and R independently represent H or C- alkyl. The most preferred compounds of the invention include those in which: the X substituent (s) is (are) bonded to the benzene ring at the position (s) which are ortho- and / or - relating to group OY; R1 represents methyl; R 2 represents H or methyl; R3 represents linear and saturated d-7 alkyl, alkyl group which is optionally substituted and / or terminated by one or more substituents selected from C4-7 cycloalkyl, OR4c, CN, Het1 or phenyl (latter group which is optionally substituted by one or more C? -2 alkyl groups); R 4c represents H, C 1-4 alkyl, C 4-6 cycloalkyl or phenyl; Het1 represents a saturated heterocyclic group of 5 to 6 members, groups containing a heteroatom selected from oxygen, sulfur or nitrogen; R8 and R9 independently represent alkyl d-2; R represents β-alkyl; R 11 represents H or C 1-5 alkyl; X represents a substituent selected from nitro, C 2-4 alkenyl, C 1 -2 alkyl (alkyl group which is optionally substituted and / or terminated by OH or N (R15a) (R15b)), C (O) R16a, C (O ) OR16b, S (O) 2R17a, N (R18a) (R18b), C (O) N (R18c) (R18d), N (H) C (O) R16f, N (H) C (O) OR19, N (H) C (O) N (R18j) (R18k) or N (H) S (O) 2 R 17b, or X represents one to three halo atoms (e.g., F, Cl, and / or Br); 153 15b I R and R independently represent H or C? -3 alkyl; 1 fia 1 fif R a R independently represent H or alkyl d-5 (last group which is optionally substituted by one or more halo atoms); R17a and R17b independently represent C? -2 alkyl (optionally substituted by one or more halo atoms) or N (R20a) (R20b); 1 ña 1 fik I R a R independently represent H or C 1-5 alkyl; R and R independently represent H or C? -2 alkyl. Particularly preferred compounds of the invention include those in which: R and R represent methyl groups in the trans configuration mutually; And represents H; R represents saturated and linear C? -6 alkyl, alkyl group which is optionally substituted and / or terminated by one or more C4-7 cycloalkyl groups; X represents fluoro or N (H) C (O) Et in the ortho position relative to the group OY. 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 of the above definitions, is: (+ _) 1 -? / - hexyl-uraps-3,4-dimethyl-4 - (4-bromo-3-hydroxyphenyl) piperidine; (+ _) 2-N-ex-rans-3,4-dimethyl-4- (3-hydroxy-4-nitrophenyl) piperidine; (+ _) 4-N-ex-iraA7s-3,4-d, methyl-4- (4-amino-3-hydroxyphenyl) p, peridine; (+ _) 5-N-ex-rans-3,4-dimethyl-4- [3-hydroxy-4- (2-methyl-butanoyl) phenyl] piperidine; (+ _) 7-N-ex? -rans-3,4-dimethyl-4- (3-hydroxy-4-methylphenyl) piperidine; (+ _) 8-N-r) ex \ -frans-3,4-dimethyl-4- (4-acetylamino-3-hydroxyphenyl) piperidine; (+,) 9 -? / - hexyl-iaRA7S-3,4-dimethyl-4- (3-hydroxy-4-hydroxymethylphenyl) piperidine; (+ _) 10 -? / - hexyl-1? Ans-3,4-dimethyl-4- (3-hydroxy-4-trifluoromethanesulfonylaminophenyl) piperidine; (+ _) 11 -? / - hexyl-uraps-3,4-dimethyl-4- (4-ethyl-3-hydroxyphenyl) piperidine; ^ + _ j 12 -? / - hexyl-1R) s-3,4-dimethyl-4- [4- (2,2-dimethylpropanoylamino) -3-hydroxyphenyljpiperidine; (+,) 13 -? / - hexyl-frans-3,4-dimethyl-4- (3-hydroxy-4-methylaminomethyl-phenyl) piperidine; (+ _) 14 -? / - hexyl-frans-3,4-dimethyl-4- (4-ethylaminomethyl-3-hydroxyphenyl) piperidine; ("+ _ 15- / V-hexyl- / rans-3,4-dimethyl-4- (4-d-methylaminomethyl-3-hydroxyphenyl) piperidine; ^ + _) 16 -? / - hexyl- / raA7s-3,4-dimethyl-4- (3-hydroxy-2-methylphenyl) piperidine; (+ _) 17 -? / - hexyl-frans-3,4-d-methyl-4- (3-hydroxy-4-methoxycarbonylphenyl) -peridine; ("+ _ i8 -? / - hexyl-rans-3,4-d, methyl-4- (4-ethoxycarbonyl-3-hydroxyphenyl) piperidine; (+ _) 19 -? / - hexyl-frans-3,4-dimethyl-4- (4 -? / '- methylaminocarbonyl-3-hydroxyphenyl) piperidine; 5 (+ _ 20 -? / - hexyl-iaA7s-3,4-d, methyl-4- (4 -? / ',? /' - dimethylaminocarbonyl-3-hydroxyphenyl) piperidine; ("+ _ 21- ? / - hexyl-rans-3,4-d-methyl-4- (4-γ / ',? /' - diethylaminocarbonyl-3-hydroxyphenyl) piperidine; ("+ _ 22 -? / - hexyl-rans-3 , 4-dimethyl-4- (3-hydroxy-4-porpionylaminophenyl) piperidine; io (+ _) 23 -? / - hexyl-frans-3,4-dimethyl-4- (4 -? / ',? / '- dimethylaminocarbonylamino-3-hydroxyphenyl) piperidine; (^ + _ >) 24 -? / - hexyl-frans-3,4-dimethyl-4- (3-hydroxy-4 -? / - methylaminocarbonylamidophenyl) piperidine; + _ 25 -? / - hexyl-fraps-3,4-dimethyl-4- (3-hydroxy-4- 15-methoxycarbonylaminophenyl) piperidine; ('+ _>) 26 -? / - hexyl-i'aA7S- 3) 4-dimethyl-4- (4-formylamino-3-aminophenyl) piperidine; ("+ _) 27 -? / - hexyl-trans-3,4-d-methyl-4- (4-? / ', ? / - dimethylaminosulfonylamino-3-hydroxyphenyl) piperidine; (+,) 28 -? / - hexyl-uraps-3,4-dimethyl-4- (3-hydroxy-4-pentane-aminophenyl) -piperidine; or (+ _) 29 -? / - hexyl-iara-7s-3,4-dimethyl-4- (2,4-dichloro-3-hydroxyphenyl) piperidine; + _j30 -? / - hexyl-frans-3 , 4-dimethyl-4- [3-hydroxyl] -4 (2-methylpropionylamino) phenyl] piperidine; ("+ _ 31 -? / - hexyl-frans-3,4-dimethyl-4- [3-hydroxy-4- (2-methylbutanoyl) phenyl] piperidine; ("+ _ 32 -? / - hexyl-urea /? S-3,4-dimethyl-4- (3-hydroxy-4-butanoylaminophenyl) p.peridine; + _j33 -? / - hexi-frans-3 , 4-dimethyl-4- (3-hydroxy-4-methanesulfonyl-phenyl) piperidine; ^ + _ 34 -? / - hexyl-trans-3,4-dimethyl-4- (4-formyl) 3-hydroxy-phenyl) piperidine; ^ + _ 35 -? / - hexyl-ia 7s-3,4-dimethyl-4- (3-hydroxy-2,4,6-trichlorophenol) p peridin; ^ + _ j36 -? / - hexyl-frans-3,4-d, methyl-4- (3-aminosulfonyl-3-hydroxyphenyl) -piperidine; ^ + _ 37 -? / - hexyl-frans-3,4-dimethyl-4- (4,6-dichloro-3-hydroxyphenyl) -piperidine; ('+ _) 38 -? / - hexyl-fAa / 7s-3,4-dimethyl-4- (3-hydroxy-4 -? /' - isopropylamino-carbonylphenyl) piperidine; + _) 39 -? / - hexyl-rans-3,4-d, methyl-4- (4-chloro-3-hydroxyphenyl) piperidine; ("+ _ 40 -? / - hexyl-frans-3,4-dimethyl-4- (6-chloro-3-hydroxyphenyl) pperidine; + _) 41 -? / - hexyl- 7'-3,4-dimethyl-4- (4-aminocarbonyl-3-hydroxyphenyl) piperidine; + _ 42 -? / - hexyl-trans-3,4-dimethyl-4- (4-fluorophenyl); 3-hydroxyphenyl) piperidine; ("+ _ 43 -? / - hexyl-frans-3,4-dimethyl-4- (2-fluoro-3-hydroxyphenyl) piperidine; (^ + _ 44 -? / - 3 -cyclohexypropyl-iaA7s-3,4-dimethyl-4- (3-hydroxy-4-nitrophenol) piperidine; ("+ _ 45 -? / - (3-cyclohexylpropyl) -i / -ans-3,4-dimethyl-4- (4-amino-3-hydroxyphenyl) piperidine; ^ + _ ^ 46 -? - ( 3-cyclohexylpropyl) -frans-3,4-dimethyl-4- (3-hydroxy-4-acetylaminophenyl) piperidine; (+,) 47 -? / - (3-cyclohexylpropyl) -frans-3,4- dimethyl-4- (3-hydroxy-4-propionylaminophenyl) piperidine; (+ X 48 -? / - hexyl-fraA7s-3,4-dimethyl-4- (4 -? / ',? /' - dimethylamino-3-hydroxy-phenyl) -piperidine; + _) 49-? / -hexyl-7a-3,4-dimethyl-4- (3-hydroxy-4-isopropenylphenyl) piperidine; (+ _ 50 -? / - hexyl-rans-3,4-dimethyl-4- (4-allyl-3 -? / ',? / - diethylcarbamyloxyphenyl) piperidine; 5 ^ + _ 51 -? / - hexyl-iris -3,4-dimethyl-4- (3 -? / ',? /' - diethylcarbamyloxy-4-methylphenyl) piperidine; ^ + _ J52 -? / - hexyl-trans-3,4-dimethyl-4- (3- ? / ',? / - diethylcarbamyloxy-4-ethylphenyl) piperidine; + _; 53 -? / - hexyl-ir / 7s-3,4-dimethyl-4- (3-? /',? / ' -diethylcarbamyloxy-4 -? / "- methylaminocarbonylphenyl) piperidine; io (+ _) 54 -? / - hexyl-trans-3,4-dimethyl-4- (3 -? /,? / '- diethylthiocarbamyloxy) -fluorophenyl) -piperidine; or + _ 55 -? / - hexyl-trans-3,4-dimethyl-4- (3-α / β, β / - diethylcarbamyloxy-4-formylphenol) piperidine, compounds which can also be "compounds of the invention." According to a further aspect of the invention there are provided methods for the preparation of the compounds of the invention, as illustrated below The following procedures are illustrative of the general synthesis procedures they can be adopted to obtain the compounds of the invention. The compounds of formula I wherein R3 represents Ci-alkyl optionally substituted by C3-8 cycloalkyl, Het, aryl, adamantyl (latter two groups which are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, d-4 alkyl, C-? -4 alkoxy and C? -5 alkanoyl (last three groups which are optionally substituted by one or more halo atoms)), or R3 represents C2-10 alkyl, C3- alkenyl? or C3-? alkynyl (three groups which are optionally substituted by one or more of the relevant substituents identified above with respect to R3), alkyl, alkenyl or alkynyl groups which are attached to the nitrogen atom of the piperidine by a CH2 group, in that Het1 is as defined above, can be prepared by reducing a corresponding compound of formula II, wherein R31 represents H, C3-8 cycloalkyl, Het1, aryl, adamantyl (latter two groups which are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C? alkyl? 4, C 1-4 alkoxy and C 1-5 alkanoyl (last three groups which are optionally substituted by one or more halo atoms), C 1-9 alkyl, C 2-9 alkenyl or C 2-9 alkynyl, alkyl, alkenyl or alkynyl groups are optionally substituted and / or terminated by one or more substituents selected from OR4c, S (O) nR4d, CN, halo, d-β-carbonyl alkoxy, C2-6 alkanoyl, C2-6 alkanoyloxy, C3-8 cycloalkyl, C4- cycloalkanoyl 9, N (R5a) S (O) 2R6, Het1, aryl, adamantyl (latter two groups which are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-4alkyl, alkoxy d-4 and C? -5 alkanoyl (last three groups which are optionally substituted by one or more halo atoms)), or -W-A1-N (R5b) (R5c), and R1, R2, R4c, R4d, R5a to R5c, R6, Het1, n, X, Y, W and A1 are as defined above, using a suitable reducing agent (for example, lithium aluminum hydride or a borane derivative), for example, as described earlier. The compounds of formula II can be prepared by reacting a corresponding compound of formula III, wherein R1, R2, X and Y are as defined above with a compound of formula IV, R31CO2H IV or a suitable derivative (e.g., carboxylic acid) thereof (e.g., an acid halide or an anhydride) , wherein R31 is as defined above, using coupling conditions known to those skilled in the art.

