MXPA00005227A

MXPA00005227A - 4-arylpiperidine derivatives for the treatment of pruritus

Info

Publication number: MXPA00005227A
Application number: MXPA/A/2000/005227A
Authority: MX
Inventors: Edward Armer Richard; Morris Gethin David; Paul Gibson Stephen; Tommasini Ivan
Original assignee: Pfizer Limited
Priority date: 1999-05-28
Filing date: 2000-05-26
Publication date: 2001-11-21

Abstract

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

Description

NEW 4-ARILPIPERIDINE DERIVATIVES FOR THE TREATMENT OF PRURITE This invention relates to novel 4-phenylpiperidines which have utility in the treatment of pruritic dermatoses including allergic and atopic dermatitis in animals and humans, and methods for the preparation of intermediates used in the preparation of said compounds. Itching or itching is a common dermatological symptom that can lead to considerable discomfort in both humans and animals. Pruritus often already associated with an inflammatory skin disease that can be commonly caused by hypersensitivity reactions, such as reaction to insect bites, for example flea bites, or to environmental allergens such as house dust mites or pollen; or bacterial and fungal infections of the skin or infections by ectoparasites. Previous treatments for pruritus include the use of corticosteroids and antihistamines, however, both have undesirable side effects. Other therapies include the use of dietary fatty acid supplements that are slow to act and offer only limited efficacy against allergic dermatitis. A variety of emollients such as mild paraffin, glycerin and lanolin are also used, but with limited success and there is a continuing need for an effective remedy.

Certain 1,4-trisubstituted 4-aryl-piperidine derivatives are described in GB-A-1525584 as potent narcotic antagonists which also have analgesic properties. These compounds are also claimed in EP-B-0287339 as opioid antagonists that block the effect of the agonist at mu or kappa receptors, having a potential utility in the treatment of a variety of disorders associated with these receptors such as eating disorders, overdose for opiates, depression, tobacco, alcoholism, sexual dysfunction, concussion, stroke, spinal damage and head trauma; its usefulness as an appetite suppressant for weight loss is also indicated. Other 1-N-substituted-4-aryl piperidines are described in EP-A-0506468 and EP-A-0506478. Its potential usefulness for preventing the undesirable effects of peripherally mediated opioids and for alleviating the symptoms of idiopathic constipation and irritable bowel syndrome is indicated.