The compounds of formula III can be prepared from appropriate precursors by analogy with other methods described herein which describe the production of the compounds of formula I. 2. The compounds of formula I can also be prepared by reacting a corresponding compound of formula III, as defined above, with a compound of formula V, R3-L1 V wherein L1 represents a leaving group (such as halo, alkanesulfonate, perfluoroalkanesulfonate or arenesulfonate) and R3 is as defined above, under conditions which are known to those skilled in the art, including, for example, alkylation at between room temperature and reflux temperature in the presence of an organic solvent inert to the reaction (eg,? /,? / - dimethylformamide) and a suitable base ( for example, NaHCO3), and the arylation between ambient temperature and reflux temperature in the presence of a suitable catalyst system (e.g., tris (dibenzylideneacetone) -palladium (O) combined with tri-o-tolylphosphine), an appropriate strong base (e.g., sodium tert-butoxide) and a reaction inert solvent (e.g., toluene). 3. The compounds of formula I in which R3 represents Ci-alkyl, which, instead of being optionally substituted by substituents as defined above, is instead optionally substituted by R31, wherein R31 is as defined above , can be prepared by reacting a corresponding compound of formula III, as defined above, with a compound of formula VI, R 31 CHO VI wherein R 31 is as defined above, for example in the presence of a suitable reducing agent (e.g. , sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride) and an appropriate solvent (eg, methanol). 4. The compounds of formula I in which R3 is a C1-10 alkyl group, C4-10 alkenyl or C4-10 alkynyl which is completely saturated with C1 to C3 (relative to the N atom of piperidine), and group R3 which is substituted on C2 (relative to the N atom of the piperidine) by S (O) R4d, S (O) 2R4d, alkanoyl, cycloalkanoyl, alkoxy carbonyl, CN, -C (O) -A1-N (R5b) ( R5c), -S (O) -A1-N (R5b) (R5c), or -S (O) 2-A1N (R5b) (R5c), wherein R4d, R5b, R5c 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 VII, R3a-Z VII in which R3a represents R3 as defined above except that it does not represent aryl, and that chain R3a contains an additional carbon-carbon double bond a, ß to the substituent Z, and Z represents S (O) R4d, S (O) 2R4d, alkanoyl, cycloalkanoyl, alkoxy carbonyl, CN, -C (O) -A1-N (R5b) (R5c), -S (O) -A1-N (R5b) (R5c), or -S (O) 2-A1-N (R5b) (R5c), in the that R4d, R5b, R5c and A1 are as defined above, for example at between room temperature and reflux temperature in the presence of a solvent inert to the reaction (for example, THF). 5. Compounds of formula I wherein Y represents -C (= E) NR8R9, wherein E, R8 and R9 are as defined above, can be prepared by reacting a corresponding compound of formula I in which Y represents H, with a compound of formula VIII, HO-C (= E) NR8R9 VIII, or a suitable derivative (e.g., carboxylic acid) thereof (e.g., an acid chloride), wherein E, R8 and R9 are as defined above, or a compound of formula IX, E = C = NR8R9 IX wherein E, R8 and R9 are as defined above, for example (in both cases) at between room temperature and reflux temperature in the presence of a suitable base (for example, KOH, triethylamine and / or pyridine) and optionally in the presence of an appropriate solvent (for example, THF, water, or a suitable mixture thereof). 6. The compounds of formula I, wherein Y represents C (O) R or C (O) OR10, wherein R10 is as defined above, can be prepared by reacting a corresponding compound of formula I in which Y represents H, with a compound of formula X, HO-C (O) R 10 X, or a compound of formula XI, HO-C (O) OR 10 XI, respectively, or suitable derivatives (e.g., carboxylic acid) of the Same (for example, acid halides or anhydrides), wherein R is as defined above, under coupling conditions known to those skilled in the art. 7. The compounds of formula I in which Y represents C (O) CH (R10a) N (G) (Ga), wherein R10a, G and Ga are as defined above can be prepared by reacting a corresponding compound of formula I wherein Y represents H, with a compound of formula XII, OH-C (O) CH (R10a) N (G) (Ga) XII or a suitable derivative (for example carboxylic acid) thereof, wherein 10a to I R, G and G are as defined above, under coupling conditions known to those skilled in the art. 8. Compounds of formula I wherein Y represents C (O) C (R13a) = C (R13b) NH2 or C (O) CH (R13a) CH (NH2) (R13b), and R3a and R13b are such as defined above, they can be prepared by reacting a corresponding compound of formula I in which Y represents H, with a compound of formula XIII, wherein the dotted line represents an optional double bond, and R13a and R13b are as defined above, for example at between room temperature and reflux in the presence of a suitable solvent (for example? /,? / - dimethylformamide) and an appropriate base (e.g.,? /,? / - dimethyl-4-aminopyridine). 9. The compounds of formula I wherein Y represents C (O) R, Wherein R represents phenyl substituted in the ortho position by an amino group, and optionally substituted by one or more additional substituents selected from OH, halo, C? -4 alkanoyl, C? -4 alkanoyloxy, N (R8) (R9) ), C (O) N (R8) (R9), alkyl d-4 and C- alkoxy (last two groups which are optionally substituted by one or more halo atoms), and R8 and R9 are as defined above, can prepare by reacting a corresponding compound of formula I wherein I represents H with a compound of formula XIV, wherein D represents one to four optional substituents selected from OH, halo, d-4 alkanoyl, C1-4 alkanoyloxy, N (R8) (R9), C (O) N (R8) (R9), C- alkyl ? -4 and C 1-4 alkoxy (last two groups which are optionally substituted by one or more halo atoms), and R 8 and R 9 are as defined above, for example at between room temperature and reflux in the presence of a suitable solvent (for example,? /,? / - dimethylformamide) and an appropriate base (for example,? /,? / - dimethyl-4-aminopyridine). 10. Compounds of formula I wherein Y represents R11, wherein R11 is as defined above, can be prepared by reacting a corresponding compound of formula I wherein Y represents H, with a compound of formula XV, R11 -L2 XV in which L2 represents a leaving group such as halo, arenesulfonate, alkanesulfonate, perfluoroalkanesulfonate or diazo, and R11 is as defined above, for example under coupling conditions known to those skilled in the art (such as those described previously regarding the previous procedure 2). 11. The compounds of formula I in which Y represents CH (R12b) C (O) OR12a or CH (R12b) OC (O) OR12a, wherein R12a and R12b are as defined above, can be prepared by reacting a corresponding compound of formula I wherein Y represents H, with a compound of formula XVI, L2-CH (R12b) C (O) OR12a XVI or a compound of formula XVll, L2-CH (R2b) OC (O) OR12a XVll in which R a, R and L are such as defined above, for example under coupling conditions known to those skilled in the art (such as those described with respect to process 2 above). 12. Compounds of formula I wherein Y represents PO (OR) 2, wherein R14 is as defined above, can be prepared by reacting a compound of formula I in which Y represents H, with a compound of formula XVlll, H-PO (OR14) 2 XVlll or a compound of formula XIX, HO-PO (OR14) 2 XIX or a suitable derivative (e.g., phosphoric acid) thereof (e.g., pyrophosphate, cyanophosphate or chlorophosphate), wherein R is as defined above, for example at between -10 C and reflux temperature in the presence of a suitable base (e.g., NaOH, triethylamine) and an appropriate organic solvent (e.g., THF, dichloromethane or tetrachloride) of carbon). 13. The compounds of formula I wherein X represents halo and optionally one or more additional substituents defined above with respect to X, can be prepared by reacting a corresponding compound of formula XX, wherein Xa represents an H and optionally from one to three of the substituents defined above with respect to X, and R1, R2, R3 and Y are as defined above, with a suitable halogenating agent (e.g., a halogen solution) in acetic acid, or a fluorinating agent such as triflate of 3-5-dichloro-1-fluoropyridinium or? -fluorobenzenesulfonimide), for example under conditions known to those skilled in the art. The compounds of formula XX can be prepared by the N-alkylation of a corresponding compound of formula XXI, wherein R, R2, Xa and Y are as defined above, for example under the conditions described above for the preparation of the compounds of formula I (see, for example, those described with respect to processes 2 to 4 above) . The compounds of formula XX wherein R3 represents Ci-alkyl, which, instead of being optionally substituted by substituents as defined above, instead is optionally substituted by R31, wherein R31 is as defined above, can alternatively prepared by reduction of a corresponding compound of formula XXII, wherein R1, R2, R31, Xa and Y are as defined above, for example under the conditions described above for the preparation of the compounds of formula I (see, for example, those described with respect to process 1 above). The compounds of formula XXI and XXII can be prepared from appropriate precursors by analogy with other methods described herein that describe the production of compounds of formula I. 14. Compounds of formula I wherein X represents nitro and optionally one or more Additional substituents defined above with respect to X, can be prepared by nitration of a corresponding compound of formula XX, as defined above, under conditions known to those skilled in the art, for example by reacting it with a suitable source of nitronium ion ( for example, nitronium tetrafluoroborate) at between -10 C and room temperature in the presence of a suitable solvent (e.g., acetonitrile). 15. Compounds of formula I wherein X represents S (O) 2? H and optionally one or more additional substituents defined above with respect to X, can be prepared by sulfonation of a corresponding compound of formula XX, as defined above, under conditions known to those skilled in the art, for example by reacting it with chlorosulfonic acid at between -10 C and room temperature in the presence of thionyl chloride, followed by hydrolysis of the resulting sulfonyl chloride. Alternatively, the reaction can be carried out with sulfur trioxide, for example at -10 C and reflux temperature in the presence of pyridine. 16. The compounds of formula I in which X represents 1 to S (O) tR, where t is 0, and optionally one or more additional substituents 173 defined above with respect to X, wherein R is as defined above except that it does not represent N (R) (R) , wherein R20a and R20b are as defined above, can be prepared by sulfenylation of a corresponding compound of formula XX, as defined above, under conditions known to those skilled in the art, for example by reacting it with a compound of formula XXIII, R21-SS-R21 XXIII wherein R21 represents R17a as defined above except that it does not represent N (R20a) (R20b), wherein R20a and R20b are as defined above, at between -90 C and room temperature in the presence of a suitable strong base (e.g., an alkyl lithium reagent) and an appropriate organic solvent (e.g.,? /,? /,? / ',? /' - tetramethylethylenediamine), or by reacting with a compound of formula XXIV, R21-S-CI XXIV wherein R21 is as defined above, at between 0 C and reflux temperature in the presence of an appropriate organic solvent (e.g., dichloromethane) and optionally in the presence of a suitable catalyst (e.g. iron powder). 16a 17. The compounds of formula I wherein X represents C (O) R and optionally one or more additional substituents defined above with respect to X, wherein R16a is as defined above except that it does not represent H, can be prepared by acylation of a corresponding compound of formula XX, as defined above, under conditions known to those skilled in the art, for example by reacting it with a compound of formula XXV, R16aC (O) -L3 XXV wherein L3 represents a leaving group (such as halo, OH, OS (O) 2CF3 or 163 163 OC (O) R) and R is as defined above except that it does not represent H, for example under Friedel-Crafts conditions (eg, at between room temperature and reflux in the presence of a suitable solvent and optionally in presence of an appropriate catalyst). 18. Compounds of formula I wherein X represents C (O) H and optionally one or more additional substituents defined above with respect to X, can be prepared by reacting a corresponding compound of formula XX, as defined above, with dimethylformamide, for example under Vilsmeier-Haack conditions or between -90 C and room temperature in the presence of a suitable strong base (eg, an alkyl lithium reagent) and an appropriate organic solvent (eg,? /, / V,? / ',? /' - tetramethylethylenediamine, THF, cyclohexane or mixtures thereof). 19. The compounds of formula I in which X represents 16c OC (O) R and optionally one or more additional substituents defined above with respect to X, wherein R 16c is as defined above, can be prepared by oxidation of a corresponding compound of formula I wherein X represents C (O ) R a, in which R a is as defined above, for example under the Baeyer-Villiger conditions, that is, between ambient and reflux temperatures in the presence of an appropriate peroxyacid (for example, 3-chloroperoxybenzoic acid) ) and a suitable organic solvent (for example, dichloromethane). 20. Compounds of formula I wherein X and / or OY represent OH, can be prepared by reacting a corresponding compound of formula I wherein X represents OC (O) R16c, wherein R16c is as defined above, and / or Y represents C (= E) NR8R9, wherein R8 and R9 are as defined above, under conditions well known to those skilled in the art (eg, hydrolysis or reductive cleavage). 21. The compounds of formula I wherein X represents C1-10 alkyl, C3-10 alkenyl, C3-10 alkynyl, C3-7 cycloalkyl (four groups which are optionally substituted as defined above, and alkenyl and alkynyl groups which are fully saturated in C1 (relative to the benzene ring)) and optionally one or more additional substituents defined above with respect to X, can be prepared by reacting a corresponding compound of formula XX, as defined above, with a compound of formula XXVI , R22-L2 XXVI wherein R represents C? -? Or C, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl (four groups that are optionally substituted, by one or more substituents selected from halo, CN, nitro, OH, C3-7 cycloalkyl, C1-6 alkoxy, C3-7 cycloalkoxy, C1-6 alkanoyl, C4-8 cycloalkanoyl, C2-6 alkoxycarbonyl, C2-6 alkanoyloxy or N (R15a) (R15b), and alkenyl groups and alkynyl that are 2 2 153 15b complete me saturated in C1 (relative to L)) and L, R and R are as defined above, for example both under Friedel-Crafts alkylation conditions and between -90 C and room temperature in the presence of a strong base suitable (for example, an alkyl lithium reagent) and an appropriate organic solvent (for example,? /,? /,? / '? /' - tetramethylethylenediamine, THF, cyclohexane or mixtures thereof). 22. Compounds of formula I wherein X represents C (O) N (R18c) (R18d), which group is in the ortho position in relation to OY, wherein R18c and R18d independently represent d-4 alkyl or cycloalkyl C3-7, and Y represents H, can be prepared by a new arrangement of a corresponding compound of formula XXVII, XXVII , In which R rep and R 2 and R 3 are as defined above, for example at -90 C to room temperature in the presence of a suitable strong base (eg, an alkyl lithium reagent) and an appropriate organic solvent (for example, N, N, N ', N'-tetramethylethylenediamine, THF, cyclohexane or mixtures thereof). 23. Compounds of formula I wherein X represents C2-10 alkenyl and optionally one or more further substituents defined above with respect to X, wherein the double bond of the alkenyl chain is, β- to the benzene ring, can be prepared by reacting a corresponding compound of formula XX, as defined above, with a C2-10 aldehyde or a C2-10 ketone, for example at -90 C to room temperature in the presence of a suitable strong base (e.g. , an alkyl lithium reagent) and an appropriate organic solvent (for example,? /,? /,? / ',? /' - tetramethylethylenediamine, THF, cyclohexane or mixtures thereof). 24. Compounds of formula I wherein X represents C (O) N (H) R and optionally one or more additional substituents defined above with respect to X, wherein R represents alkyl d-4 O cycloalkyl C3-7 prepare by reacting a corresponding compound of formula XX, as defined above, with a compound of formula XXVIII, O = C = N-R23 XXVIII wherein R23 is as defined above, for example at -90 C to room temperature in the presence of a suitable strong base (eg, an alkyl lithium reagent) and a solvent appropriate organic (for example, ? /,? /,? / ',? /' - tetramethylethylenediamine, THF, cyclohexane or mixtures thereof). 25. Compounds of formula I wherein X represents B (OCH3) 2 and optionally one or more additional substituents defined above with respect to X, can be prepared by reacting a corresponding compound of formula XX, as defined above, with borate trimethyl, for example at -90 C to room temperature in the presence of a suitable strong base (for example, an alkyl lithium reagent) and an appropriate organic solvent (for example, N, N, N ', N'-tetramethylethylenediamine, THF) , cyclohexane or mixtures thereof). 26. Compounds of formula I wherein X represents C2-10 alkenyl or C2-10 alkynyl, alkenyl and alkynyl groups containing a carbon-carbon multiple bond that is a, ß to the benzene ring, and alkenyl and alkynyl groups which are optionally substituted as defined above with respect to X, and optionally one or more additional substituents defined above with respect to X, can be prepared by reacting a corresponding compound of formula I wherein at least one X represents halo with a compound of formula XXIX , R24-M XXIX wherein R24 represents C2-10 terminal alkenyl or C2-10 terminal alkynyl, alkenyl and alkynyl groups which are optionally substituted by one or more substituents selected from halo, CN, nitro, OH, C3-7 cycloalkyl, C6-6 alkoxy, C3-7 cycloalkoxy, C1-6 alkanoyl, C4-8 cycloalkanoyl, C2-6 alkoxycarbonyl, 15s 15b C2-6 alkanoyloxy or N (R) (R), M represents (as appropriate) H, a rest that cont It has tin (for example, tributylstannyl), a boron derivative (for example boronic acid), a zinc halide, a magnesium halide or an alkali metal (last three groups that can be formed in situ from the corresponding 15s halide 15b). ), and R and R are as defined above, for example at between ambient and reflux temperatures in the presence of a suitable catalyst system (e.g., tetrakis (triphenylphosphine) palladium (0), bis ( triphenylphosphine) palladium (ll), or bis (triphenylphosphine) palladium (II) chloride combined with copper iodide (I)) and both (as appropriate) a suitable source of a halide ion (eg, lithium chloride) and a suitable base (for example, triethylamine). The compounds of formula Ill to XIX, XXIII to XXIX, and the derivatives thereof, when they are not commercially available or are not subsequently described, can be obtained either by analogy with the methods described herein, or by conventional synthetic methods, in accordance with conventional techniques, starting from readily available starting materials using appropriate reagents and reaction conditions (see, eg, "Comprehensive Organic Transformations - A Guide to Functional Group Preparations," RC Larrock, VCH (1989), or "Advanced Organic Chemistry - Reactions, Mechanism and Structure ", 4 edition, J. March, Wiley-lnterscience (1992)). For example, compounds of formula XX in which both Xa and Y represent H can be obtained according to or by analogy with the processes described in the publications mentioned above in relation to the compounds based on 4-arylpiperidine. The skilled person will appreciate that certain groups falling within the definition of Y will serve as protecting groups during the introduction and / or the conversion of certain X groups, by the synthesis of the corresponding compounds in which Y represents H. For example, the group -C (= E) NR8R9 can serve to avoid the reaction in phenolic oxygen under conditions such as those described in relation to the procedures 16, 18, 19, 21 and 23 to 25 above. The substituents on the alkyl, heterocyclic and aryl groups in the aforementioned compounds can also be introduced, removed and interconverted, using techniques that are well known to those skilled in the art (including those specifically described above). For example, nitro can be reduced to amino, OH can be alkylated to give alkoxy, alkoxy and alkanoyloxy can be hydrolyzed to OH, alkenes can be hydrogenated to alkanes, halo can be hydrogenated to H, etc. The skilled person will also appreciate that various other interconversions and conventional transformations of substituents or functional groups within the compounds of formula I will provide other compounds of formula I. In particular, certain functional groups that fall within the definitions of group X can be converted to other similar definitions. For example: amino can be converted to alkylamino, dialkylamino, alkylcarbonylamino, alkylsulfonylamino, aminocarbonylamino, alkoxycarbonylamino and aminosulfonylamino; sulfonate can be converted to aminosulfonyl; formyl can be converted to hydroxymethyl, aminomethyl, alkylaminomethyl, dialkylaminomethyl and alkoxycarbonyl; methyl can be converted to ethyl, alkoxycarbonyl can be converted to aminocarbonyl, alkylaminocarbonyl and dialkylaminocarbonyl; aminocarbonyl can be converted to alkanoyl; Sulfanyl can be converted to sulfinyl or sulfonyl; and dialkyl borate can be converted to dihydroxyboron, all transformations which can be carried out using techniques, and under reaction conditions, which are known to those skilled in the art. Also, certain groups that represent Y can be converted to certain other groups that represent Y. The compounds of the invention can be isolated from their reaction mixtures using conventional techniques. It will be appreciated by those skilled in the art that, during the performance of the method described above, the functional groups of the intermediates may need to be protected by protecting groups. The functional groups that it is desirable to protect include oxo, OH, amino and carboxylic acid. Suitable protecting groups for oxo include acetals, ketals (e.g., ethylene ketals) and dithianes. Suitable protecting groups for OH include trialkylsilyl and diarylalkysilyl groups (for example, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) and tetrahydropyranyl. Suitable protecting groups for amino include tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for the carboxylic acid include Ci-β alkyl or benzyl esters. Suitable protecting groups for the terminal alkynes include trialkylsilyl and diarylalkysilyl groups (for example, tere-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl). Suitable protecting groups for arene protons include trialkylsilyl groups. The protection and deprotection of the functional groups can take place before or after any of the reaction steps described above. The protecting groups can be removed according to techniques that are well known to those skilled in the art. The use of protecting groups is fully described in "Protective Groups in Organic Chemistry", edited by JWF McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis", 2nd edition, TW Greene & PGM Wutz, Wiley-lnterscience (1991). Those skilled in the art will also appreciate that, to obtain compounds of formula I alternatively and, on some occasions, more conveniently, the individual steps of the aforementioned process can be carried out in a different order, and / or the individual reactions they can be carried out at a different stage in the overall route (i.e. substituents can be added and / or chemical transformations performed with intermediates different from those mentioned above in conjunction with a particular 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 strategy of protective groups (if any) that are adopted. Clearly, the type of chemistry involved will influence the choice of reagent used in ^ Such synthetic steps, the need and type of the protective groups used, and the sequence to effect the synthesis. The methods may be adapted as appropriate to the reactants, reagents and other parameters of the reaction so that they will be apparent to the skilled person by reference to conventional textbooks and the examples provided herein. The pharmaceutically acceptable acid addition salts of the compounds of formula I containing a basic center can be prepared in conventional manner. For example, a solution of the free base can be treated with the appropriate acid, either neat or in a suitable solvent, and then the resulting salt isolated either by filtration or by vacuum evaporation of the reaction solvent. The pharmaceutically acceptable basic addition salts can be obtained analogously by treating a solution of a compound of formula I with the appropriate base. Both types of salt can be formed or interconverted using ion exchange resin techniques. The above procedures can be adapted as appropriate to the particular reagents and groups involved and other variants will be apparent to the skilled chemist by reference to conventional textbooks and the examples provided herein to allow the preparation of all compounds of formula I The compounds of the invention may possess pharmacological activity as such. The compounds of the invention which may possess such activity include those in which Y represents H, but are not limited thereto. Other compounds of formula I (which include those in which Y does not represent H, but are not limited to them) may not possess such activity per se, but may be administered parenterally or orally, and then metabolized in the body to form compounds that are pharmacologically active (which include the corresponding compounds in which Y represents H, but are not limited to them). Therefore, such compounds (which also include compounds that may possess some pharmacological activity, but that activation is appreciably less than that of the active compounds in which they are metabolized), can be described as "prodrugs". It will further be appreciated by those skilled in the art that certain protected derivatives of the compounds of formula I, which may be made before a final phase of deprotection, may not possess pharmacological activity as such, but may, in certain cases, be administered orally or parenterally and then metabolized in the body to form the compounds of the invention that are pharmacologically active. Therefore, such derivatives can also be described as "prodrugs". In addition, certain compounds of formula I can act as prodrugs of other compounds of formula I. Further it will be appreciated by those skilled in the art that certain moieties, known to those skilled in the art as "pro-moieties", for example as described in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985 (the description in the document is incorporated herein by reference), can be placed in appropriate functionalities, when such functionalities are present within the compounds of formula I. Protected derivatives, and prodrugs, of the compounds of formula I are included within the scope of the invention. The compounds of the invention are useful because they possess pharmacological activity and / or are metabolized in the organism after oral or parenteral administration to form compounds possessing pharmacological activity. Therefore, the compounds of the invention are indicated as pharmaceuticals and, in particular, for use as medicaments for animals. According to a further aspect of the invention, the compounds of the invention are provided for use as medicaments, such as pharmaceuticals and medicaments for animals. Through the term "treatment", we include both therapeutic (curative) and prophylactic treatment. In particular, it has been found that the compounds of the invention are useful in the treatment of pruritus and of the conditions 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 in the manufacture of a medicament for the treatment of pruritus or a medical condition characterized by pruritus as a symptom. In this way, the compounds of the invention are expected to be useful for the curative or prophylactic treatment of pruritic dermatosis which includes allergic dermatitis and atopy in animals and humans. Other diseases and conditions that may be mentioned include contact dermatitis, psoriasis, eczema and insect bites. Thus, the invention provides a method for treating or preventing pruritus or a 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. to an animal that needs such treatment. The compounds of the invention will normally be administered orally or by any parenteral route, in the form of pharmaceutical preparations comprising the active component, optionally in the form of an acidic or basic, non-toxic, organic or inorganic addition salt, in a dosage form pharmaceutically acceptable. Depending on the disorder and the patient in question, as well as the route of administration, the compositions may be administered in varying doses (see below). Although 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 can be selected with due consideration to the route of administration and to the desired 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 component. The methods by which the compounds can be administered for veterinary use include oral administration by a capsule, bolus, tablet or potion formulation, topical administration as an ointment, application on a wound, application on grains, bath, spray, cream , shampoo, collar or powder or, alternatively, can be administered by injection (eg, 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 species of the animal being treated, the severity and type of infection and the body weight of the animal. For parenteral, topical and oral administration, the normal dosage ranges of the active component are 0.01 mg to 100 mg per kg of body weight of the animal. Preferably, the range is from 0.1 mg to 10 mg per kg. The compositions are preferably formulated in a unit dosage form, wherein each dose contains about 1 mg to 500 mg, more usually about 5 mg to 300 mg, of the active component. The term "unit dosage form" refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier. . In any case, the veterinarian, or the expert person, will be able to determine the actual dose that will be most suitable for an individual patient, which may vary with the species, age, weight and response of the particular patient. The above doses are exemplary of the average case; of course, they may be individual examples where higher or lower dosage ranges are advantageous, and such are within the scope of the invention. For veterinary use, the compounds of the invention are of particular importance for treating 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 feed and for this purpose a concentrated feed additive or a premix can be prepared to mix it with the animal's usual feed. For human use, the compounds are administered as a pharmaceutical formulation containing the active component together with a pharmaceutically acceptable diluent or carrier. Such compositions include conventional preparations of tablets, capsules and ointments that are formulated in accordance with conventional pharmaceutical practice. The compounds of the invention can be administered either alone or in combination with one or more agents used in the treatment or prophylaxis of the disease or in the reduction or suppression of symptoms. Examples of such agents (which are provided by way of example and not to be construed as limiting) include antiparasitics, eg, fipronil, lufenuron, imidacloprid, avermectins (eg, 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, marbofloxacin, 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 of the above 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 as a single dose or on a "as required" basis (i.e., as needed or desired). Thus, according to a further aspect of the invention there is provided a pharmaceutical or veterinary formulation that includes a compound of the invention mixed 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, or may be metabolized to form compounds that may be more effective, be less toxic, have a wider range of activity. , be more potent, produce fewer side effects, be more easily absorbed or may have other useful pharmacological properties over the compounds known in the prior art. The biological activity of the compounds of the present invention was determined by the following test procedure.

Biological Test The compounds of the invention are evaluated for their activity as antipruritic agents by measuring their ability to inhibit the scratching behavior of the hind legs, induced in rats by the administration of a known pruritogenic agent. These studies are based on the procedure described by Berendsen and Broekkamp in European Journal of Pharmacology, 1991, 194, 201. The assay is carried out as follows: Wistar male rats (approximately 150 g of body weight) with a pruritogen by subcutaneous injection of 5-methoxytryptamine hydrochloride (4 mg / 3 ml / kg) dissolved in physiological saline in the neck. With this dose you get a quantifiable and constant response of scratching on the hind legs that lasts 90 minutes. The test compound is administered to the test animals by subcutaneous injection into an aqueous micelle formulation. The test compound is prepared in the following manner. The compound is dissolved in a vehicle (% v / v composition: glycerol formal, 24, in 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 above vehicle to give the aqueous micelle formulation. The compounds may be administered before or after the test or may be administered at the same time as the pruritogenic test. After the pruritogenic test has been administered, the scratching of the hind paws is scored by each animal, recording the presence or absence of scratching during each 30-second interval as a score of 1 or 0, respectively. The score for each animal is totalized after 25 minutes (maximum score 50). The efficacy of the compounds is evaluated by their ability to significantly reduce the score in the treated groups compared to the control group. The invention is illustrated by the following Preparations and Examples in which the following abbreviations can be used: APCI = chemical ionization at atmospheric pressure br (in relation to NMR) = width Cl = chemical ionization DMF =? /,? / - dimethylformamide DMSO = dimethylsulfoxide d (in relation to time) = day d (relative to NMR) = doublet dd (relative to NMR) = doublet of doublets EtOAc = ethyl acetate EtOH = ethanol ESI = electrospray ionization h = hour (s) m (relative to NMR) = multiplet MeOH = methanol min = minute c (relative to NMR) = quadruplet s (relative to NMR) = singlet t (relative to NMR) = triplet td (relative to NMR) = triplet of doublets THF = tetrahydrofuran TSI = ionization by thermal spray When the reversed phase HPLC is mentioned in the text, the following 2 sets of conditions are used: Condition 1: A Phenomenex Magellen® column, 150 x 21 mm, packed with silica 5m Cie, eluting with a gradient of acetonitrile : 0.1 M aqueous ammonium acetate (30:70 to 95: 5 over 10 mins, flow rate 20 ml per minute). Condition 2: A Dynamax® column, 42 x 250 mm, packed with 8μc silica, eluting with acetonitrile: 0.1M aqueous ammonium acetate (30:70), at 45ml per minute.

In both cases, the combination and evaporation of the appropriate fractions, determined by analytical HPLC, provided the desired compounds as acetate salts. The analytical HPLC conditions used to underline the appropriate fractions were: Phenomenex Magellan® column, 4.6 x 150 mm, packed with 5μ silica, eluting with a gradient of acetonitrile: 0.1 M aqueous heptasulfonic acid (10:90 to 90 : 10 over 30 min, followed by an additional 10 min at 90:10) at 1 ml per minute. The furnace temperature of the column was 40 ° C, and ultraviolet detection of the components was performed at 220 nM. When column chromatography is mentioned, it usually refers to a glass column packed with silica gel (40-63 μm). Generally a pressure of about 165 kPa is applied, and the gross product ratio: silica gel required for purification is typically 50: 1. Alternatively, an lsolute® SPE column (solid phase extraction) or a Waters Sep-Pak® cartridge packaged with silica gel can be used at atmospheric pressure. The ratio of crude product to silica gel required for purification is typically 100: 1. Nuclear magnetic resonance (NMR) data were obtained using a Brucker AC3000, AM300 or AM 400 spectrometer, with chemical shifts (d) being observed, consistent with the proposed structures. The mass spectrum (MS) data were obtained on a Finnigan Mat spectrometer. TSQ 7000 or a Fisons Instruments Trio 1000 spectrometer. The calculated and observed ions given refer to the lower mass isotopic composition. HPLC means high performance liquid chromatography. Ambient temperature means 20 to 25 ° C.

EXAMPLES EXAMPLE 1 (±) -? / - Hexyl-frar7S-3,4-dimethyl-4- (4-bromo-3-hydroxyphenyl) piperidine Bromine (9 μl, 0.17 mmol) was added to a stirred solution of (±) -? / - hexyl-3-dimethyl-4- (3-hydroxyphenyl) piperidine (Preparation 7, 49 mg, 0.17 mmol) in acetic acid (1 ml) at 10 ° C . After 5 minutes, the reaction mixture was diluted with water (10 ml), adjusted to pH 9 with 2 / V sodium hydroxide, and then extracted with dichloromethane (3 x 10 ml). The combined extracts were washed with brine (15 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane. -ammonia 0.880 (10: 989: 1 to 20: 978: 2), giving the title compound as a yellow oil (53 mg). NMR (C? Dd, data selected from the free base): 0.82 (d, 3H), 0.86 (t, 3H), 1, 10 (s, 3H), 1, 16-1.28 (m, 6H), 1.33 (m, 1 H), 1.47 (m, 2H), 1.71 (m, 1 H), 2.12-2.43 (m, 6H), 2.69 (m, 1 H), 6.40 (dd, 1 H), 6.94 ( d, 1 H), 7.33 (d, 1 H) and 8.16 (br s, 1 H).

MS (APCI +): m / z [MH +] 368.2; C? 9H3oBrNO + H requires 368.2.

EXAMPLE 2 (±) -? -Hexyl-frans-3,4-dimethyl-4- (3-hydroxy-4-nitrophenyl) piperidine A solution of nitronium tetrafluoroborate (1.59 g, 12.0 mmol), in acetonitrile (15 ml), was added to a stirred solution of (±) -? / - hexyl-frans-3,4-dimethyl-4 - (3-hydroxyphenyl) pyridine (Preparation 7, 2.88 g, 9.96 mmol) in acetonitrile (85 ml) at 0 ° C. After 2 hours, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate (100 ml), and extracted with ethyl acetate (3 x 100 ml). The combined extracts were washed with brine (100 ml), dried (Na 2 S 4), filtered and concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with methanol-dichloromethane-hydroxide of ammonium (10: 489: 1), giving the title compound (1.07 g) as a yellow oil. NMR (C? Dd, data selected from the free base): 0.71 (d, 3H), 0.87 (t, 3H), 0.92 (s, 3H), 1, 02 (m, 1 H), 1, 23-1, 32 (m, 6H), 1, 42 (m, 2H), 1, 52 (m, 1 H), 1, 93 (m, 2H), 2.18 (m, 3H), 2.33 (m, 1 H), 2.55 (m, 1 H), 6.28 (dd, 1 H), 6.78 (d, 1 H), and 7.62 (d, 1 HOUR). MS (APCI +): m / z [MH +] 335.3; C19H30N2O3 + H requires 335.2.

EXAMPLE 3 (±) -? / - Hexyl-fra 7S-3,4-dimethyl-4- (2,4-dibromo-3-hydroxyphenylpiperidine) Isolation of the compound eluting more slowly from Example 1 gave the title compound (4 mg). NMR (CßDβ, data selected from the free base): 0.80 (d, 3H), 0.87 (t, 3H), 1, 08-1, 44 (m, 9H), 1, 36 (s, 3H), 2.04 (m, 1 H), 2.12-2, 25 (m, 4H), 2.43 (m, 1 H), 2.67 (m, 1 H), 2.99 (m, 1 H), 6.33 (d, 1 H), and 7, 05-7.11 (m, 1 H). MS (APCI +): m / z [MH +] 446.1; + H requires 446.1.

EXAMPLE 4 ±) - V-Hexyl-fra / 7s-3,4-dimethyl-4- (4-amino-3-hydroxyphenyl) piperidine Platinum (IV) oxide (9 mg, 0.039 mmol) was added to a solution of (±) -? / - hexyl-uraA7s-3,4-dimethyl-4- (3-hydroxy-4-nitrophenyl) piperidine ( Example 2, 644 mg, 1.93 mmol) in tetrahydrofuran (15 ml), and the reaction mixture was stirred at 345 kPa of hydrogen gas for 10 hours. The reaction mixture was purged with nitrogen, filtered under nitrogen, and the crude product was routinely employed directly in the subsequent reaction. The product can be purified, after concentration in vacuo, via silica gel chromatography, eluting with methanol-dichloromethane-ammonium hydroxide (10: 989: 1), giving the title compound as an air-sensitive oil. NMR (CßDβ, data selected from the free base): 0.86 (t, 3H), 0.97 (d, 3H), 1, 24-1, 32 (m, 9H), 1.45 (m , 3H), 1.81 (m, 1 H), 2.16-2.41 (m, 5H), 2.53 (m, 1 H), 2.78 (m, 1 H), 6.42. -6.46 (m, 2H) and 6.64 (dd, 1 H). MS (APCI +): m / z [MH +] 305.3; C19H32N2O + H requires 305.3.

EXAMPLE 5 f ±) -? / - Hexyl-frans-3,4-dimethyl-4-r3-hydroxy-4-f2-methylbutanoylphenpiperidine S-Butyl lithium (0.46 mL of 1.3 M in cyclohexane, 0.60 mmol) was added to a stirred solution of (±) -? / - hexyl-frans-3, 4-dimethyl-4- (3 -? / ',? / - d.ethylcarbamiloxyphenyl) piperidine (Preparation 4, 97 mg, 0.25 mmol) and? /, A /,? /',? / '- tetramethylethylenediamine (45 μl, 0.30 mmol) in tetrahydrofuran (2 ml) at -78 ° C, and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was diluted with water (25 ml) and extracted with dichloromethane (3 x 20 ml). The combined extracts were washed with brine (30 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane-ammonia. 0.880 (10: 989: 1 to 30: 969: 1), giving the title compound as a pale yellow oil (26 mg). NMR (CeD ?, data selected from the free base): 0.68 (t, 3H), 0.84-0.89 (m, 6H), 0.95 (d, 3H), 1, 12 ( s, 3H), 1, 18-1, 31 (m, 8H), 1, 42 (m, 2H), 1, 65-1, 74 (m, 2H), 2.01-2.41 (m, 6H), 2.63 (m, 1 H), 2.97 (m, 1 H), 6.64 (dd, 1 H), 7.04 (m, 1 H) and 7.36 (d, 1 H). MS (APCI +): m / z [MH +] 374.3; C24H39NO2 + H requires 374.3.

EXAMPLE 6 f ±) -? / - Hexyl-frans-3,4-dimethyl-4- (4-allyl-3-hydroxyphenipiperidine) Lithium aluminum hydride (0.5 ml of 1.0 M in tetrahydrofuran, 0.5 mmol) was added to a stirred solution of (±) -? / - hexy rar7S-3,4-dimethyl-4- (4 -alyl-3-α / ',? / - diethylcarbamyloxyphenyl) piperidine (Example 50, 0.107 g, 0.25 mmol) in tetrahydrofuran (2 ml) at 0 ° C, and the reaction mixture was allowed to warm to room temperature. After 4 hours, the reaction mixture was sequentially diluted with water (20 μl), 15% aqueous sodium hydroxide (20 μl) and water (60 μl), and then allowed to stir for 1 hour. The reaction mixture was filtered through Celite® with the aid of tetrahydrofuran, and concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane-0.880 ammonia (10%). : 989: 1 to 30: 969: 1), giving the title compound as a pale yellow oil (56 mg). NMR (C? Dβ, data selected from the free base): 0.85 (t, 3H), 0.90 (d, 3H), 1, 23 (s, 3H), 1, 23-1, 27 (m, 6H), 1, 47-1, 50 (m, 3H), 1, 82 (m, 1 H), 2.15-2.51 (m, 6H), 2.80 (m, 1 H) ), 3.38 (d, 2H), 5.00 (m, 2H), 5.98 (m, 1 H), 6.71-6.73 (m, 2H), and 7.03 (d, 1 HOUR).} MS (APCI +): m / z [MH +] 330.3; C22H35NO + H requires 330.2.

EXAMPLE 7 (±) -? / - Hexyl-frans-3,4-dimethyl-4- (3-hydroxy-4-methylphenyl) piperidine Lithium aluminum hydride (0.22 ml of 1.0 M in tetrahydrofuran, 0.22 mmol) was added to a stirred solution of (±) -? / - hexyl-trans-3,4-dimethyl-4- ( 3 -? / ', / V-diethylcarbamyloxy-4-methylphenyl) piperidine (Example 51, 45 mg, 0.11 mmol) in tetrahydrofuran (2 ml) at 0 ° C, and the reaction mixture was allowed to warm to room temperature . After 4 hours, the reaction mixture was sequentially diluted with water (8 μl), 15% aqueous sodium hydroxide (8 μl) and water (24 μl), and then allowed to stir for 0.5 hour. The reaction mixture was filtered through Celite® with the aid of tetrahydrofuran, and concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane-0.880 ammonia (10%). : 989: 1 to 30: 969: 1), giving the title compound as a pale yellow oil (20 mg). NMR (CßDβ, data selected from the free base): 0.85 (t, 3H), 0.93 (d, 3H), 1, 23-1, 29 (m, 6H), 1, 24 (s) , 3H), 1, 46-1, 50 (m, 3H), 1, 83 (m, 1H), 2.16-2.53 (m, 6H), 2.18 (s, 3H), 2, 80 (m, 1 H), 6.61 (d, 1H), 6.68 (dd, 1H) and 6.98 (d, 1 H). MS (APCI +): m / z [MH +] 304.3; C2H33NO + H requires 304.3.

EXAMPLE 8 (±) -? / - Hexyl-frans-3,4-dimethyl-4- (4-acetylamino-3-hydroxyphenyl) piperidine Acetic anhydride (34 μl, 0.36 mmol) was added to a stirred solution of (±) -? / - hexyl-trans-3,4-d, methyl-4- (4-amino-3-hydroxyphenyl) piperidine (Example 4, 0.100 g, 0.33 mmole) and pyridine (53 μl, 0.66 mmole) in tetrahydrofuran (3 ml). After 12 h, additional pyridine (27 μl, 0.33 mmole) and acetic anhydride (34 μl, 0.36 mmole). After an additional 12 h, the reaction mixture was diluted with aqueous sodium hydrogencarbonate (10 ml), and extracted with dichloromethane (3 x 10 ml). The combined extracts were washed with brine (20 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude product, which was dissolved in methanol and allowed to stir for 48 h. The reaction mixture was concentrated in vacuo, and purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane-0.880 ammonia (2: 97.8 0.2), giving the title compound as a yellow oil (42 mg). NMR (CβDe, data selected from the free base): 0.86 (t, 3H), 0.93 (d, 3H), 1, 19 (s, 3H), 1.21-1, 34 (m , 6H), 1.40-1.51 (m, 3H), 1.53 (s, 3H), 1.82 (m, 1 H), 2.12-2.47 (m, 6H), 2 , 71 (m, 1 H), 6.72 (dd, 1 H), 7.13 (d, 1 H), 7.28 (d, 1 H), 7.73 (s, 1 H). MS (APCI +): m / z [MH +] 347.3; C 21 H 34 N 2 O 2 + H requires 347.3.

EXAMPLE 9 (±) -? / - Hexyl-frans-3,4-dimethyl-4- (3-hydroxy-4-hydroxymethylphenipiperidine) Lithium aluminum hydride (0.36 ml of 1.0 M in tetrahydrofuran, 0.36 mmole) was added to a stirred solution of (±) - / V-hexyl-uraps-3,4-dimethyl-4- ( 3 -? / ',? /' - diethylcarbamyloxy-4-formylphenyl) piperidine (Example 55, 60 mg, 0.14 mmol) in tetrahydrofuran (2 ml) at 0 ° C, and the reaction mixture was allowed to warm to room temperature ambient. After 14 hours, the reaction mixture was sequentially diluted with water (20 μl), 15% aqueous sodium hydroxide (20 μl) and water (60 μl), and then allowed to stir for 0.5 hour. The reaction mixture was filtered through Celite® with the aid of tetrahydrofuran, and concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane-0.880 ammonia (20%). : 479: 1), giving the title compound as a pale yellow oil (37 mg). NMR (CßDβ, data selected from the free base): 0.84-0.89 (m, 6H), 1, 20 (s, 3H), 1, 23-1, 31 (m, 6H), 1 , 38-1, 44 (m, 3H), 1.80 (m, 1 H), 2.10-2.43 (m, 6H), 2.65 (m, 1 H), 3.29 (m , 1 H), 4.47 (s, 2H), 6.69 (dd, 1 H), 6.77 (d, 1 H) and 6.99 (d, 1 H). MS (APCI +): m / z [MH +] 320.2; C2? H33NO2 + H requires 320.3.

EXAMPLE 10 (± -? / - Hexyl-fra /? S-3,4-dimethyl-4- (3-hydroxy-4-trifluoromethanesulfonylaminophenihpiperidine Trifluoromethanesulfonic anhydride (95 μl, 0.56 mmol) was added to a stirred solution of (±) -? / - hexyl-trans-3,4-dimethyl-4- (3-hydroxy-4-aminophenyl) piperidine (Example 4 , 0.163 g, 0.54 mmol) and triethylamine (82 μl, 0.59 mmol) in dichloromethane (5 ml) at 0 ° C. After 2 hours, the reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate (10 ml), and extracted with dichloromethane (3 x 10 ml). The combined extracts were washed with brine (20 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane-ammonia. 0.880 (10: 489: 1 to 25: 474: 1), giving the title compound as a brown solid (53 mg). NMR (CD3OD, data selected from the free base): 0.77 (d, 3H), 0.93 (t, 3H), 1, 20 (s, 3H), 1, 20-1, 61 (m , 9H), 1, 93 (m, 1 H), 2.20 (m, 1 H), 2.49-2.94 (m, 6H), 6.60 (dd, 1 H), 6.87 (d, 1 H), and 7.51 (d, 1 H). MS (APCI +): m / z [MH +] 437.2; C2oH31F3N2? 3S + H requires 437.2.

EXAMPLE 11 f ±) -? / - Hexyl-trans-3,4-dimethyl-4-ethyl-3-hydroxyphenyl) piperidine Lithium aluminum hydride (0.57 mL of 1.0 M in tetrahydrofuran, 0.57 mmol) was added to a stirred solution of (±) -? / - hexyl-trans-3,4-dimethyl-4- ( 3 -? / ',? / - diethylcarbamyloxy-4-ethylphenyl) piperidine (Example 52, 94 mg, 0.23 mmol) in tetrahydrofuran (2.5 ml) at 0 ° C, and the reaction mixture was allowed to warm to room temperature. room temperature. After 14 hours, the reaction mixture was sequentially diluted with water (8 μl), 15% aqueous sodium hydroxide (8 μl) and water (24 μl), and then allowed to stir for 0.5 hour. The reaction mixture was filtered through Celite® with the aid of tetrahydrofuran, and concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane-0.880 ammonia (10%). : 989: 1 to 50: 949: 1), giving the title compound as a pale yellow oil (43 mg). NMR (CßDβ, data selected from the free base): 0.85 (t, 3H), 0.92 (d, 3H), 1, 18-1, 25 (m, 12H), 1, 46-1 , 51 (m, 3H), 1.84 (m, 1 H), 2.16-2.53 (m, 6H), 2.66 (m, 2H), 2.82 (m, 1H), 6 , 61 (d, 1H), 6.73 (dd, 1H) and 7.03 (d, 1 H). MS (APCI +): m / z [MH +] 318.3; C21H35NO + H requires 318.3.

EXAMPLE 12 (±) -? / - Hexyl-frans-3,4-d-methyl-4-r4- (2,2-dimethylpropane-ylamino) -3-hydroxyphenylpiperidine Trimethylacetyl chloride (55 μl, 0.45 mmol) was added in three equivalent portions to a stirred solution of (±) -? / - hexyl-frans-3,4-dimethyl-4- (3-hydroxy-4) -aminophenyl) piperidine (Example 4, 0.129 g, 0.42 mmol) and triethylamine (65 μl, 0.47 mmol) in dichloromethane (5 ml) at 0 ° C. Additional trimethylacetyl chloride was introduced after 1 hour (18 μl, 0.15 mmol), 2.5 hours (8 μl, 0.065 mmol). After an additional 1 hour, the reaction mixture was diluted with a saturated aqueous solution of sodium hydrogencarbonate (20 ml), and extracted with dichloromethane (3 x 20 ml). The combined extracts were washed with brine (20 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane-ammonia. 0.880 (10: 489: 1 to 15: 484: 1), giving the title compound as a pale yellow oil (77 mg, 47%). NMR (CD3OD, data selected from the free base): 0.77 (d, 3H), 0.88 (t, 3H), 1, 23-1, 38 (m, 9H), 1, 28 (s) , 9H), 1, 42-1, 61 (m, 3H), 1, 97 (m, 1 H), 2.20-2.62 (m, 6H), 2.78 (m, 1 H), 6.73 (m, 1 H), 6.81 (m, 1 H), and 7.69 (m, 1 H). MS (APCI +): m / z [MH +] 389.3; C 24 H 40 N 2 O 2 + H requires 389.3.