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 the formula I: wherein R and R2 are each independently H or C? -4 alkyl; R 3 represents aryl (optionally substituted by one or more substituents selected from OH, nitro, halo, CN, CH 2 CN, CONH 2, C 1-4 alkyl, C 1-4 alkoxy, C? -5 alconoyl (the last three groups being optionally substituted by one or more halo atoms) and -N (R4a) (R4b), CMO alkyl, alkenyl C3-? Oo C3-? O alkynyl, said alkyl, alkenyl or alkynyl groups being optionally substituted and / or terminated by one or more substituents selected from OR4c, S (O) nR4d, CN, halo, C6-6 carbonyl alkoxy, C2-6 alkoxy, C2-6 alkoxyloxy, C3-8 cycloalkyl, C4-9 cycloalkanoyl, N (R5a) S (O) 2R6, Het1, aryl, adamantyl (the last two groups being optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C- alkyl, C1-4 alkoxy and C1-5 alkanoyl (the last three groups being optionally substituted by one or more halo atoms)) or -W-A1-N (R5b) (R5c); 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 represent simple bonds, then the group -N (R5b) (R5c) is not directly bonded to an unsaturated carbon atom; p is 0, 1 or 2; R 4a to R 4d each independently represents H, C 1 -alkyl. or, C3-? 0 alkenyl, C3-? 0 alkynyl, C3-8 cycloalkyl, C1- alkylphenyl, aryl (the last six groups being optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C? - alkyl, C? -4 alkoxy and C1-5 alkanoyl (the last three groups being 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, C? -? Or alkyl, C3 -? Alkenyl, C3 -? 0 alkynyl, C3 - 8 cycloalkyl, C? - alkylphenyl, aryl (the last six groups being optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C? - alkyl, C-? alkoxy and C? -5 alkanoyl (the last three groups being optionally substituted by one or more halo atoms)) , Het3, or R5b and R5c jutes represent unbranched C2-6alkylene, an alkylene group which is optionally interrupted by O, S and / or a group N (R7) and is optionally substituted by one or more C? - alkyl groups; R6 represents C? -6 alkyl, C3-8 cycloalkyl, C? -4 alkylphenyl or aryl, the four groups being optionally substituted by one or more substituents selected from C-? -4 alkyl, C? - alkoxy, OH, nitro, amino or halo; R7 represents H, C? -6 alkyl, C3-8 cycloalkyl, A2- (C3- cycloalkyl) 8) or A2-aryl; A2 represents C1-6 alkylene; Het1, Het2 and Het3 independently represent 3 to 8 membered heterocyclic groups, said groups containing at least one heteroatom selected from oxygen, sulfur and / or nitrogen, said groups being optionally fused to a benzene ring, and said groups being optionally substituted in the part of the heterocyclic ring and / or the benzene ring condensed by one or more substituents selected from OH, = 0, nitro, amino, halo, CN, aryl, alkyl, CM, C? -4 alkoxy and C? -5 alkanoyl? (the last three groups being optionally substituted by one or more halo atoms); Y represents -C (= E) NR8R9, C (O) OR10, C (O) CH (R10) 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) (R3b) or PO (OR14) 2; E represents O or S; R8 and R9 independently represent H, C-MO alkyl, C3-? Alkenyl or (the last two groups being optionally substituted by one or more C4-7 aryl or cycloalkyl groups (the two groups being optionally substituted by one or more substituents selected from halo, d-4 alkyl, C- alkoxy, C 1-4 haloalkyl or C 1-4 haloalkoxy), aryl, C-7 cycloalkyl (optionally substituted by one or more substituents selected from halo, C 1-4 alkyl and C- alkoxy? -4 (the last two groups being optionally substituted by one or more halo atoms), or R8 and R9, together with the N atom to which both are attached, 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 C1-4 alkyl groups; R 10 represents H, C-7 cycloalkyl (optionally substituted by one or more C 1-4 alkyl groups), C 1-11 alkyl (substituted by one or more substituents selected from aryl (optionally substituted by one or more substituents selected from OH, halo, alkanoyl C? -4, C? 4 alkanoyloxy, N (R8) (R9), C (O) N (R8) (R9), C1-4 alkyl, C1-4 alkoxy, haloalkyl d-4 and haloalkoxy d-4 ) or C4- cycloalkyl (the latter group being optionally substituted by one or more d-4 alkyl groups) or aryl (optionally substituted by one or more substituents selected from OH, C? -4 alkanoyl halo, d-4 alkanoyloxy, N) (R8) (R9), C (O) N (R8) (R9), d4 alkyl and C1-4 alkoxy (the last two groups being optionally substituted by one or more groups of halo atoms)); R10a represents C4 cycloalkyl (optionally substituted by one or more d-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, C1 alkanoyl) -4, alkanoyloxy d-4, C 1-4 alkanoyloxy, N (R 8) (R 9), C (O) N (R 8) (R 9), C 1-4 alkyl, C 1-4 alkoxy, haloalkyl d-4 and haloalkoxy d -4) or C4-7 cycloalkyl (the latter group optionally being substituted by one or more C1-4 alkyl groups), aryl (optionally substituted by one or more substituents selected from OH, halo, d-4 alkanoyl, C1-6 alkanoyloxy) 4, N (R8) (R9), C (O) N (R8) (R9), alkyl d.4 and C4-4 alkoxy (the latter two groups being optionally substituted by one or more halo atoms) or Het5; R 10 represents H, C 4-7 cycloalkyl, d-10 alkyl (optionally substituted by one or more substituents selected from aryl or C 4 cycloalkyl), aryl, or R 10b (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 R1 ° b, represents a naturally occurring amino acid substituent; R 11 represents C 4-7 cycloalkyl (optionally substituted by one or more C 1-4 alkyl groups), aryl (optionally substituted by one or more substituents selected from OH, halo, C 4 alkanoyl, alkanoyloxy d 4 N (R 8) (R9), C (O) N (R8) (R9), C4-4alkyl and C- (C2) alkoxy (the latter two groups being optionally substituted by one or more halo atoms), C6-6alkyl, alkenyl C3-? O, said alkyl or alkenyl group being optionally substituted by one or more substituents selected from C (O) NH2, Het6, cycloalkyl d-7 (optionally substituted by one or more C1-4 alkyl groups). aryl, aryloxy or aryl-C 1-4 alkyloxy (the last three groups being optionally substituted by one or more substituents selected from OH, halo, C 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 (the last two groups being optionally substituted by one or more halo atoms), or R 11 represents Het 7 or d-5 alkyl substituted by one or more substituents selected from C (O) NH2, Het8, C4-7 cycloalkyl (optionally substituted by one or more C1-4 alkyl groups), aryl, aryloxy or arylalkoxy C1- (the last three groups being optionally substituted by one or more substituents selected from OH, halo, C 1-4 alkanoyl, alkanoyloxy CMf N (R 8) (R 9), C (O) N (R 8) (R 9), C 1-4 alkyl and C 1-4 alkoxy (the latter two groups being optionally substituted by one or more halo atoms)); Het5 to Het8 independently represent 4 to 6 membered heterocyclic rings, said rings containing at least one hereroatome selected from oxygen, sulfur and / or nitrogen, said rings optionally being fused to a benzene ring, and said rings being optionally substituted in the part of the heterocyclic ring and / or the benzene ring condensed by one or more substituents selected from OH, = 0, nitro, amino, halo, CN, aryl, C1- alkyl, C1-4 alkoxy, C3-β cycloalkyl and alkanoyl d- 5 (the last four groups being optionally substituted by one or more halo atoms); pi2a and pi2b independently represent H, cycloalkyl d-7 (optionally substituted by one or more Ci ^ alkyl groups), C-MO alkyl (optionally substituted by one or more substituents selected from aryl or C4-7 cycloalkyl (being in the latter group optionally substituted by one or more alkyl d-4) or aryl groups (optionally substituted by one or more substituents selected from OH, halo, C? -4 alkanoyl, alkanoyloxy Cl. 4, C? -4 alkyl and d-4 alkoxy (the last two groups being optionally substituted by one or more halo atoms)); 13a and R13b independently represent H, C4-7 cycloalkyl (optionally substituted by one or more alkyl groups d-), C1-10 alkyl, C2-? 