EXAMPLE 13 (±) -? / - Hexyl-frans-3,4-dimethyl-4-f3-hydroxy-4-methylaminomethylphenyl) piperidine Sodium triacetoxyborohydride (0.113 g, 0.53 mmol) was added to a stirred solution of (±) -? / - hexyl-trans-3,4-dimethyl-4- (4-formyl-3-hydroxyphenyl) piperidine (Example 34, 0.113 g, 0.36 mmol), methylamine (0.195 ml of 2.0 M in methanol, 0.39 mmol) and acetic acid (22.7 μl, 0.39 mmol) in 1,2-dichloroethane (2.5 ml). After 2.5 hours, the reaction mixture was diluted with a saturated aqueous solution of sodium hydrogencarbonate (25 ml), and extracted with dichloromethane (3 x 25 ml). The combined extracts were washed with brine (30 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane. -ammonia 0.880 (5: 494: 1 to 5: 444: 1), giving the title compound as a yellow oil (45 mg). NMR (CßDβ, data selected from the free base): 0.85 (t, 3H), 1, 00 (d, 3H), 1, 03-1, 31 (m, 6H), 1, 26 (s) , 3H), 1, 40-1, 45 (m, 3H), 1, 72 (s, 3H), 1, 77 (m, 1 H), 2.09-2.46 (m, 6H), 2 , 67 (m, 1 H), 3.32 (s, 2H), 6.73 (dd, 1 H), 6.80 (d, 1 H) and 7.12 (d, 1 H). MS (APCI +): m / z [MH +] 333.3; C2? H36N2O + H requires 333.3.

EXAMPLE 14 (±) -? / - Hexyl-frans-3,4-dimethyl-4- (4-ethylaminomethyl-3-hydroxyphenyl) pperidine Sodium triacetoxyborohydride (0.139 g, 0.66 mmol) was added to a stirred solution of (±) -? / - hexyl-frans-3,4-dimethyl-4- (4-formyl-3-hydroxyphenyl) piperidine (Example 34, 0.139 g, 0.44 mmol), ethylamine (0.241 mL of 2.0 M in methanol, 0.48 mmol) and acetic acid (28 μL, 0.48 mmol) in 1,2-dichloroethane (3 mM). ml). After 2.5 hours, the reaction mixture was diluted with a saturated aqueous solution of sodium hydrogencarbonate (25 ml), and extracted with dichloromethane (3 x 25 ml). The combined extracts were washed with brine (30 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane. -ammonia 0.880 (5: 494: 1 to 5: 444: 1), giving the title compound as a yellow oil (64 mg). NMR { C Dß, data selected from the free base): 0.59 (t, 3H), 0.84 (t, 3H), 1, 00 (d, 3H), 1, 16-1, 31 (m, 6H), 1, 27 (s, 3H), 1, 38-1, 45 (m, 3H), 1, 86 (m, 1 H), 2.04 (c, 2H), 2.10-2, 46 (m, 6H), 2.68 (m, 1 H), 3.41 (s, 2H), 6.74 (dd, 1 H), 6.82 (d, 1 H) and 7.12 ( d, 1 H). MS (APCI +): m / z [MH +] 347.3; C 22 H 38 N 2 O + H requires 347.3.

EXAMPLE 15 (±) -? -Hexyl-frans-3,4-dimethyl-4- (4-dimethylaminomethyl-3-hydroxy-phenylpiperidine) Sodium triacetoxyborohydride (0.101 g, 0.48 mmol) was added to a stirred solution of (±) -? / - hexyl-frans-3,4-dimethyl-4- (4-formyl-3-hyd roxyphene) piperid Na (Example 34, 0.101 g, 0.32 mmol), dimethylamine (0.175 mL of 2.0 M in methanol, 0.35 mmol) and acetic acid (20 μL, 0.35 mmol) in 1,2-dichloroethane (3 ml). After 2.5 hours, the reaction mixture was diluted with a saturated aqueous solution of sodium hydrogencarbonate (25 ml), and extracted with dichloromethane (3 x 25 ml). The combined extracts were washed with brine (30 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane. -ammonia 0.880 (5: 494: 1 to 25: 474: 1), giving the title compound as a yellow oil (54 mg). NMR (CßDe, data selected from the free base): 0.85 (t, 3H), 1, 00 (d, 3H), 1, 23-1, 29 (m, 6H), 1.26 (s) , 3H), 1.38-1.44 (m, 3H), 1.71 (s, 6H), 1.86 (m, 1 H), 2.12-2.43 (m, 6H), 2 , 66 (m, 1 H), 3.15 (s, 2H), 6.74 (dd, 1 H), 6.79 (d, 1 H) and 7.15 (d, 1 H). MS (APCI +): m / z [MH +] 347.3; C 22 H 38 N 2 O + H requires 347.3.

EXAMPLE 16 (±) -? / - Hexl-fra / 7s-3,4-dimethyl-4- (3-hydroxy-2-methylphenyl) piperidine The mixture was allowed to stir at room temperature for 1 hour at a mixture of (±) -? / - hexyl-rans-3, 4-dimethyl-4- (3-hydroxy-2-methyl-4-trimethylsilylphenyl) piperidine (Preparation 2, 51 mg, 0.11 mmol) and 20% aqueous hydrochloric acid (2.5 ml) . The reaction mixture was diluted with water (10 ml), adjusted to pH 9 with 5% sodium hydroxide, and extracted with dichloromethane (3 x 20 ml). The combined extracts were concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane-0.880 ammonia (5: 494: 1 to 15: 484: 1), giving the Compound the title as a yellow oil (27 mg). NMR (CdD ?, data selected from the free base): 0.85 (t, 3H), 0.92 (d, 3H), 1, 21 (s, 3H), 1, 21-1, 29 ( m, 6H), 1, 37-1, 44 (m, 3H), 1.83 (m, 1 H), 2.09-2.45 (m, 6H), 2.66 (m, 1 H) , 3.33 (s, 3H), 6.59 (dd, 1 H), 6.82 (d, 1 H), 6.95 (s, 1 H), and 7.10-7.14 (m) , 1 HOUR). MS (APCI +): m / z [MH +] 304.4; C20H33NO + H requires 304.3.

EXAMPLE 17 (±) -? / - Hexyl-frans-3,4-dimethyl-4- (3-hydroxy-4-methoxycarbonylphenyl) piperidine Sodium cyanide (26 mg, 0.53 mmol) and manganese (IV) oxide (0.291 g, 3.51 mmol) were added to a stirred solution of (±) -? / - hexyl-trans-3,4- dimethyl-4- (4-formyl-3-hydroxyphenyl) piperidine (Example 34, 93 mg, 0.29 mmol) and acetic acid (10 μl, 0.18 mmol) in methanol (10 ml). After 36 hours, the reaction mixture was filtered through Celite® with the help of methanol, and concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane -ammonia 0.880 (5: 494: 1 to 15: 484: 1), giving the title compound as a yellow oil (42 mg). NMR (C6D6, data selected from the free base): 0.84-0.88 (m, 6H), 1, 09 (s, 3H), 1, 21-1, 31 (m, 6H), 1 , 37-1, 42 (m, 3H), 1, 70 (m, 1 H), 1, 99-2.39 (m, 6H), 2.60 (m, 1 H), 3.28 (s) , 3H), 6.63 (dd, 1 H), 7.03 (d, 1 H), and 7.72 (d, 1 H). MS (APCI +): m / z [MH +] 348.3; C22H33NO3 + H requires 348.3.

EXAMPLE 18 (±) -? -Hexi-frans-3,4-dimethyl-4- (4-ethoxycarbonyl-3-hydroxyphenyl) piperidine Sodium cyanide (26 mg, 0.53 mmol) and manganese (IV) oxide (0.291 g, 3.51 mmol) were added to a stirred solution of (±) -? / - hexyl-frans-3,4- dimethyl-4- (4-formyl-3-hydroxyphenyl) p.peridine (Example 34, 93 mg, 0.29 mmol) and acetic acid (10 μl, 0.18 mmol) in methanol (10 ml). After 36 hours, the reaction mixture was filtered through Celite® with the help of methanol, and concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane -ammonia 0.880 (5: 494: 1 to 15: 484: 1), giving the title compound as a yellow oil (48 mg). NMR (CßDβ, data selected from the free base): 0.84-0.89 (m, 9H), 1, 10 (s, 3H), 1, 22-1, 31 (m, 6H), 1 , 37-1, 44 (m, 3H), 1, 70 (m, 1 H), 1, 99-2.39 (m, 6H), 2.60 (m, 1 H), 3.92 (c , 2H), 6.65 (dd, 1 H), 7.04 (d, 1 H), and 7.77 (d, 1 H). MS (APCI +): m / z [MH +] 362.3; C22H35NO3 + H requires 362.3.

EXAMPLE 19 (±) -? -Hexyl-frans-3,4-dimethyl-4- (4 -? / '- methylaminocarbonyl-3-hydroxy-phenyl-piperidine A stirred solution of (±) -? / - hexyl-fra 7s-3,4-dimethyl-4- (S -? / '.? /' - diethylcarbamilox -? / '- methylaminocarbonifeni piperidine was treated (Example 53, 0.163 g, 0.37 mmol), in methanol (2.5 ml), with methylamine (5.5 ml of 2.0 M in methanol, 11 mmol) After 24 hours, the reaction mixture was concentrated in vacuo giving the crude product, which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane-0.880 ammonia (5: 494: 1 to 15: 484: 1), giving the title compound as a pale yellow oil ( 28 mg). NMR (CßDβ, data selected from the free base): 0.86 (t, 3H), 0.91 (d, 3H), 1.15 (s, 3H), 1, 25-1 , 32 (m, 6H), 1, 39-1.44 (m, 3H), 1.76 (m, 1 H), 2.04-2.40 (m, 9H), 2.64 (m, 1H), 5.31 (br s, 3H), 6.61 (dd, 1 H), 6.69 (d, 1 H), and 7.07 (d, 1 H) .MS (APCI +): m / z [MH +] 347.3; C2iH34N2? 2 + H requires 347.3.

EXAMPLE 20 (±) -? -Hexyl-frafis-3,4-dimethyl-4- (4 -? / ',?' -dimethylaminocarbonyl-3-hydroxy-phenylpiperidine S-butyl lithium (0.6 ml of 1.3 M in cyclohexane, 0.78 mmol) was added to a stirred solution of (±) -? / - hexyl-1/3-dimethyl -4- (3 -? / ',? / - dimethylcarbamioxyphenyl) piperidine (Preparation 5, 0.285 g, 0.71 mmol) and? /,? /,? /',? / - tetramethylethylenediamine (0.118 ml) , 0.78 mmol) in tetrahydrofuran (5 ml) at -78 ° C, and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was diluted with water (25 ml), and extracted with ethyl acetate (3 x 25 ml). The combined extracts were washed with brine (30 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude product which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane-0.880 ammonia. (10: 989: 1 to 30: 969: 1), giving the title compound as a yellow oil (65 mg). NMR (CßDβ, data selected from the free base): 0.86 (t, 3H), 0.92 (d, 3H), 1.17 (s, 3H), 1, 21-1, 34 (m, 7H), 1.42 (m, 2H), 1.78 (m, 1 H), 2.05-2.33 (m, 6H), 2.43 (s, 6H), 2.64 (m, 1 H), 6.61 (dd, 1 H), 6.96 (m , 1 H), and 7.13 (m, 1 H).

MS (APCI +): m / z [MH +] 361.3; C 24 H 36 N 2 O 2 + H requires 361, 3.

EXAMPLE 21 (±) -? / - Hexyl-frans-3,4-dlmethyl-4- (4 -? / ',? /' - diethylaminocarbonyl-3-hydroxyphenyl) piperidine S-Butyl lithium (0.238 ml of 1.3 M in cyclohexane, 0.31 mmol) was added to a stirred solution of (±) -? / - hexyl-frans-3,4-dimethyl-4- (3-? / ',? / - diethylcarbamyloxyphenyl) piperidine (Preparation 4, 0.109 g, 0.28 mmol) and? /,? /,? /',? / '- tetramethylethylenediamine (47 μl, 0.31 mmol) in tetrahydrofuran (5). ml) at -78 ° C, and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was diluted with water (25 ml), and extracted with ethyl acetate (3 x 25 ml). The combined extracts were washed with brine (30 ml), dried over Na 2 S 4, filtered and concentrated in vacuo to give the crude product which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane. ammonia 0.880 (10: 989: 1 to 30: 969: 1), giving the title compound as a yellow oil (38 mg). NMR (CßDβ, data selected from the free base): 0.80 (t, 6H), 0.86 (t, 3H), 0.93 (d, 3H), 1, 18 (s, 3H), 1.24-1.34 (m, 7H), 1.41 (m, 2H), 1.77 (m, 1 H), 2.05-2.43 (m, 6H), 2.65 (m , 1 H), 3.00 (c, 4H), 6.62 (dd, 1 H), 7.06 (d, 1 H), and 7.16 (d, 1 H). MS (APCf): m / z [MH +] 389.3; C 24 H 40 N 2 O 2 + H requires 389.3.

EXAMPLE 22 (±) -? / - Hexyl-frans-3,4-dimethyl-4-f3-hydroxy-4-propionylaminophenyl) piperidine Propionyl chloride (0.109 mL, 1.25 mmol) was added to a stirred solution of (±) -? / - hexyl-ia 7s-3,4-dimethyl-4- (4-amino-3-hydroxyphenyl) piperidine (Example 4, 0.185 g, 0.61 mmol) and pyridine (0.108 mL, 1.28 mmol) in tetrahydrofuran (8 ml) at 0 ° C, and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was again cooled to 0 ° C, and additional pyridine (54 μl, 0.64 mmol) and propionyl chloride (25 μl, 0.31 mmol) was introduced. After an additional 4 hours, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate (10 ml), and extracted with dichloromethane (3 x 10 ml). The combined extracts were washed with brine (20 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane. -ammonia 0.880 (10: 989: 1 to 30: 967: 3), giving the title compound as a pale yellow oil (38 mg). NMR (CßDe, data selected from the free base): 0.84-0.90 (m, 6H), 0.93 (d, 3H), 1, 22 (s, 3H), 1, 22-1 , 29 (m, 6H), 1, 39-1, 46 (m, 3H), 1.75 (c, 2H), 1.81 (m, 1 H), 2.11-2.47 (m, 6H), 2.69 (m, 1 H), 6.72 (dd, 1 H), 7.12-7.17 (m, 2H), and 7.38 (m, 1 H). MS (APCI +): m / z [MH +] 361.4; C 22 H 36 N 2 O 2 + H requires 361, 3.

EXAMPLE 23 (±) -? -Hexyl-frans-3,4-dimethyl-4- (4 -? / ',? /' - dimethylaminocarbonyl-3-hydroxyphenyl) piperidine Dimethylcarbamyl chloride (0.12 ml, 1.3 mmol) was added to a stirred solution of (±) -? / - hexyl-frans-3,4-dimethyl-4- (4-amino-3-hydroxyphenyl) ) piperidine (Example 4, 0.189 g, 0.62 mmol) and pyridine (5 ml) at 0 ° C, and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate (10 ml), and extracted with dichloromethane (3 x 10 ml). The combined extracts were washed with brine (20 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane. -ammonia 0.880 (10: 989: 1 to 40: 969: 3), giving the title compound as a pale yellow oil (52 mg). NMR (CßDβ, data selected from the free base): 0.85 (t, 3H), 0.97 (d, 3H), 1, 22 (s, 3H), 1, 22-1, 25 (m , 6H), 1, 38-1, 41 (m, 3H), 1.80 (m, 1 H), 2.11-2.43 (m, 6H), 2.48 (s, 3H), 2 , 54 (s, 3H), 2.65 (m, 1 H), 3.18 (s, 1 H), 6.46 (m, 1 H), 6.86 (m, 1 H), and 7 , 15 (m, 1 H). MS (APCI +): m / z [MH +] 376.3; C 22 H 37 N 3 O 2 + H requires 376.3.

EXAMPLE 24 (±) -? -Hexyl-frans-3,4-dimethyl-4- (3-hydroxy-4 -? / '- methylaminocarbonylaminophenpipiidine) Methyl isocyanate (58 μL, 0.98 mmol) was added to a stirred solution of (±) -? / - hexyl-uraps-3,4-dimethyl-4- (4-amino-3-hydroxyphenyl) piperidine (Example 4, 0.283 g, 0.93 mmol) and pyridine (0.23 ml, 2.9 mmol) in tetrahydrofuran (8 ml) at 0 ° C, and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate (10 ml), and extracted with dichloromethane (3 x 10 ml). The combined extracts were washed with brine (20 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with a gradient of ethyl acetate-dichloromethane. (10:90 to 60:40), giving the title compound as a pale yellow oil (28 mg). NMR (CeDβ, data selected from the free base): 0.87 (t, 3H), 0.93 (d, 3H), 1, 24 (s, 3H), 1, 24-1, 31 (m , 6H), 1, 42-1, 51 (m, 3H), 1.87 (m, 1 H), 2.24-2.51 (m, 6H), 2.46 (s, 3H), 2 , 74 (m, 1 H), 5.69 (br s, 1 H), 6.70 (m, 1 H), 7.10-7.12 (m, 1 H), 7.32 (m, 1 H), and 7.74 (br s, 1 H). MS (APCI +): m / z [MH +] 362.3; C2? H35N3O2 + H requires 362.3.

EXAMPLE 25 (±) -? / - Hexyl-ans-3,4-dimethyl-4- (3-hydroxy-4-methoxycarbonylaminophenidepiperidine Methyl chloroformate (50 μl, 0.66 mmol) was added to a stirred solution of (±) -? / - hexyl-uraps-3,4-dimethyl-4- (4-amino-3-hydroxyphenyl) piperidine (Example 4, 0.183 g, 0.60 mmol) in tetrahydrofuran (10 ml). After 6 hours, the reaction mixture was diluted with water (20 ml), and extracted with ethyl acetate (3 x 20 ml). The combined extracts were washed with brine (20 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with a gradient of ethyl acetate. -dichloromethane-ammonia 0.880 (150: 349: 1 to 200: 299: 1), giving the title compound as a pale yellow oil (44 mg). NMR (CßDβ, data selected from the free base): 0.83-0.86 (m, 6H), 1.17 (s, 3H), 1, 21-1, 34 (m, 6H), 1 , 37-1, 45 (m, 3H), 1, 74 (m, 1 H), 2.08-2.43 (m, 6H), 2.70 (m, 1H), 3.25 (s, 3H), 6.66 (m, 1 H), 6.77 (br s, 1 H), 6.93 (s, 1 H), and 7.45 (m, 1 H). MS (APCI +): m / z [MH +] 363.4; C2? H34N2O3 + H requires 363.3.

EXAMPLE 26 (±) -? -Hexyl-frans-3,4-dimethyl-4- (4-formylamino-3-aminophenyl) piperidine Pyridine (55 μL, 0.69 mmol) was added to a stirred solution of formic acid (26 μL, 0.69 mmol) and acetyl chloride (49 μL, 0.69 mmol) in tetrahydrofuran (5 mL) at 0 °. C. After 0.5 hours, a solution of (±) -W-hexyl-frans-3,4-dimethyl-4- (4-amino-3-hydroxyphenyl) piperidine () was added to the reaction vessel. Example 4, 0.200 g, 0.66 mmol) and pyridine (55 μl, 0.69 mmol) in tetrahydrofuran (5 ml). After a further 4 hours, the reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate (20 ml), and extracted with dichloromethane (3 x 20 ml). The combined extracts were washed with brine (20 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with a gradient of ethyl acetate-dichloromethane. -ammonia 0.880 (150: 349: 12), giving the title compound as a pale yellow oil (22 mg). NMR (CßDβ, data selected from the free base): 0.82-0.88 (m, 6H), 1, 16 (s, 3H), 1, 21-1, 33 (m, 6H), 1 , 36-1, 42 (m, 3H), 1, 76 (m, 1 H), 2.10-2.45 (m, 6H), 2.68 (m, 1 H), 6.65 (m , 1 H), 7.06-7.10 (m, 1 H), 7.21 (m, 1 H), 7.55 (s, 1 H), and 8.46 (br s, 1 H) . MS (APCI +): m / z [MH +] 333.4; C20H32N2O2 + H requires 333.3.

EXAMPLE 27 (±) -? -Hexyl-frans-3,4-dimethyl-4- (4-? ',? /' - dimethylaminosulfonylamino-3-hydroxypheni-piperidine Dimethylsulfamyl chloride (0.144 ml, 1.34 mmol) was added to a stirred solution of (±) -A / -hexyl-f? Aps-3,4-dimethyl-4- (4-amino-3-hydroxyphenyl) piperidine (Example 4, 0.194 g, 0.64 mmol) and pyridine (0.108 mL, 1.34 mmol) in tetrahydrofuran (10 mL). The reaction was then heated to reflux overnight. Upon cooling, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate (20 ml), and extracted with dichloromethane (3 x 20 ml). The combined extracts were washed with brine (20 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with a gradient of ethyl acetate. -dichloromethane-ammonia 0.880 (150: 349: 1 to 200: 299: 1), giving the title compound as a pale yellow oil (77 mg). NMR (CßDβ, data selected from the free base): 0.81 (d, 3H), 0.87 (t, 3H), 1, 18 (s, 3H), 1, 23-1, 27 (m , 6H), 1, 38-1, 49 (m, 3H), 1.80 (m, 1 H), 2.18-2.44 (m, 6H), 2.51 (s, 6H), 2 , 83 (m, 1 H), 6.62 (m, 1 H), 6.97 (s, 1 H), 7.56 (d, 1 H), and 7.82 (br s, 1 H) . MS (APCI +): m / z [MH +] 412.2; C 21 H 37 N 3 O 3 S + H requires 412.3.

EXAMPLE 28 (±) -? -Hexyl-frans-3,4-dimethyl-4- (3-hydroxy-4-pentanoylaminophenyl) pperiodine Valeryl chloride (63 μl, 0.53 mmol) was added to a stirred solution of (±) -? / - hexyl-frans-3,4-dimethyl-4- (4-amino-3-hydroxyphenyl) piperidine (Example 4, 0.155 g, 0.51 mmol) and pyridine (43 μL, 0.53 mmol) in tetrahydrofuran (5 mL) at 0 ° C. After 2 hours, the reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate (10 ml), and extracted with dichloromethane (3 x 10 ml). The combined extracts were washed with brine (20 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane. -ammonia 0.880 (10: 989: 1 to 30: 967: 3), giving the title compound as a pale yellow oil (96 mg). NMR (CßDβ, data selected from the free base): 0.72 (t, 3H), 0.85 (t, 3H), 0.93 (d, 3H), 1, 07-1, 16 (m, 2H), 1, 22 (s, 3H), 1, 22-1, 25 (m, 6H), 1, 42-1, 50 (m, 5H), 1, 83 (m, 1 H), 1, 90-1, 94 (m, 2H), 2.14-2.48 ( m, 6H), 2.71 (m, 1 H), 6.73 (dd, 1 H), 7.10-7.12 (m, 1H), 7.46 (d, 1 H) and 7, 98 (s, 1 H). MS (APCI +): m / z [MH +] 389.3; C 24 H 40 N 2 O 2 + H requires 389.3.

EXAMPLE 29 (±) -? / - Hexyl-frans-3,4-dimethyl "4- (2,4-dichloro-3-hydroxyphenyl) piperidine A solution of chlorine (324 mg, 4.56 mmol) in acetic acid (6 ml) was added dropwise to a solution of (±) -? / - hexyl-fraps-3,4-dimethyl-4- (3 -hydroxyphenyl) piperidine (Preparation 7, 662 mg, 2.28 mmol) in acetic acid (20 ml). The reaction was followed by mass spectrometry to control the formation of the title compound, as well as the loss of starting material and monochlorinated product. The acetic acid was then removed in vacuo, and the residue was washed with saturated aqueous sodium hydrogencarbonate and extracted with dichloromethane. The solvent was removed in vacuo, and the residue was purified by preparative silica thin layer chromatography, eluting with hexane-ethyl acetate (2: 1), to give the title compound (150 mg) from the band advances faster NMR (CDCI3, data selected from the free base): 0.77 (d, 3H), 0.88 (t, 3H), 1, 28 (s, 3H), 6.83 (d, 1 H), and 7.20 (d, 1 H). MS (APCI +): m / z [MH +] 358.4; C19H29Cl2NO + H requires 358.2.

EXAMPLE 30 f ±) -? / - Hexyl-frans-3,4-d-methyl-r3-hydroxy ^ 4- (2-methylpropionamino) phenypiperidine Isobutyryl chloride (68 μl, 0.65 mmol) was added to a stirred solution of (±) - / V-hexyl-frans-3,4-dimethyl-4- (4-amino-3-hydroxyphenyl) piperidine (Example 4, 0.188 g, 0.62 mmol) and pyridine (52 μl, 0.65 mmol) in tetrahydrofuran (10 ml) at 0 ° C. After 1.5 hours, the reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate (10 ml), and extracted with dichloromethane (3 x 10 ml). The combined extracts were washed with brine (20 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane. -ammonia 0.880 (10: 989: 1 to 30: 967: 3), giving the title compound as a pale yellow oil (0.112 g). NMR (CßDβ, data selected from the free base): 0.85 (t, 3H), 0.91 (d, 3H), 0.95 (d, 6H), 1, 21 (s, 3H), 1, 21-1, 27 (m, 6H), 1, 40-1, 45 (m, 3H), 1.81 (m, 1 H), 2.02 (m, 1 H), 2.12- 2.46 (m, 6H), 2.70 (m, 1 H), 6.70 (dd, 1 H), 7.09-7.10 (m, 1 H), 7.43 (d, 1 H) and 7.81 (s, 1 H). MS (APCI +): m / z [MH +] 375.3; C23H38N2O2 + H requires 375.3.

EXAMPLE 31 (±) -? -Hexyl-fra / 7S-3,4-dimethyl-4-r3-hydroxy-4- (2-methylbutanoyl) pheninpiperidine Isovaleryl chloride (77 μl, 0.63 mmol) was added to a stirred solution of (±) -? / - hexyl-frans-3,4-dimethyl-4- (4-amino-3-hydroxyphenyl) ) piperidine (Example 4, 0.183 g, 0.60 mmol) and pyridine (51 μl, 0.63 mmol) in tetrahydrofuran (5 ml) at 0 ° C. After 2.5 hours, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate (10 ml), and extracted with dichloromethane (3 x 15 ml). The combined extracts were washed with saturated aqueous sodium hydrogencarbonate (10 ml) and brine (15 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane-0.880 ammonia (10: 489: 1) to give the compound of the title as a pale yellow oil (0.100 g). NMR { CeDe, data selected from the free base): 0.76 (d, 6H), 0.85 (t, 3H), 0.92 (d, 3H), 1, 22 (s, 3H), 1, 22-1, 28 (m, 6H), 1, 40-1, 46 (m, 3H), 1, 79-1, 83 (m, 3H), 2.02-2.09 (m, 1 H), 2.13-2.47 (m, 6H), 2.70 ( m, 1 H), 6.72 (dd, 1 H), 7.09-7.11 (m, 1 H), 7.46 (d, 1 H) and 7.94 (s, 1 H). MS (APCI +): m / z [MH +] 389.4; C24H4oN2? 2 + H requires 389.3.

EXAMPLE 32 (±) -? / - HTXII-fraps-3,4-dimethyl-4- (3-hydroxy-4-butanoylaminophenyl) piperidine Butyryl chloride (67 μl, 0.65 mmol) was added to a stirred solution of (±) -? / - hexyl-frans-3,4-dimethyl-4- (4-amino-3-hydroxyphenyl) piperidine (Example 4, 0.188 g, 0.62 mmol) and pyridine (52 μl, 0.65 mmol) in tetrahydrofuran (10 ml) at 0 ° C. After 2.5 hours, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate (10 ml), and extracted with diclonemethane (3 x 15 ml). The combined extracts were washed with saturated aqueous sodium hydrogencarbonate (10 ml) and brine (15 ml), dried over Ma2SO, filtered and concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane-0.880 ammonia (10: 489: 1 to 15: 484: 1), giving the title compound as a pale yellow oil (0.104 g). NMR (ßDβ, data selected from the free base): 0.68 (t, 3H), 0.85 (t, 3H), 0.93 (d, 3H), 1, 21 (s, 3H), 1, 23-1, 30 (m, 6H), 1, 37-1, 47 (m, 5H), 1, 68-1, 72 (m, 2H), 1.80 (m, 1 H), 2.10-2.46 (m, 6H), 2.68 (m, 1 H) ), 6.72 (dd, 1 H), 7.04 (d, 1 H), and 7.09-7.20 (m, 2H). MS (AF> CI +): m / z [MH +] 375.3; C23H38N2O2 + H requires 375.3.

EXAMPLE 33 i? L? -Hexyl-frans-3,4-dimethyl-4- (3-hydroxy-4-methanesulfonylaminophenyl) piperidine Methanesulfonyl chloride (34 μL, 0.45 mmol) was added to a stirred solution of (±) -? / - hexyl-trans-3,4-dimethyl-4- (3-hydroxy-4-aminophenyl) piperidine (Example 4, 0.129 g, 0.42 mmol) and pyridine (38 μl, 0.47 mmol) in dichloromethane (5 ml) at 0 ° C. Additional methanesulfonyl chloride was introduced at 0.5 hours (12 μl, 0.16 mmol), 1 hour (12 μl, 0.16 mmol), 3 hours (10 μl, 0.13 mmol, and 4 hours (6 μl, 0.8 mmol), and the reaction mixture was allowed to warm to room temperature while stirring overnight.The reaction mixture was diluted with sodium hydrogen carbonate. saturated aqueous (10 ml), and extracted with dichloromethane (3 x 10 ml) The combined extracts were washed with brine (20 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane-ammon 0.880 (10: 489: 1 to 15: 484: 1), to give the title compound as a brown solid. mg). NMR (C? Dβ, data selected from the free base): 0.82 (d, 3H), 0.87 (t, 3H), 1, 3 (s, 3H), 1, 26-1, 28 (m, 6H), 1, 44-1, 49 (m, 3H), 1, 78 (m, 1 H), 2.15-2.52 (m, 6H), 2.44 (s, 3H), 2.81 (m, 1 H), 6.38 (br s, 2H), 6 , 63 (m, 1 H), 6.98 (m, 1 H) and 7.39 (ihn, 1 H). MS (CI CI +): m / z [MH +] 383.2; C2oH34N2O3S + H requires 383.2.

EXAMPLE 34 (±) -? -Hexi-frans-3,4-dimethyl-4- (4-formyl-3-hydroxyphenyl) piperidine S-Butyl lithium (1.18 mL of 1.3 M in cyclohexane, 1.53 mmol) was added to a stirred solution of (±) -? / - hexyl-fraps-3,4-dimethyl-4- (3 -? / ',? / - diethylcarbamyloxyphenyl) piperidine (Preparation 4, 0.495 g, 1.27 mmoles) and ? /,? /,? / ',? /' - tetramethyl-ethylenediamine (0.231 ml, 1.53 mmol), in tetrahydrofuran (5 ml) at -78 ° C. After 1 hour, DMF (0.493 ml, 6.37 mmol) was added, and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate (25 ml), and extracted with dichloromethane (3 x 30 ml). The combined extracts were washed with brine (15 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane-ammonia. 0.880 (2: 197: 1 to 4: 195: 1), giving the title compound as a pale yellow oil (0.308 g). NMR (CßDβ, data selected from the free base): 0.79 (d, 3H), 0.86 (t, 3H), 1, 04 (s, 3H), 1, 16-1, 33 (m , 6H), 1, 38-1, 42 (m, 3H), 1, 66 (m, 1 H), 1, 99-2.39 (m, 6H), 2.59 (m, 1 H), 6.57 (dd, 1 H), 6.78 (d, 1 H), 6.88 (d, 1 H) and 9.25 (s, 1 H). MS (APCI +): m / z [MH +] 318.2; C20H31NO2 + H requires 318.2.

EXAMPLE 35 (±) -? -Hexyl-frans-3,4-dimethyl-4- (3-hydroxy-2,4,6-trichlorophenyl) piperidine A solution of chlorine (98 mg, 1.38 mmol) in acetic acid (1 ml) was added dropwise to a solution of (±) -A / -hexyl-f? Ans-3,4-dimethyl-4- (3-hydroxyphenyl) piperidine (Preparation 7, 100 mg, 0.345 mmol) in acetic acid (2 ml). The reaction was followed by mass spectrometry to control the formation of the title compound. The acetic acid was then removed under vacuum and the residue was washed with saturated sodium hydrogencarbonate solution, and the solution was then extracted with dichloromethane. The solvent was removed in vacuo, and the residue was chromatographed on Merck silica gel 230-400 mesh, eluting with ethyl acetate-hexane (1: 25), to give the title compound (18 mg). NMR (CDC, data selected from the free base): 0.80 (d, 3H), 0.88 (t, 3H), 1.29 (s, 3H), and 7.15 (s, 1 H) ). MS (APCI +): m / z [MH +] 392.1; C19H28Cl3NO + H requires 392.1.

EXAMPLE 36 (±) -? / - Hexyl-fra / 7S-3,4-dimethyl-4-f3-aminosulfonyl-3-hydroxyphenyl) piperidine A solution of (±) -? / - hexyl-uraps-3,4-dimethyl-4- (3-γ / ω, ω-diethylcarbamyloxyphenyl) piperidine was cooled to 0 ° C (Preparation 4, 200 mg, , 51 mmol) in chlorosulfonic acid (0.5 ml), before thionyl chloride (0.2 ml) was added, and the mixture was stirred at room temperature overnight. A mixture of ice and water (50:50, 10 ml) was added to the reaction mixture, and the resulting creamy precipitate was filtered off and dried in vacuo. This crude intermediate (0.10 g, 0.20 mmol) was dissolved in methylamine (5 mL of 2 M in tetrahydrofuran, excess), and the reaction mixture was stirred overnight. The solvents were removed in vacuo, and the residue was chromatographed on silica gel, eluting with methanol and dichloromethane (5:95), giving the product as a white powder (25 mg). NMR (DMSO, data selected from the free base): 0.7 (d, 3H), 0.85 (t, 3H), 1, 2-1, 4 (m, 10H), 2.45 (s) , 3H), 6.6 (s, 1 H), 6.75 (d, 1 H), 7.4 (d, 1 H) and 10.5 (s, 1 H). MS (APCI +): m / z [MH +] 383.3; C2oH34N2O3S + H requires 383.2.

EXAMPLE 37 (±) -? / - Hexyl-7s-3,4-dimethyl-4- (4,6-dichloro-3-hydroxyphenyl) piperidine Isolation of the compound proceeding more slowly, from Example 29, followed by thin layer chromatography of silica preparation, eluting with hexane-ethyl acetate (2: 1), gave the title compound (56 mg). NMR (CDCI3, data selected from the free base): 0.75 (d, 3H), 0.91 (t, 3H), 1.32 (s, 3H), 6.95 (s, 1 H) , and 7.28 (s, 1 H). MS (APCf): m / z [MH +] 358.3; C19H29Cl2NO + H requires 358.2.

EXAMPLE 38 (±) -? / - Hexyl-fra /? S-3,4-dimethyl-4- 3-hydroxy-4 -? / '- isopropylaminocarbonyl phenypiperidine It was heated at 100 ° C overnight, in a Wheaton vial, a solution of (±) -? / - hexyl-fraps-3,4-dimethyl-4- (3-hydroxy-4-methoxycarbonylphenyl) piperidine (Example 17 , 20 mg, 0.055 mmol) in isopropylamine (5 ml). The solution was then cooled and evaporated to dryness in vacuo to give the desired product (20 mg) as a colorless oil. NMR (CDCI3, data selected from the free base): 0.95 (d, 3H), 1, 30 (d, 6H), 1, 33 (s, 3H), 4.28 (m, 1 H), 6.22 (br s, 1 H), 6.75 (d , 1 H), 6.85 (s, 1 H), and 7.35 (d, 1 H). MS (Cl +): m / z [MH +] 375.3; C23H38N2O2 + H requires 375.6.

EXAMPLE 39 (±) -? -Hexyl-frans-3,4-dimethyl-4- (4-chloro-3-hydroxyphenyl) piperidine Isolation of the compound proceeding more slowly, a * from Example 29, followed by preparative HPLC, eluting with 0.05 M aqueous ammonium acetate-methanol (3: 7), gave the title compound (10 mg) as its acetate salt. NMR (CDCI3, data selected from the free base): 0.88 (d, 3H), 0.92 (t, 3H), 1.31 (s, 3H), 6.77 (d, 1 H) , 6.97 (s, 1 H), and 7.23 (d, 1 H).

MS (APCI +): m / z [MH +] 324.0; C19H30CINO + H requires 324.2.

EXAMPLE 40 (±) -? / - Hexyl-frans-3,4-dimethyl-4- (6-chloro-3-hydroxyphenylpiperidine A solution of chlorine (36 mg, 0.510 mmol) in acetic acid (0.degree., 5 ml) to a solution of (±) -? / - hexyl-trans-3,4-dimethyl-4- (3-triisopropylsilyloxyphenyl) piperidine (Preparation 3, 151, 8 mg, 0.340 mmol) in acetic acid (2 ml). The reaction was followed by mass spectrometry to control the loss of starting material, and the acetic acid was removed under vacuum, the residue was washed with saturated sodium hydrogencarbonate solution, and then extracted with dichloromethane. The dichloromethane was removed in vacuo, the residue was dissolved in tetrahydrofuran (3 ml), and stirred overnight with a solution of tetrabutylammonium fluoride (0.66 ml of 1 M in tetrahydrofuran, 0.66 mmol). The reaction mixture was washed with saturated sodium hydrogencarbonate solution, the solvents were removed in vacuo, and the solid mixture of monochlorophenols was purified by preparative HPLC on a Beckmann Ultrasphere ™ column, 250 mm x 10 mm.; flow rate 20 ml min ", using UV detection at 220 nm, eluent methanol-aqueous ammonium acetate 0.05 M (30:70) to give the title compound (6 mg) as its acetate salt. NMR (CDCl 3, selected data from the free base): 0.84 (d, 3H), 0.91 (t, 3H), 1, 28 (s, 3H), 6.67 (d, 1 H), 6.90 (s , 1 H), and 7.13 (d, 1 H).

MS (APCI +): m / z [MH +] 323.9; C19H30CINO + H requires 324.2.

EXAMPLE 41 (±) -? / - HTXyl-fra / 7S-3,4-dimethyl-4- (4-aminocarbonyl-3-hydroxyphenyl) piperidine A solution of (±) -? / - hexyl-trans-3,4-dimethyl-4- (3-hydroxy-4-methoxycarbonylphenyl) piperidine (Example 17, 40 mg, 0.11 mmol) in 1,2-dioxane ammonia (4 ml of 0.5 M NH3, 2.0 mmol). The solution was heated at 100 ° C overnight in a Wheaton vial. Then the solution was cooled, evaporated to dryness in vacuo, and the crude residue was chromatographed on Merck silica gel 230-400 mesh (10 g), using hexane-ethyl acetate (1: 1) as eluent, giving an oil (30 mg). This oil was dissolved in dichloromethane (5 ml), and extracted into 2 / V hydrochloric acid (5 ml). The aqueous phase was then evaporated to dryness in vacuo to give the desired product (10 mg) as an oil. NMR (CD3OD, data selected from the free base): 0.85 (d, 3H), 1.33 (s, 3H), 6.82 (d, 1 H), 6.85 (s, 1 H) ), and 7.75 (d, 1 H). MS (Cl +): m / z [MH +] 333.5; C20H32N2O2 + H requires 333.5.