0 alkenyl, (alkyl or alkenyl groups which are optionally substituted by one or more substituents selected between aryl or C7-cycloalkyl (the latter group optionally being substituted by one or more alkyl d-) or aryl groups (optionally substituted by one or more substituents selected from OH, halo, C-γ4 alkanoyl, d-alkanoyloxy) , alkyl C- and alkoxy-4 (the last two groups being optionally substituted by one or more halo atoms)); R 14 represents H, cycloalkyl d-7 (optionally substituted by one or more C? -4 alquilo alkyl groups), C C1-10 alquilo alkyl (optionally substituted by one or more substituents selected from aryl or C 4 cycloalkyl (the latter group being optionally substituted by one or more alkyl groups C-), or aryl (optionally substituted by one or more substituents selected from OH, halo, C 1-4 alkanoyl, C- alkanoyloxy, d-4 alkyl and C 1-4 alkoxy (the last two groups being optionally substituted by one or more halo atoms)); or derivatives thereof acceptable veterinarily or pharmaceutically; these compounds are referred to collectively as "compound of the invention". In the definitions used herein, alkyl, alkylene alkoxy, alkoxycarbonyl, alkanoyl, alkanoyloxy, alkenyl, alkynyl and the alkyl portions of the aliphenyl and arylalkoxy groups may, when there is a sufficient number of carbon atoms, be straight or branched chain and / or optionally interrupted by one or more atom ( s) of oxygen and / or sulfur. The term halo includes fluorine, chlorine, bromine and iodine. 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 (for example one to three) substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH, C- alkyl, C.sub.4 alkoxy, C.sub.1-4 alkoxycarbon and C.sub.30 alkanoyl (the last four groups are optionally substituted by one or more halogen atoms). The heterocyclic rings representing Het1, Het2, Het3, Het4, Het5, Het6, Het7 and Het8 may be fully saturated, partially unsaturated and / or of a total or partially aromatic character. Specific rings may be mentioned which include: Het1, dioxane, dioxolane, morpholine, piperidine, perhydroazepine, pyrazole, pyridine, triazole, tetrahydrofuran, tetrahydropyran, pyrrole, pyrrolidine or tetrazole; for Het2, tetrahydropyran. To avoid doubts, when groups Het (Het1, Het2, Het3, Het4, Het5, Het6, Het7 and Het8) are at least partially saturated, 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. The Het groups can also be linked to the rest of the molecule via a heteroatom. The piperidine radical in compounds of formula I may be in the N-oxidized form. Sulfur atoms which can interrupt substituents (for example alkyl) in compounds of the formula I can be present in oxidized form (for example as sulfoxides or sulfones). All the groups Het1, Het2, Het3, Het4, Het5, Het6, Het7 and Het8 can also be in the N- or S-oxidized forms. The term "amino protecting group" as used herein will be understood by the skilled person to include those already mentioned in "Protective Groups in Organic Synthesis", 2pdedition, TW Greene & PGM Wiley-lnterscience (1991), in particular those indicated on pages 218 to 222 of that reference, incorporating the description of said document, herein, as a reference. - Specific examples of amino protecting groups, therefore, include carbamate groups (for example, methyl, cyclopropylmethyl, 1-methyl-1-cyclopropylmethyl, diisopropylmethyl, 9-fluorenylmethyl, 9- (2-sulfo) fluorenylmethyl, 2-furanylmethyl groups , 2,2,2-trichloroethyl, 2-haloethyl, 2-trimethylsilylethyl, 2-methylthioethyl, 2-methyl-sulfonyl-ethyl, 2 (p-toluenesulfonyl) ethyl, 2-phosphononoethyl, 1,1-dimethylpropynyl, 1-1-dimethyl -3 - (? / J? / - dimethylcarboxamido) propyl, 1,1-d.methyl-3 - (? /,? / - d.ethylamino) propyl, 1-methyl-1 - (l-adamantyl) ethyl, 1-methyl-1-phenylethyl, 1-methyl-1- (3, 5-dimethoxyphenyl) 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, f-butyl, f-amyl , cyclobutyl, 1-methylcyclobutyl, cyclopentyl, cyclohexyl, 1-methyl-cyclohexyl, 1-adamantyl, isobornyl, vinyl, allyl, cinnamyl, phenyl, 2,4,6-tri-1-butylphenyl, m-nitrophenyl, S-phenyl , 8-quinolinyl, N-hydroxypiperidinyl, 4- (1,4-dimethylpiper) idintl), 4,5-diphenyl-3-oxazolin-2-one, benzyl, 2,4,6-trimethylbenzyl, p-methoxybenzyl, 3,5-dimethoxybenzyl, p-decyloxybenzyl, p-nitrobenzyl, o-nitrobenzyl, , 4-dimethoxy-6-nitrobenzyl, p-bromobenzyl, chlorobenzyl, 