EXAMPLE 42 (±) -? / - Hexyl-fra / 7s-3,4-dimethyl-4- (4-fluoro-3-hydroxyphenyl) pyridine Lithium triethyl borohydride (0.82 ml of 1.0 M in tetrahydrofuran, 0.82 mmol) was added to a stirred solution of (±) -? / - hexyl-urans-3,4-dimethyl-4- (3 -? / ',? / - diethylthiocarbamyloxy-4-fluorophenyl) piperidine (Example 54, 35 mg, 0.08 mmol) in tetrahydrofuran (2.5 ml) at 0 ° C, and the reaction mixture was allowed to warm to room temperature ambient. After 72, 96 and 120 hours, lithium triethylborohydride (1.6 ml of 1.0 M in tetrahydrofuran, 1.6 mmol) was added and stirring was continued at reflux. After a further 24 hours, the reaction mixture was diluted with water (20 ml), and extracted with dichloromethane (3 x 20 ml). The combined extracts were dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude product which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane-0.880 ammonia (10: 989: 1 to 50: 949: 1), giving the title compound as a pale yellow oil (13 mg). NMR (CßDd, data selected from the free base): 0.83-0.86 (m, 6H), 1, 10 (s, 3H), 1, 18-1, 24 (m, 6H), 1 , 42-1, 46 (m, 3H), 1, 70 (m, 1 H), 2.07-2.44 (m, 6H), 2.67 (m, 1 H), 6.44 (m , 1 H), 6.80 (m, 1 H) and 6.93 (m, 1 H). MS (APCI +): m / z [MH +] 308.3; C19H30FNO + H requires 308.2.

EXAMPLE 43 (±) -? / - Hexyl-fraps-3,4-dimethyl-4- (2-fluoro-3-hydroxyphenyl) piperidine 3,5-Dichloro-1-fluoropyridinium triflate (481 mg, 1.54 mmol) was added to a solution of (±) -? / - hexyl-fraps-3,4-dimethyl-4- (3-hydroxyphenyl) piperidine (Preparation 7, 100 mg, 0.26 mmol) in dichloromethane (5 ml) at room temperature. The mixture was refluxed for 3 hours, and then cooled to room temperature. The solution was poured into water (5 ml), and the two layers were separated. The aqueous layer was extracted with dichloromethane (3 x 5 ml), and the combined organics were dried over MgSO4, filtered and concentrated in vacuo to give the crude product. This was chromatographed on Merck 230-400 mesh silica gel, using hexane-ethyl acetate (4: 1), to give the title compound (10 mg) as a colorless oil. NMR (CDC, data selected from the free base): 0.90 (m, 3H), 0.96 (d, 3H), 1, 20-1, 36 (m, 7H), 1.38 (s) , 3H), 1, 40-1, 50 (m, 2H), 2.10-2.53 (m, 7H), 2.70 (m, 1 H), 6.54 (td, 1 H), 6.67 (td, 1 H) and 6.77 (td, 1 H). MS (TSI +): m / z [MH +] 308.0; C19H30FNO + H requires 308.2.

EXAMPLE 44 (±) -? -3-Cyclohexylpropyl-frans-3,4-dimethyl-4- (3-hydroxy-4-nitrophenol) pperidine Nitronium tetrafluoroborate (0.341 g, 3.02 mmol) was added to a stirred solution of (±) -? / - (3-cyclohexylpropyl) -fra / 7s-3,4-d-methyl-4- (3 - hydroxyphenyl) piperidine (Preparation 8, 0.997 g, 3.02 mmol) in acetonitrile (9 ml) and dichloromethane (1 ml) at 0 ° C, and the reaction mixture was allowed to warm to room temperature. After 2 hours, the reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate (30 ml), and extracted with dichloromethane (3 x 30 ml). The combined extracts were washed with brine (30 ml), dried over Na 2 S 4, and concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with ethyl acetate-dichloromethane-0.880 ammonia. (300: 699: 1), giving the title compound as a yellow oil (0.213 g). NMR (CßDβ, data selected from the free base): 0.78 (d, 3H), 0.78-0.87 (m, 2H), 1, 07-1, 23 (m, 6H), 1, 28 (s, 3H), 1, 41-1, 47 (m, 2H) , 1, 59-1, 67 (m, 6H), 2.01 (m, 1 H), 2.23-2.39 (m, 4H), 2.48-2.61 (m, 2H), 2.83 (m, 1 H), 6.92 (dd, 1 H), 7.01 (d, 1 H), and 8.00 (d, 1 H). MS (APCI +): m / z [MH +] 375.3; C 22 H 34 N 2 O 3 + H requires 375.3.

EXAMPLE 45 (±) - / V- (3-Cyclohexylpropyl) -frans-3,4-dimethyl-4- (4-amino-3-hydroxypheni-piperidine Platinum (IV) oxide (2 mg, 0.57 mmol) was added to a solution of (±) -? / - (3-cyclohexylpropyl) -rans-3,4-dimethyl-4- (3-hydroxy-4) -nitrophenyl) piperidine (Example 44, 0.213 g, 0.57 mmol) in tetrahydrofuran (4 ml), and the reaction mixture was stirred at 345 kPa of hydrogen gas for 14 hours. The reaction mixture was purged with nitrogen, filtered under nitrogen, and the crude product sensitive to air was used without further purification. MS (APCI +): m / z [MH +] 345.2; C 22 H 36 N 2 O + H requires 345.3.

EXAMPLE 46 (±) -? - (3-Cyclohexylpropyl) -frans-3,4-dimethyl-4- (3-hydroxy ^ 4- acetylaminopheniDpiperidine Acetyl chloride (45 μL, 0.63 mmol) was added to a stirred solution of (±) - / V- (3-cyclohexylpropyl) -frans-3,4-d-methyl-4- (4 -amino-3-hydroxy-phenyl) piperidine (Example 45, 0.106 g, 0.30 mmol) and pyridine (27 μl, 0.33 mmol) in tetrahydrofuran (7 ml) at 0 ° C. After 1.5 hours, the reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate (10 ml), and extracted with dichloromethane (3 x 10 ml). The combined extracts were washed with brine (20 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo to give a residue which was dissolved in methanol (10 ml) and allowed to stir for 18 hours. The reaction mixture was concentrated in vacuo to give the crude product which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane-0.880 ammonia (10: 989: 1 to 30: 967: 3), giving the Compound the title as a pale yellow oil (33 mg). NMR (CßDβ, data selected from the free base): 0.82-0.88 (m, 2H), 0.94 (d, 3H), 1, 10-1, 22 (m, 6H), 1 , 22 (s, 3H), 1, 39-1, 49 (m, 3H), 1, 42 (s, 3H), 1, 58-1, 69 (m, 5H), 1, 82 (m, 1 H), 2.15-2.48 (m, 6H), 2.71 (m, 1 H), 6.72 (dd, 1 H), 7.00 (d, 1 H), 7.14 ( d, 1 H), and 7.16 (br s, 1 H). MS (APCI +): m / z [MH +] 387.3; C24H38N2? 2 + H requires 387.3.

EXAMPLE 47 (±) -? / - (3-Cyclohexylpropyl) -trans-3,4-d-methyl-4- (3-hydroxy-4-propionylaminopheniPpiperidine Propionyl chloride (28 μL, 0.33 mmol) was added to a stirred solution of (±) -? / - (3-cyclohexylpropyl) -rans-3,4-dimethyl-4- (4-amino-3-hydroxyphenyl) ) piperidine (Example 45, 0.105 g, 0.30 mmol) and pyridine (27 μl, 0.33 mmol) in tetrahydrofuran (7 ml) at 0 ° C. After an additional 1.5 hours, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate (10 ml), and extracted with dichloromethane (3 x 10 ml). The combined extracts were washed with brine (20 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo to give a residue which was dissolved in methanol (10 ml) and allowed to stir for 18 hours. The reaction mixture was concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane-0.880 ammonia (10: 989: 1 to 30: 967: 3), giving the title compound as a pale yellow oil (33 mg). NMR (CßD ?, data selected from the free base): 0.82-0.88 (m, 2H), 0.84 (t, 3H), 0.94 (d, 3H), 1, 07- 1, 21 (m, 6H), 1, 21 (s, 3H), 1, 39-1, 51 (m, 3H), 1, 58-1, 69 (m, 7H), 1.81 (m, 1 H), 2.12-2.48 (m, 6H), 2.70 (m, 1 H), 6.71 (dd, 1 H), 6.84 (s, 1 H), 6.86 (d, 1H), and 7.15 (d, 1 H). MS (APCI +): m / z [MH +] 401.4; C25H40N2O2 + H requires 401, 3.

EXAMPLE 48 f ±) -? / - Hexyl- (rans-3,4-dimethyl-4-f4-? ', / V-dimethalamine-3-hydroxypheniDpiperidine Formaldehyde (82 μl of 37% solution w / w aqueous, 1.09 mmol) was added to a stirred solution of (±) -? / - hexyl-trans-3,4-dimethyl-4- (3-h) droxi-4-aminophenyl) piperidine (Example 4, 0.100 g, 0.33 mmol) and formic acid (41 μl, 1.09 mmol) in chloroform (3 ml), and the reaction mixture was heated to reflux. Formaldehyde (82 μl of 37% solution w / w aqueous, 1.09 mmol) and additional formic acid (41 μl, 1.09 mmol) were introduced after 12 and 36 hours, and the reaction mixture was stirred at reflux for an additional 4 hours. Upon cooling, the reaction mixture was diluted with water (10 ml), adjusted to pH 11 with 5 V sodium hydroxide, and extracted with 3: 1 n-butanol-toluene (3 x 10 ml). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with methanol-dichloromethane-0.880 ammonia (10: 489: 1) to give the compound of the title as a pale yellow oil (5 mg). NMR (CßDβ, data selected from the free base): 0.85 (t, 3H), 0.94 (d, 3H), 1, 21 (s, 3H), 1, 21-1, 27 (m , 6H), 1, 40-1, 44 (m, 3H), 1.81 (m, 1 H), 2.06-2.41 (m, 6H), 2.18 (s, 6H), 2 , 66 (m, 1 H), 6.74 (m, 1 H), 6.88 (m, 1 H), and 7.13 (m, 1 H). MS (APCI +): m / z [MH +] 333.4; C2? H36N2O + H requires 333.3.

EXAMPLE 49 (±) -? -Hexyl-fra /? S-3,4-dimethyl-4- (3-hydroxy-4-isopropenylphenyl) piperidine S-Butyl lithium (0.25 mL of 1.3 M in cyclohexane, 0.32 mmol) was added to a stirred solution of (±) -? / - hexy ra / 7s-3,4-di-methyl -4- (3 -? / ',? / - diethylcarbamiloxyphenyl) piperidine (Preparation 4, 0.103 g, 0.27 mmol) and? /,? /,? /',? / - tetramethyl-ethylenediamine (48 μl, 0 , 32 mmol) in tetrahydrofuran (1 ml) at -78 ° C. After 1 hour, acetone (98 μL, 1.33 mmol) was added, and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate (25 ml), and extracted with dichloromethane (3 x 30 ml). The combined extracts were washed with brine (15 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude product, which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane. -ammonia 0.880 (2: 197: 1 to 4: 195: 1), giving the title compound as a pale yellow oil (64 mg). NMR (C6D6, data selected from the free base): 0.85 (t, 3H), 0.94 (d, 3H), 1, 19-1, 28 (m, 6H), 1, 21 (s) , 3H), 1, 38-1, 46 (m, 3H), 1, 81 (m, 1 H), 1, 89 (s, 3H), 2.10-2.46 (m, 6H), 2 , 69 (m, 1 H), 5.01 (m, 2H), 6.73 (dd, 1 H), 6.91 (d, 1 H), and 7.04 (d, 1 H). MS (APCI +): m / z [MH +] 330.3; C22H35NO + H requires 330.3.

EXAMPLE 50 (±) -? / - Hexyl-frans-3,4-dimethyl-4- (4-allyl-3? ',?' -diethylcarbamyl-phenyl) pperidine S-Butyl lithium (0.246 ml of 1.3 M in cyclohexane, 0.32 mmol) was added to a stirred solution of (±) -? / - hexyl-trans-3,4-dimethyl-4- (3-? / ', / V-diethylcarbamyloxyphenyl) piperidine (Preparation 4, 0.104 g, 0.27 mmol) and? /,? /,? /', / V-tetramethylethylenediamine (48 μl, 0.32 mmol), in tetrahydrofuran (1 ml) at -78 ° C. After 1 hour, allyl bromide (0.115 ml, 1.33 mmol) was added, and stirring was continued for an additional 1 hour. The reaction mixture was diluted with water (25 ml), and extracted with dichloromethane (3 x 20 ml). The combined organic extracts were washed with brine (30 ml), dried over Na 2 S 4, filtered and concentrated in vacuo to give the crude product which was used without further purification (0.107 g). NMR (CßDβ, data selected from the free base): 0.84-0.95 (m, 12H), 1.17 (s, 3H), 1, 19-1, 24 (m, 6H), 1 , 32-1.41 (m, 3H), 1.76 (m, 1H), 2.05-2.40 (m, 6H), 2.63 (m, 1 H), 3.08 (m, 4H), 3.33 (d, 2H), 4.98 (m, 2H), 5.93 (m, 1 H), 6.96 (dd, 1 H), 7.07-7.10 (d , 1 H), and 7.23 (d, 1 H). MS (APCI +): m / z [MH +] 429.3; C27H44N2O2 + H requires 429.3.

EXAMPLE 51 (±) -V-Hexyl-fraps-3,4-dimethyl-4- (3-V '/ V'-diethylcarbamyl) -4-methylpheni piperidine S-Butyl lithium (0.511 ml of 1.3 M in cyclohexane, 0.67 mmol) was added to a stirred solution of (±) -? / - hexyl-trans-3,4-dimethyl-4- (3 -? / ',? / - diethylcarbamylloxyphenyl) piperidine (Preparation 4, 0.215 g, 0.55 mmol) and? /,? /,? /',? / - tetramethylethylenediamine (0.100 ml, 0.67 mmol ), in tetrahydrofuran (1 ml) at -78 ° C. After 1 hour, methyl iodide (0.173 ml, 2.77 mmol) was added, and stirring was continued for an additional 1 hour. The reaction mixture was diluted with water (25 ml), and extracted with dichloromethane (3 x 20 ml). The combined extracts were washed with brine (30 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude product which was used without further purification (0.213 g). NMR (CßDβ, data selected from the free base): 0.80-1.04 (m, 12H), 1.17 (s, 3H), 1, 20-1, 24 (m, 6H), 1 , 32-1, 41 (m, 3H), 1, 76 (m, 1 H), 2.05-2.40 (m, 6H), 2.11 (s, 3H), 2.63 (m, 1 H), 3.08 (m, 4H), 6.90 (m, 1 H), 6.99 (m, 1 H), and 7.10-7.15 (m, 1 H). MS (APCI +): m / z [MH +] 403.4; C25H42N2? 2 + H requires 403.3.

EXAMPLE 52 (±) - / V-Hexyl-frans-3,4-dimethyl-4- (3 -? /,.? / '- diethylcarbamyloxy! 4-ethylphenyl) piperidine S-Butyl lithium (0.597 ml of 1.3 M in cyclohexane, 0.78 mmol) was added to a stirred solution of (±) -? / - hexyl-uraps-3,4-dimethyl-4- (3-? / ',? / - diethylcarbamyloxy-4-methylphenyl) piperidine (Example 51, 0.260 g, 0.65 mmol) and? /,? /,? / ',? /' - tetramethylethylenediamine (0.117 ml, 0.78 mmol), in tetrahydrofuran (2 ml) at -78 ° C. After 1 hour, methyl iodide (0.201 ml, 3.23 mmol) was added, and stirring was continued for an additional 1 hour. The reaction mixture was diluted with water (25 ml), and extracted with dichloromethane (3 x 20 ml). The combined extracts were washed with brine (30 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude product which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane-0.880 ammonia. (5: 494: 1 to 10: 489: 1), giving the title compound as a pale yellow oil (90 mg). NMR (CßDβ, data selected from the free base): 0.86 (t, 3H), 0.90-0.96 (m, 12H), 1, 08 (s, 3H), 1, 10-1 , 26 (m, 6H), 1, 43-1, 58 (m, 3H), 1, 71 (m, 1 H), 2.08-2.62 (m, 6H), 2.29 (c, 2H), 2.71 (m, 1 H), 3.09 (m, 4H), 6.86 (dd, 1 H), 7.04 (d, 1 H), and 7.10-7.13 (d, 1 H). MS (APCI +): m / z [MH +] 417.3; C 26 H 44 N 2 O 2 + H requires 417.3.

EXAMPLE 53 (±) - / V-Hexyl-frans-3,4-dimethyl-4- (3 -? / ',? /' - diethylcarbamyloxy-4-? "- methylaminocarbonylpheniDpiperidine S-Butyl lithium (0.263 ml of 1.3 M in cyclohexane, 0.34 mmol) was added to a stirred solution of (±) - / V-hexyl-trans-3,4-dimethyl-4- (3 - / V ', / V-diethylcarbamyloxyphenyl) piperidine (Preparation 4, 0.111 g, 0.29 mmol) and? /,? /,? /',? / '- tetramethylethylenediamine (52 μl, 0.34 mmol), tetrahydrofuran (1 ml) at -78 ° C. After 1 hour, methyl isocyanate (84 μL, 1.43 mmol) was added, and stirring was continued for an additional 1 hour. The reaction mixture was diluted with water (25 ml), and extracted with dichloromethane (3 x 20 ml). The combined extracts were washed with brine (30 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude product which was used without further purification (0,113 g). MS (APCI +): m / z [MH +] 446.3; C 26 H 43 N 3 O 3 + H requires 446.3.

EXAMPLE 54 (±) -? / - Hexyl-frans-3,4-dimethyl-4- (3 -? / ',? / - diethylthiocarbamyloxy-4-fluorophenypiperidine S-Butyl lithium (0.395 mL of 1.3 M in cyclohexane, 0.51 mmol) was added to a stirred solution of (±) -? / - hexyl-uraps-3,4-dimethyl-4- (3-? / ',? / - diethylthiocarbamyloxyphenyl) piperidine (Preparation 6, 0.104 g, 0.26 mmol) and? /,? /,? /',? / - tetramethylethylenediamine (78 μl, 0.51 mmol), in tetrahydrofuran (2 ml) at -78 ° C. After 1 hour, a solution of N-fluorobenzenesulfonimide (0.405 g, 1.28 mmol) in tetrahydrofuran (1 ml) was added, and stirring was continued for an additional 3 hours. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate (25 ml), and extracted with dichloromethane (3 x 20 ml). The combined extracts were dried over Na 2 S 4, filtered and concentrated in vacuo to give the crude product which was purified via silica gel chromatography, eluting with a gradient of ethyl acetate-dichloromethane (30:70 to 50:50). ), giving the title compound as a yellow oil (40 mg). NMR (CßDβ, data selected from the free base): 0.83-0.97 (m, 12H), 1.12 (s, 3H), 1, 18-1, 27 (m, 6H), 1 , 37-1, 42 (m, 3H), 1, 68 (m, 1 H), 2.07-2.39 (m, 6H), 2.62 (m, 1 H), 3.12 (m , 2H), 3.50 (m, 2H), 6.73 (m, 1 H), 6.83 (m, 1 H), and 7.14 (m, 1 H). MS (APCI +): m / z [MH +] 423.3; C24H39FN2OS + H requires 423.3.

EXAMPLE 55 (±) -? / - Hexyl-frans-3,4-dimethyl-4-f3-? ',? '-diethylcarbamyloxy-4- formylpheniPpiperidine S-Butyl lithium (1.22 mL of 1.3 M in cyclohexane, 1.59 mmol) was added to a stirred solution of (±) -? / - hexyl-fraA7s-3,4-dimethyl-4- (3 -? / ',? / - diethylcarbamyloxyphenyl) piperidine (Preparation 4, 0.515 g, 1.32 mmol) and? /,? /,? /',? / '- tetramethylethylenediamine (0.240 ml, 1.59 mmoles), in tetrahydrofuran (5 ml) at -78 ° C. After 1 hour,? /,? / - dimethylformamide (0.513 ml, 6.62 mmol) was added, and stirring was continued for an additional 1 hour. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate (25 ml), and extracted with dichloromethane (3 x 20 ml). The combined extracts were dried over Na 2 S 4, filtered and concentrated in vacuo to give the crude product which was used without further purification (0.456 g). NMR (CTD6, data selected from the free base): 0.77 (d, 3H), 0.82-0.94 (m, 9H), 1, 04 (s, 3H), 1, 18-1 , 34 (m, 6H), 1, 37-1, 40 (m, 3H), 1, 66 (m, 1 H), 1, 99-2.38 (m, 6H), 2.58 (m, 1 H), 3.07 (c, 4H), 6.57 (dd, 1 H), 6.86-6.89 (m, 2H), and 9.32 (s, 1 H). MS (APCI +): m / z [MH +] 417.3; C25H40N2O3 + H requires 417.3.

EXAMPLE 56 It was found that the compounds according to the present invention, for example the compound of Example 8, perform antipruritic activity when tested according to the above procedure.

Preparation of starting materials PREPARATION 1 f ±) - / V-Hexyl-frans-3,4-dimethyl-4-f3 -? / '.? /' - Diethylcarbamyloxy-4-trimethylsilylphenylpiperidine S-Butyl lithium (0.489 ml of 1.3 M in cyclohexane, 0.66 mmol) was added to a stirred solution of (±) -? / - hexyl-frans-3,4-dimethyl-4- (3-? / ',? / - diethylcarbamyloxyphenyl) piperidine (Preparation 4, 0.206 g, 0.53 mmol) and? /,? /,? / ',? /' - tetramethylethylenediamine (96 μl, 0.66 mmol), in tetrahydrofuran (2 ml) at -78 ° C. After 1 hour, chlorotrimethylsilane (0.336 ml, 2.65 mmol) was added, and stirring was continued for an additional 10 minutes. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate (25 ml), and extracted with dichloromethane (3 x 20 ml). The combined extracts were dried over Na 2 S 4, filtered and concentrated in vacuo to give the crude product which was used without further purification (0.241 g). NMR (CßDβ, data selected from the free base): 0.28 (s, 9H), 0.83 (t, 3H), 0.91-0.96 (m, 9H), 1, 18 (s) , 3H), 1, 21-1, 27 (m, 6H), 1, 35-1, 38 (m, 3H), 1.79 (m, 1 H), 2.06-2.40 (m, 6H), 2.62 (m, 1 H), 3.14 (m, 4H), 7.03 (dd, 1 H), 7.18 (d, 1 H), and 7.39 (d, 1 H). MS (APCI +): m / z [MH +] 461, 3; C27H48N2O2SÍ + H requires 461, 3.

PREPARATION 2 (± - V-Hexyl-fra / 7s-3,4-dimethyl-4- (3-hydroxy-4-trimethylsilylphenyl) p.pe ^ ina S-Butyl lithium (0.503 ml of 1.3 M in cyclohexane, 0.65 mmol) was added to a stirred solution of (±) -? / - hexyl-fra / 7s-3,4-dimetyl-4- (3-N ',? / - diethylcarbamyloxy-4-trimethylsilylphenyl) piperidine (Preparation 1, 0.251 g, 0.51 mmol) and? /,? /,? /',? / '- tetramethylethylenediamine (99 μl, 0, 65 mmol), in tetrahydrofuran (2 ml) at -78 ° C. After 1 hour, methyl iodide (0.170 ml, 2.72 mmol) was added, and stirring was continued for an additional 2 hours. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate (25 ml), and extracted with dichloromethane (3 x 20 ml). The combined extracts were dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude product which was purified via silica gel chromatography, eluting with a gradient of methanol-dichloromethane-0.880 ammonia (5: 494: 1 a). 20: 479: 1), giving the title compound as a yellow oil (71 mg). NMR (CßDβ, data selected from the free base): 0.36 (s, 9H), 0.87 (t, 3H), 1, 02 (d, 3H), 1, 21 (s, 3H), 1, 21-1, 32 (m, 6H), 1, 46-1, 79 (m, 3H), 2.03 (m, 1 H), 2.44-2.82 (m, 6H), 3 , 03 (m, 1 H), 3.39 (s, 3 H), 6.60 (s, 1 H), 6.73 (d, 1 H) and 7.36 (d, 1 H). MS (APCI +): m / z [MH +] 376.3; C23H41NOSÍ + H requires 376.3.

PREPARATION 3 (±) -? -Hexyl-frans-3,4-dimetir-4- (3-triisopropylsilyloxyphenyl) piperidine Imidazole (47 mg, 0.690 mol) and chlorotriisopropylsilane (106 mg, 0.552 mmol) were added to a solution of (±) -? / - hexyl-uraps-3,4-dimethyl-4- (3-hydroxyphenyl) piperidine (Preparation 7, 100 mg, 0.345 mmol) in N, N-dimethylformamide (1 ml). The reaction was stirred under nitrogen for 60 hours, then washed with saturated aqueous sodium hydrogencarbonate solution, and extracted with dichloromethane. The solvents were removed in vacuo, and the residue was dissolved in hexane, filtered and the hexane removed in vacuo to give the title compound as an oil (152 mg). NMR (CDC, data selected from the free base): 0.77 (3H, d), 0.87 (3H, t), 1, 09 (21H, m), 1.31 (3H, s) , 6.67 (1 H, d), 6.80 (1 H, s), 6.87 (1 H, d) and 7.13 (1 H, t). MS (APCI +): m / z [MH +] 446, 1; C28H5? NOSi + H requires 446.4.

PREPARATION 4 (±) -? / - Hex¡l-frans-3,4-d¡met¡l-4- (3-? '.?' -diethylcarbamiloxyphenyl) piperidine 1 - [(Chlorocarbonyl) (ethyl) amino] ethane (3.8 ml, 30.0 mmol) was added to a solution of (±) -? / - hexyl-fra /? S-3,4-dimethyl-4 - (3-hydroxyphenyl) piperidine (Preparation 7, 8.0 g, 28 mmol) in pyridine (32 ml), and the reaction mixture was stirred overnight. Water (200 ml) was added to the reaction mixture, and the product was extracted with dichloromethane (3 x 200 ml). The organics were dried (Na 2 SO 4), and then concentrated in vacuo. The crude residue was chromatographed on silica gel, eluting with ethyl acetate-hexane (20:80), giving the product as a colorless oil (4.0 g). NMR (CDCI3) data selected from the free base): 0.8 (d, 3H), 0.9 (t, 3H), 1, 2-1, 4 (m, 14H), 3.3-3.5 (m, 4H), 6.9 (d, 1H), 7, 0 (s, 1 H), 7.1 (d, 1 H), and 7.3 (t, 1 H). MS (ESI +): m / z [MH +] 389.2; C 24 H 40 N 2 O 2 + H requires 389.3.

PREPARATION 5 (±) -? / - Hexyl-frans-3,4-dimethyl-4- (3-V '.? / - dimethylcarbamiloxyphenylpiperidine Triethylamine (0.279 ml, 2 mmol) was added to a stirred solution of (±) -? / - hexyl-trans-3,4-dimethyl-4- (3-hydroxyphenyl) piperidine (Preparation 7, 0.289 g, 1.00 mmoles) and dimethylcarbamyl chloride (0.101 ml, 1.1 mmol) in tetrahydrofuran (2 ml) and in pyridine (2 ml). After 24 hours, the reaction mixture was diluted with water (20 ml), and extracted with dichloromethane (3 x 20 ml). The combined extracts were washed with brine (30 ml), dried (Na 2 S 4), filtered and concentrated in vacuo to give the crude product, which was chromatographed on silica gel, eluting with a gradient of methanol-dichloromethane. ammonia 0.880 (10: 989: 1 to 30: 967: 3), giving the title compound as a yellow oil (0.329 g). NMR (CTDT, data selected from the free base): 0.85 (t, 3H), 0.90 (d, 3H), 1.17 (s, 3H), 1, 19-1, 29 (m , 6H), 1, 33-1, 43 (m, 3H), 1, 78 (m, 1 H), 2.05-2.40 (m, 6H), 2.51 (s, 1 H), 2.55 (s, 3H), 2.63 (m, 1 H), 6.93 (m, 1 H), 7.04-7.12 (m, 2H), and 7.24 (m, 1) H). MS (APCI +): m / z [MH +] 361.3; C22H36N2? 2 + H requires 361, 3.

PREPARATION 6 (±) -? / - Hexyl-frans-3,4-dimethyl-4- (3 -? / '.? /' - diethylthiocarbamiloxyphenyl) piperidine Diethylthiocarbamyl chloride (0.485 g, 3.2 mmol) was added to a stirred solution of (±) -? / - hexyl-frans-3,4-dimethyl-4- (3-hydroxyphenyl) piperidine (Preparation 7, 0.710 g, 2.45 mmol) and potassium hydroxide (0.137 g, 2.45 mmol) in water (5 ml) and tetrahydrofuran (5 ml). After 24 hours, potassium hydroxide (0.137 g, 2.45 mmol) and additional diethylthiocarbamyl chloride (0.485 g, 3.2 mmol) were added. After a further 24 hours, the reaction mixture was diluted with water (20 ml), and extracted with dichloromethane (3 x 25 ml). The combined extracts were washed with brine (30 ml), dried over Na 2 S 4, filtered and concentrated in vacuo to give the crude product, which was chromatographed on silica gel, eluting with a gradient of methanol-dichloromethane-0.880 ammonia (10: 989: 1). to 30: 967: 3), giving the title compound as a yellow oil (0.627 g). NMR (CeDβ, data selected from the free base): 0.83-0.88 (m, 6H), 0.95-1, 01 (m, 6H), 1, 20 (s, 3H), 1 , 23-1, 42 (m, 9H), 1, 77 (m, 1 H), 2.05-2.42 (m, 6H), 2.64 (m, 1 H), 3.10 (c , 2H), 3.55 (c, 2H), 6.91 (m, 1 H), 6.98 (m, 1 H), 7.05-7.13 (m, 1 H), and 7, 19 (m, 1 H). MS (APCI +): m / z [MH +] 405.3; C24H40N2OS + H requires 405.3.

PREPARATION 7 (±) - / V-Hexyl-frans-3,4-dimethyl-4- (3-hydroxyphenyl) piperidine Sodium hydrogencarbonate (1.76 g, 20.95 mmol) and bromohexane (1.64 g, 9.9 mmol) were added to a stirred solution of. { ±) -trans-3,4-dimethyl-4- (3-hydroxyphenyl) piperidine (JA Werner et al., J. Org. Chem., 1996, 61, 587: 2.0 g, 9.8 mmol ) in? /,? / - dimethylformamide (50 ml). The reaction mixture was heated to reflux for 3 hours, and then cooled to room temperature. The reaction mixture was diluted with water (100 ml), and extracted with dichloromethane (4 x 50 ml). The combined extracts were washed with brine (100 ml), dried (MgSO4), filtered and concentrated in vacuo to give the crude product. The crude product was chromatographed on silica gel (50 g), eluting with 0.880 ethyl acetate-hexane-ammonia (30: 69: 1), to give the title compound as a light brown oil (2.68 g). NMR (CDCI3, data selected from the free base): 0.75 (d, 3H), 0.85 (t, 3H), 1, 15-1, 25 (m, 6H), 1, 3 (s) , 3H), 2.0 (m, 1 H), 2.35 (m, 4H), 2.6 (m, 2H) and 6.55-7.2 (m, 4H). MS (TSI +): m / z [MH +] 290.2; C19H31NO + H requires 290.3.

PREPARATION 8 (±) -? - (3-Cyclohexyp-frans-3,4-dimethyl-4- (3-hydroxyphenyl) piperidine A mixture of was heated at 70 ° C for 8 hours. { ±) -trans-3,4-dimethyl-4- (3-hydroxy-phenyl) piperidine (J. A. Werner et al., J. Org. Chem., 1996, 61, 587: 82 mg, 0.4 mmol), 3- (cyclohexyl) chloropropane (71 mg, 0.4 mmol), sodium hydrogen carbonate (37 mg, 0.44 mmol), sodium iodide (3 mg, 0.02 mmol) and dimethylformamide (5 ml), then cooled to room temperature, and quenched with water (30 ml). The resulting mixture was extracted with dichloromethane (30 ml), and the organic layer was retained. The aqueous layer was back extracted with dichloromethane (2 x 20 ml), and the organic portions were combined, washed with brine (40 ml), dried (Na 2 SO 4), filtered and concentrated in vacuo to give the gross material. This was chromatographed on silica gel, eluting with a gradient system of methanol-dichloromethane-0.880 ammonia (10: 989: 1 to 20: 978: 2), giving the title compound as a colorless viscous oil (56 mg). . NMR (CßDβ, data selected from the free base): 0.90 (d, 3H), 1, 20 (s, 3H), 1.80 (m, 1 H), 2.80 (m, 1 H ), and 6.60-7.10 (m, 4H). MS (APCI +): m / z [MH +] 330.3; C22H35NO + H requires 330.5.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A composition of formula I. wherein R and R are each independently H or C 1-4 alkyl; R3 represents aryl (optionally substituted by one or more substituents selected from OH, nitro, halo, CN, CH2CN, CONH2, C1-4alkyl, C4alkoxy, alkanoyl d-5 (last three groups which are optionally substituted by one or more halo atoms) and -N (R4a) (R4)), C? -alkyl, C3-10 alkenyl or C3-10 alkynyl wherein said alkyl, alkenyl or alkynyl groups are optionally substituted and / or terminated by one or more substituents selected from OR c, S (O) nR, CN, halo, alkoxy-β carbonyl, C2-6 alkanoyl, C2-6 alkanoyloxy, C3-8 cycloalkyl, C4-9 cycloalkanoyl, N (R5a) S ( O) 2R6, Het1, aryl, adamantyl (latter two groups which are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-4 alkyl, C1-4 alkoxy and C alkanoyl ? -5 (last three groups that are 1 5b 5c optionally substituted by one or more halo atoms)), or -WA -N (R) (R); n is 0, 1 or 2; W represents a simple bond, C (O) or S (O) p; A1 represents a single bond or alkylene C-MO; provided that when both W and A1 5b 5c represent single bonds, then the group -N (R) (R) does not directly attach to an unsaturated carbon atom; p is 0, 1 or 2; R a to R represent each independently H, C 1-10 alkyl, C 3 -? Alkenyl, C 3-10 alkynyl, C 3-8 cycloalkyl, C 1-4 alkylphenyl, aryl (last six groups which are optionally substituted by one or more substituents selected between OH, nitro, amino, halo, CN, CH2CN, CONH2, C? -4 alkyl, C- alkoxy and C? -5 alkanoyl (last three groups which are optionally substituted by one or more halo atoms)) or Het2; provided that R4d does not represent H when n represents 1 or 2; R5a to R5c each independently represent H, C1-10 alkyl, C3-10 alkenyl, C3-10 alkynyl, C3-8 cycloalkyl, C3-4 alkylphenyl, aryl (last six groups which are optionally substituted by one or more substituents selected between OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-4 alkyl, C1-4 alkoxy and d-5 alkanoyl (last three groups that are 3 5b 5c optionally substituted by one or more halo atoms)), Het , or R and R together represent unbranched C2-6 alkylene, alkylene group which is optionally interrupted by O, S and / or a group N (R7) and is optionally substituted by one or more d-4 alkyl groups; R represents C? -6 alkyl, cycloalkyl OJ-S, C? -4 alkyl phenyl or aryl, four groups which are optionally substituted by one or more substituents selected from alkyl d-4, C? -4 alkoxy, OH, nitro, amine or halo; R represents H, C? -6 alkyl, C3-8 cycloalkyl, A2- (C3-cycloalkyl) or A2-aryl; A2 represents alkylene d-β; Het1, Het2 and Het3 independently represent 3 to 8 membered heterocyclic groups, groups containing at least one heteroatom selected from oxygen, sulfur and / or nitrogen, groups which are optionally fused to a benzene ring, and groups which are optionally substituted the part of the heterocyclic ring and / or the benzene ring condensed by one or more substituents selected from OH, = O, nitro, amino, halo, CN, aryl, C 1-4 alkyl, C 1-4 alkoxy and C 1-5 alkanoyl ( last three groups that are optionally substituted by one or more halo atoms); Y represents -C (= E) NR8R9, C (O) R10, C (O) OR10, C (O) CH (R10a) N (G) Ga, R11, CH (R12b) C (O) OR12a, CH ( R12b) OCO2R12a, C (O) C (R13a) = C (R13b) NH2, C (O) CH (R13a) CH (NH2) (R13b) or PO (OR14) 2; E represents O or S; R8 and R9 independently represent H, CMO alkyl, C3-10 alkenyl (last two groups which are optionally substituted by one or more C4-7 aryl or cycloalkyl groups (two groups which are optionally substituted by one or more substituents selected from halo, alkyl d-4, C 1-4 alkoxy, d-haloalkyl or haloalkoxy C-), aryl, C 4-7 cycloalkyl (optionally substituted by one or more substituents selected from halo, C 1-4 alkyl and C 1-4 alkoxy. groups that are optionally substituted by one or more halo atoms), or R8 and R9, together with the N atom to which both bind, represent Het4; Het4 represents a 5- to 8-membered heterocyclic ring comprising at least one nitrogen atom and optionally one or more additional heteroatoms selected from oxygen and sulfur, heterocyclic ring which is optionally substituted by one or more C? -4 -4 alkyl groups; R represents H, Het, C4-7 cycloalkyl (optionally substituted by one or more C? -4 alkyl groups), C1-11 alkyl (optionally substituted by one or more substituents selected from aryl (optionally substituted by one or more substituents selected from OH, halo, alkanoyl d-4, alkanoyloxy d-4, N (R8) (R9), C (O) N (R8) (R9), alkyl d-4, alkoxy C-? -4, haloalkyl C? * and C 1-4 haloalkoxy) or C 4-7 cycloalkyl (the latter group which is optionally substituted by one or more C 1-4 alkyl groups)) or aryl (optionally substituted by one or more substituents selected from OH, halo C 1-6 alkanoyl, C- * alkanoyloxy, N (R8) (R9), C (O) N (R8) (R9), d-4 alkyl and C- -4 alkoxy (last two groups which are optionally substituted by one or 10a plus groups atoms halo)); R represents H, cycloalkyl d-7, C1-10 alkyl (optionally substituted by one or more substituents selected from aryl or C4-7 cycloalkyl), aryl or R10a (optionally, together with Ga) represents a naturally occurring amino acid substituent; G and Ga independently represent H, an amino protecting group, or Ga, together with 10 to 11 R, represents a naturally occurring amino acid substituent; R represents H, C4-7 cycloalkyl (optionally substituted by one or more CM alkyl groups), aryl (optionally substituted by one or more substituents selected from OH, halo, C- alkanoyl, C1-4 alkanoyloxy, N (R8) (R9) ), C (O) N (R 8) (R 9), C 1-4 alkyl and C 1-6 alkoxy (last two groups which are optionally substituted by one or more halo atoms), CMO alkyl, C 3-10 alkenyl, alkyl group or alkenyl which is optionally substituted by one or more substituents selected from C (O) NH2, Het, C4-7 cycloalkyl (optionally substituted by one or more C? -4 alkyl groups), aryl, aryloxy or C1-4 arylalkoxy (last three) groups which are optionally substituted by one or more substituents selected from OH, halo, d-4 alkanoyl, Ci-4 alkanoyloxy, N (R8) (R9), C (O) N (R8) (R9), C? and alkoxy d-4 (last two groups which are optionally substituted by one or more halo atoms)) or R represents Het7; Het5 to Het7 independently represent 4- to 6-membered heterocyclic rings, rings containing at least one heteroatom selected from oxygen, sulfur and / or nitrogen, rings that are optionally fused to a benzene ring, and rings that are optionally substituted in the of the heterocyclic ring and / or the benzene ring condensed by one or more substituents selected from OH, = O, nitro, amino, halo, CN, aryl, C -? - 4 alkyl, C -? - 4 alkoxy, C3 - cycloalkyl 6 and C? -5 alkanoyl (last four groups which are optionally substituted by one or more halo atoms); R12a and R12b independently represent H, C4-7 cycloalkyl (optionally substituted by one or more C1-4 alkyl groups), C? -? Alkyl or (optionally substituted by one or more substituents selected from aryl or C4-7 cycloalkyl (last group which is optionally substituted by one or more alkyl groups CM)) or aryl (optionally substituted by one or more substituents selected from OH, halo, C1-4 alkanoyl, alkanoyloxy d-4, C1-4 alkyl and C1-4 alkoxy (last two groups which are optionally substituted by one or more halo atoms)); R13a and R independently represent H, cycloalkyl 4-7 (optionally substituted by one or more C- alkyl groups), CMO alkyl, C2-10 alkenyl (alkyl or alkenyl groups which are optionally substituted by one or more substituents selected from aryl or cycloalkyl C4-7 (last group which is optionally substituted by one or more C1-4 alkyl groups) or aryl (optionally substituted by one or more substituents selected from OH, halo, d-4 alkanoyl, d-4 alkanoyloxy, C1-4 alkyl and C- alkoxy (last two groups which are optionally substituted by one or more halo atoms)): R represents H, C4-7 cycloalkyl (optionally substituted by one or more C? -4 alkyl groups), C1-10 alkyl (optionally substituted by one or more substituents selected from aryl or C4-7 cycloalkyl (the latter group being optionally substituted by one or more C-) alkyl groups, or aryl (optionally substituted by one or more substituents selected from O H, halo, C 1-4 alkanoyl, C 1-4 alkanoyloxy, C 1-4 alkyl and C 1-4 alkoxy (last two groups which are optionally substituted by one or more halo atoms)); X represents one or more substituents on the benzene ring, substituents which are independently selected from halo, CN, nitro, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl (last three groups which are optionally substituted and / or terminated by one or more substituents selected from halo, CN, nitro, OH, C3-7 cycloalkyl, d-β alkoxy, C3-7 cycloalkoxy, C1-6 alkanoyl, C-β cycloalkanoyl, C2-6 alkoxycarbonyl, C2-6 alkanoyloxy or N (R15a) (R5b)), C (O) R16a, C (O) OR16b, OC (O) R16c, S (O) rOR16d, S (O) tR17a, OR16e, N (R18a ) (R18b), C (O) N (R18c) (R18d), OC (O) N (R18e) (R18f), N (R189) C (O) R16f, N (R18h) C (O) OR19, N (R18i) C (O) N (R18j) (R18k), N (R18m) S (O) 2R17b or B (OR15c) 2; R15a to R15c independently represent H, d-6 alkyl or C3-7 cycloalkyl (latter two groups which are optionally substituted by one or more halo atoms); R16a to R16f independently represent H, d-alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl (last four groups which are optionally substituted by one or more substituents selected from halo, nitro, OH, C1-4 alkyl or C-M alkoxy) O Het; R and R represent independently C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl (last four groups which are optionally substituted by one or more substituents selected from halo, nitro, OH, alkyl d-4 or alkoxy C-), Het9 or N (R20a) (R20b); provided that R17a does not represent N (R20a) (R20b) when t is 1; R18a a R18m independently represent H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl (last four groups which are optionally substituted by one or more substituents selected from halo, nitro, OH, 0 1 fii 1 ftk C C -4 alkyl or C? -4 alkoxy) Het, or R and R together represent unbranched C 3-6 alkylene, alkylene group which is optionally interrupted by oxygen, 20c 19 sulfur or a NR group; R represents C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl (last four groups which are optionally substituted by one or more substituents selected from halo, nitro, OH, C1-4alkyl or C1-6alkoxy) 4) O Het11; R20a to R20c independently represent H, C- O alkyl C3-7 cycloalkyl (latter two groups which are optionally substituted by one or more halo atoms); r is 1 or 2; t is 0, 1 or 2; Het8 to Het11 represent heterocyclic rings of 4 to 7 members, rings containing at least one heteroatom selected from oxygen, sulfur and / or nitrogen, and rings that are optionally substituted by one or more substituents selected from OH, = 0, nitro, amino, halo, CN, aryl, C 1-4 alkyl, C 1-4 alkoxy, C 1-6 cycloalkyl and C 1-5 alkanoyl (last four groups which are optionally substituted by one or more halo atoms) ); or pharmaceutically or veterinarily acceptable derivatives thereof.

2. A compound according to claim 1, wherein the group OY is attached to a benzene ring in the meta position relative to the piperidine group.

3. A compound according to claim 1 or claim 2, wherein the substituent (s) X is (are) bonded to the benzene ring at the position (s) which are orthogonal to the and / or para- relative to the piperidine group.

4. A compound according to any one of Claims 1 to 3, wherein R represents C? -2 alkyl.

5. A compound according to any one of Claims 1 to 4, wherein R2 represents H or C -? - 2 alkyl.

6. A compound according to any one of Claims 1 to 5, wherein R3 represents C1-8 alkyl, C3-8 alkenyl or C3-8 alkynyl wherein said alkyl, alkenyl or alkynyl groups are optionally substituted and / or terminated by one or more substituents selected from C3-8 cycloalkyl, OR4c, CN, Het1 or aryl (the latter group being optionally substituted by one or more substituents selected from OH, d2 alkyl, C2-2 alkoxy or halo).

7. A compound according to any one of Claims 1 to 6, wherein R4c represents H, alkyl d-β, cycloalkyl d-6, aryl or Het2.

8. A compound according to any one of Claims 1 to 7, wherein Het1 and Het2 independently represent 5- to 7-membered heterocyclic groups, groups containing at least one heteroatom selected from oxygen, sulfur and / or nitrogen, and groups which are optionally substituted by one or more C? -2 alquilo alkyl groups (alkyl groups which are optionally substituted by one or more halo atoms).

9. A compound according to any one of Claims 1 to 8, wherein Y represents C (= E) NR8R9, C (O) R10 or R11.

10. A compound according to any one of Claims 8 9 10 1 to 9, wherein R and R independently represent H or C- alkyl; R represents d-β alkyl (substituted by one or more phenyl groups) or aryl (optionally substituted by one or more substituents selected from OH, halo, C? -2 alca alkanoyloxy, NH 2, C (O) NH 2 and C? -2 alquilo alkyl; (last group which is optionally substituted by one or more halo atoms)); R 1 represents H, C 1-10 alkyl or C 3-10 alkenyl, the latter two groups being optionally substituted by one or more substituents selected from Het and phenyl; Het represents a 5-6 membered heterocyclic ring, ring containing at least one heteroatom selected from oxygen, sulfur and / or nitrogen, ring that is optionally fused to a benzene ring, and ring that is optionally substituted on the ring part heterocyclic and / or benzene ring condensed by one or more substituents selected from OH, = 0 and C- alkyl); and / or Het is in the S-oxidized form.

11. A compound according to any one of the Claims 1 to 10, wherein X represents one to three substituents selected from halo, nitro, C2-6 alkenyl, d-β alkyl (alkyl group which is optionally substituted and / or terminated by a substituent selected from OH, C-alkoxy OR - ™ ~~ - "" ** "• N (R15a) (R15b)), C (O) R16a, C (O) OR16b, S (O) tR17a, N (R18a) (R18b), C (O) N (R18c) (R18d), N (R189) C (O) R16f, N (R18h) C (O) OR19, N (R18i) C (O) N (R18j) (R18k) or N (R18m) S ( O) 2R 7b

12. A compound according to any one of Claims 1 to 11, wherein R15a and R15b independently represent H or alkylCM; R16a to R16f independently represent H or alkyl d-6 (last group which is optionally substituted by one or more halo atoms); R a and R independently represent d 4 alkyl (optionally substituted by one 0 more halo atoms) or N (R20a) (R20b); R18b to R18m represent 1 fti 1 ñk independently H, alkyl d-6, or R and R together represent unbranched 19 C3-6alkylene optionally interrupted by oxygen; R represents C 1-4 alkyl; and / or R20a and R20b independently represent H or C1-4 alkyl.

13. A compound according to any one of the Claims 1 to 12, wherein the substituent (s) X is (are) bonded to the benzene ring at the position (s) which are ortho- and / or para- relative to the group OY.

14. A compound according to any one of the Claims 1 to 13, for use as a medication.

15. A compound according to any one of Claims 1 to 13, for use as an animal medicament.

16. A formulation comprising a compound according to any one of Claims 1 to 13, mixed with a pharmaceutically or veterinarily acceptable adjuvant, diluent or vehicle.

17. A formulation according to Claim 16, which is a veterinary formulation.

18. The use of a compound according to any one of Claims 1 to 13, in the manufacture of a medicament for the curative or prophylactic treatment of pruritus.

19. A process for the preparation of a compound according to claim 1, comprising: a) for the compounds of formula I wherein R3 represents Ci alkyl optionally substituted by C3-8 cycloalkyl, Het1, aryl, adamantyl (last two groups which are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, CM alkyl, C- alkoxy and d-5 alkanoyl (last three groups which are optionally substituted by one or more atoms halo)), or R3 represents C2-10 alkyl, C3-10 alkenyl or C3-10 alkynyl (three groups which are optionally substituted by one or more of the relevant substituents identified in Claim 1 with respect to R3), alkyl, alkenyl groups or alkynyl which are attached to the nitrogen atom of the piperidine by a CH2 group, in which Het is as defined in claim 1, reduction of a corresponding compound of formula II, wherein R31 represents H, C3-8 cycloalkyl, Het1, aryl, adamantyl (latter two groups which are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C? alkyl? 4, C 1-4 alkoxy and C 1-5 alkanoyl (last three groups which are optionally substituted by one or more halo atoms), C 1-9 alkyl, C 2-9 alkenyl or C 2-9 alkynyl, alkyl, alkenyl or alkynyl groups are optionally substituted and / or terminated by one or more substituents selected from OR4c, S (O) nR4d, CN, halo, d-6-alkoxycarbonyl, C2-6 alkanoyl, C2-6 alkanoyloxy, C3-8 cycloalkyl, C4- cycloalkanoyl 9, N (R5a) S (O) 2R6, Het1, aryl, adamantyl (latter two groups which are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, alkyl d-4 , C1-4 alkoxy and d-5 alkanoyl (last three groups which are 1 5b 5c optionally substituted by one or more halo atoms), or -WA -N ( R) (R), and R1, R2, R4c, R4d, R5a to R5c, R6, Het1, n, X, Y, W and A1 are as defined in Claim 1; b) reaction of a corresponding compound of formula III, wherein R, R, X and Y are as defined in Claim 1, with a compound of formula V, R3-L1 V wherein L represents a leaving group and R3 is as defined in Claim 1; c) for the compounds of formula I wherein R3 represents Ci-alkyl, which, instead of being optionally substituted by the substituents as defined in Claim 1, is optionally substituted by R31, wherein R31 is such as defined above, reaction of a corresponding compound of formula III, as defined above, with a compound of formula VI, R 31 CHO VI wherein R 31 is as defined above, in the presence of a reducing agent; d) for the compounds of formula I in which R3 is a C -? - 10 alkyl, C4-10 alkenyl or C4-10 alkynyl group which is completely saturated with C1 to C3 (relative to the N atom of piperidine), and group R3 which is substituted on C2 (relative to the N atom of piperidine) by S (O) R4d, S (O) 2R4d, alkanoyl, cycloalkanoyl, alkoxycarbonyl, CN, -C (O) -A1-N ( R5b) (R5c), -S (O) -A1-N (R5b) (R5c), or -S (O) 2-A1-N (R5b) (R5c), wherein R4d, R5b, R5c and A1 are as defined in Claim 1, reaction of a corresponding compound of formula III, as defined above, with a compound of formula VII, R3a-Z VII in which R3a represents R3 as defined in Claim 1 except that it does not represent aryl, and that the chain R 3a contains an additional carbon-carbon double bond, ß to the substituent Z, and Z represents S (O) R4d, S (O) 2R4d, alkanoyl, cycloalkanoyl, alkoxy carbonyl, CN , -C (O) -A1-N (R5b) (R5c), -S (O) -A1-N (R5b) (R5c), or -S (O) 2-A1-N (R5b) (R5c) , in wherein R4d, R5b, R5c and A1 are as defined in Claim 1; e) for the compounds of formula I wherein Y represents -C (= E) NR8R9, wherein E, R8 and R9 are as defined in Claim 1, reaction of a corresponding compound of formula I in which Y represents H, with a compound of formula VIII, HO-C (= E) NR8R9 VIII, or a suitable derivative thereof, wherein E, R8 and R9 are as defined in Claim 1, or a compound of formula IX, E = C = NR8R9 IX wherein E, R8 and R9 are as defined in Claim 1; f) for compounds of formula I in which Y represents C (O) R10 or C (O) OR10, in the Wherein R is as defined in Claim 1, reaction of a corresponding compound of formula I in which Y represents H, with a compound of formula X, HO-C (O) R 10 X, or a compound of formula XI , HO-C (O) OR10 XI, 10 respectively, or suitable derivatives thereof, wherein R is as defined in Claim 1; g) for the compounds of formula I wherein Y represents C (O) CH (R10a) N (G) (Ga), wherein R10a, G and Ga are as defined in Claim 1. Reaction of a corresponding compound of formula I wherein Y represents H, with a compound of formula XII, HO-C (O) CH (R10a) N (G) (Ga) XII 10a a or a suitable derivative thereof, wherein R, G and G are as defined in Claim 1; h) for the compounds of formula I wherein Y represents C (O) C (R13a) = C (R13b) NH2 or C (O) CH (R13a) CH (NH2) (R13b), and R13a and R13b are such as defined in Claim 1, reaction of a corresponding compound of formula I in which Y represents H, with a compound of formula XIII, wherein the broken line represents an optional double bond, and R13a and R13b are as defined in Claim 1; i) for the compounds of formula I wherein Y represents C (O) R, wherein R represents phenyl substituted at the ortho position by an amino group, and optionally substituted by one or more additional substituents selected from OH, halo, C alca-alkanoyl, C C1-alkanoyloxy, N (R 8) (R 9), C (O) N (R 8) (R 9), C 1-4 alkyl and C 1 - * alkoxy (last two groups which are optionally substituted by one or more halo atoms), and R8 and R9 are as defined in Claim 1, reaction of a corresponding compound of formula I wherein Y represents H with a compound of formula XIV, wherein D represents one to four optional substituents selected from OH, halo, Ci- * alkanoyl, C1- * alkanoyloxy, N (R8) (R9), C (O) N (R8) (R9), C1- alkyl 4 and alkoxy d-4 (last two groups which are optionally substituted by one or more halo atoms), and R8 and R9 are as defined in Claim 1; j) for the compounds of formula I wherein Y represents R11, wherein R11 is as defined in Claim 1, reaction of a corresponding compound of formula I wherein Y represents H, with a compound of formula XV , R11-L2 XV wherein L2 represents a leaving group and R11 is as defined in Claim 1; k) for the compounds of formula I wherein Y represents CH (R12b) C (O) OR12a or CH (R12b) OC (O) OR12a, wherein R12a and R12b are as defined in Claim 1, of a corresponding compound of formula I in which Y represents H, with a compound of formula XVI, L2-CH (R12b) C (O) OR12a XVI or a compound of formula XVll, L2-CH (R12b) OC (O) OR12a XVll wherein R12a, R12b are as defined in Claim 1 and L2 is as defined above; I) for the compounds of formula I in which Y represents PO (OR14) 2, wherein R14 is as defined in Claim 1, reaction of a compound of formula I in which Y represents H, with a compound of formula XVlll, H-PO (OR14) 2 XVlll or a compound of formula XIX, HO-PO (OR14) 2 XIX or a suitable derivative thereof, wherein R14 is as defined in Claim 1; m) for the compounds of formula I wherein X represents halo and optionally one or more additional substituents defined in Claim 1 with respect to X, reaction of a corresponding compound of formula XX, wherein Xa represents an H and optionally one to three of the substituents defined in Claim 1 with respect to X, and R1, R2, R3 and Y are as defined in Claim 1, with a halogenating agent; n) for compounds of formula I wherein X represents nitro and optionally one or more additional substituents defined in Claim 1 with respect to X, nitration of a corresponding compound of formula XX, as defined above; o) for compounds of formula I wherein X represents S (O) 2? H and optionally one or more additional substituents defined in Claim 1 with respect to X, sulfonation of a corresponding compound of formula XX, as defined above; p) for the compounds of formula I wherein X 17a represents S (O) tR, wherein t is 0, and optionally one or more additional substituents defined in Claim 1 with respect to X, wherein R17a is such as was defined in Claim 1 except that it does not represent N (R20a) (R20b), wherein R20a and R20b are as defined in Claim 1, sulfenylation of a corresponding compound of formula XX, as defined above; q) for the compounds of formula I wherein X represents C (O) R16a and optionally one or more additional substituents defined in Claim 1 with respect to X, wherein R16a is as defined in Claim 1 except that no represents H, acylation of a corresponding compound of formula XX, as defined above; r) for the compounds of formula I wherein X represents C (O) H and optionally one or more additional substituents defined in Claim 1 with respect to X, reaction of a corresponding compound of formula XX, as defined above, with dimethylformamide; s) for the compounds of formula I wherein X represents OC (O) R16c and optionally one or more additional substituents defined in Claim 1 with respect to X, wherein R16c is as defined in Claim 1, oxidation of a corresponding compound of formula I wherein X represents C (O) R16a, 16a wherein R is as defined in Claim 1; t) for compounds of formula I wherein X and / or OY represent OH, hydrolysis and / or reductive cleavage of a corresponding compound of formula I wherein X represents OC (O) R16c, wherein R16c is such as was defined in Claim 1, and / or Y represents C (= E) NR8R9, wherein R8 and R9 are as defined in Claim 1; u) for the compounds of formula I wherein X represents d.io alkyl, C3-10 alkenyl, C3-10 alkynyl, C3-7 cycloalkyl (four groups which are optionally substituted as defined in Claim 1, and alkenyl and alkynyl groups which are fully saturated in C1 (relative to the benzene ring)) and optionally one or more additional substituents defined in Claim 1 with respect to X, reaction of a corresponding compound of formula XX, as defined above, with a compound of formula XXVI, R22-L2 XXVI wherein R22 represents CMO alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl (four groups which are optionally substituted by one or more substituents selected from halo, CN , nitro, OH, C3-7 cycloalkyl, Ci-β alkoxy, C3-7 cycloalkoxy, C1-6 alkanoyl, C4-8 cycloalkanoyl, C2-6 alkoxycarbonyl, 15a 15b C2-6 alkanoyloxy or N (R) (R), and alkenyl and alkynyl groups that are completely sat urated C1 (relative to L2)) and L2, R15a and R15b are as defined in Claim 1; v) for compounds of formula I in which X represents C (O) N (R18c) (R18d), which group is in the ortho position in relation to OY, in which R18c and R18d independently represent C3-7 cycloalkyl CO alkyl , and Y represents H, new arrangement of a corresponding compound of formula XXVII. XXVII wherein R 23 represents C 3 -C 7 cycloalkyl alkyl, and R 1, R 2 and R 3 are as defined in Claim 1; W) for the compounds of formula I wherein X represents C2-10 alkenyl and optionally one or more additional substituents defined in Claim 1 with respect to X, wherein the double bond of the alkenyl chain is a, ß- to the ring of benzene, reaction of a corresponding compound of formula XX, as defined above, with a C2-10 aldehyde or a C2-10 ketone; x) for the compounds of formula I wherein X represents C (O) N (H) R18c and optionally one or more additional substituents 18c defined in Claim 1 with respect to X, wherein R represents C3-7 cycloalkyl CO alkyl , reaction of a corresponding compound of formula XX, as defined above, with a compound of formula XXVIII, 0 = C = N-R23 XXVIII wherein R23 is as defined above; y) for the compounds of formula I wherein X represents B (OCH3) 2 and optionally one or more additional substituents defined in Claim 1 with respect to X, reaction of a corresponding compound of formula XX, as defined above, with trimethyl borate: z) for the compounds of formula I wherein X represents C2-10 alkenyl or C2-10 alkynyl, alkenyl and alkynyl groups containing a carbon-carbon multiple bond that is a, ß to the benzene ring, and alkenyl and alkynyl groups which are optionally substituted as defined in Claim 1 with respect to X, and optionally one or more additional substituents defined in Claim 1 with respect to X, reaction of a corresponding compound of formula I in which at least one X represents halo with a compound of formula XXIX, R24-M XXIX wherein R24 represents C2-10 terminal alkenyl or C2-10 terminal alkynyl, alkenyl and alkynyl groups which are substituted optionally by one or more substituents selected from halo, CN, nitro, OH, C3-7 cycloalkyl, C-? 6 alkoxy, C3-7 cycloalkoxy, d-6 alkanoyl, C4-8 cycloalkanoyl, C2-6 alkoxycarbonyl, 15a 15b C2-6 alkanoyloxy or N (R) (R), M represents (as appropriate) H, a tin-containing moiety, a boron derivative, a zinc halide, a magnesium halide or an alkali metal (last three groups) which may be formed in situ at 15a to 15b from the corresponding halide), and R and R are as defined in Claim 1; aa) conversion of a functional group in an alkyl, heterocyclic or aryl group in a compound of formula I to another.

20. A compound of formula II, as defined in claim 19.

21. A compound of formula III, as defined in claim 19.

22. A compound of formula XX, as defined in Claim 19.

23. A compound of formula XXVII, as defined in Claim 19.