2,4-dichloro-benzyl, p-cyanobenzyl, o- (N, N-dimethylcarboxamidobenzyl) benzyl, m-chloro-p-acyloxybenzyl, p- (dihydroxyboron ) benzyl, p- (phenylazo) -benzyl, p- (p-methoxyphenylaz) 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 (for example? / -formyl,? / -acetyl, N-chloroacetyl,? / - dichloroacetyl,? / - trichloroacetyl, ? / - trifluoroacetyl,? / - o-nitrophenylacetyl, / Vo-nitrophenoxyactyl,? / - acetoacetyl,? / - acetyl-pyridino,? / - 3-phenylpropionyl,? / - 3- (p-hydroxyphenyl) propionyl,? / -3- (o-nitrophenyl) propionyl,? / - 2-methyl-2- (o-nitrophenoxy) propionyl,? / - 2-methyl-2- (o-phenylazophenoxy) propionyl,? / - 4-chlorobutyryl, N -isobutyryl,? / - o-nitrocinamoyl,? / - picolinoyl,? / - (? / '- a cetylmethionyl) -? / - (? / '- benzoylphenylalanyl),? / - benzoyl,? / - p-phenylbenzoyl,? / - p-methoxybenzoyl,? / - o -nitrobenzoyl or? / - o- (benzoyloxymethyl) benzoyl amide ), alkyl groups (for example? -alyl,? / - phenacyl,? / - 3-acetoxypropyl,? / - (4-nitro-1-cyclohexyl-2-oxo-pyrroline-3-yl),? / - methoxymethyl,? / - chloro-ethoxymethyl, ? / - benzyloxymethyl,? / - pivaloyloxymethyl,? / - 2-tetrahydropyranyl,? / - 2,4-dinitrophenyl,? / -benzyl,? / - 3,4-dimethoxybenzyl, No-nitrobenzyl,? / - di (p. -methoxyphenyl) methyl,? / - phenylmethyl,? / - (p-methoxyphenyl) diphenylmethyl,? / - diphenyl-4-pyridylmethyl, groups? / - 2-picolyl? / '- oxide or? / - dibenzosuberil ), phosphinyl and phosphoryl groups (for example N-diphenylphosphinyl,? / - dimethylthiophosphinyl,? / - diphenylthiophosphinyl,? / - diethylphosphoryl, N-dibenzylphosphoryl or? / - phenylphosphoryl groups), sulfenyl groups (for example N-benzenesulfenyl groups) ,? / - o-nitrobenzenesulfenyl,? / - 2,4-dinitrobenzenesulfenyl, N-pentachlorobenzenesulfenyl,? / - 2-nitro-4-methoxybenzenesulfenyl or N-triphenylmethylsulfenyl), sulfonyl groups (for example? / -benzenesulfonyl,? / - p-methoxybenzenesulfonyl,? / - 2,4,6-trimethylbenzenesulfonyl,? / -toluenesulfonyl, N-benzylsulfonyl,? / - p-methylbenzylsulfonyl,? / - trifluoromethylsulfonyl or N-phenylsulfonyl) or the? / -trimethylsilyl group. The term "naturally occurring amino acids", as used herein, includes the amino acids glycine, alanine, valine, leucine, isoleucine, phenylalanine, trioptophane, tyrosine, histidine, serine, threonine, methionine, cysteine, aspartic acid , glutamic acid, asparagine, glutamine, lysine, arginine and proline. The term "veterinarily or pharmaceutically acceptable derivatives" includes non-toxic salts. Salts may be mentioned which include: acid addition salts, for example, salts formed with sulfuric, hydrochloric, hydrobromic, phosphoric, iodohydric, sulfamic, organosulfonic, citric, carboxylic (eg, acetic, benzoic, etc.) salts. maleic, malic, succinic, tartaric, cinnamic, ascorbic and related acids, base addition salts; salts formed with bases, for example, sodium, potassium and C 1 -C 4 alkyl ammonium salts. The compounds of the invention can also be in the form of quaternary ammonium salts, e.g. in the piperidine radical, salts that can be formed by reaction with a variety of alkylating agents, such as an alkyl halide or a sulfuric acid 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, therefore, may exist as enantiomers or diastereoisomers. The diastereoisomers can be separated using conventional techniques, for example by fractional crystallization or chromatography. The various stereoisomers can be isolated by separation of a racemic and other mixture of the compounds using conventional techniques, for example fractional crystallization or chromatography. The various stereoisomers can be isolated by 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 reaction of the appropriate optically active starting materials under conditions that do not produce racemization or epimerization. Alternatively, the desired optical isomers can be prepared by resolution, either by HPLC of the racemate using a suitable chiral support or, where appropriate, by fractional crystallization of the diastereoisomeric salts formed by reaction of the racemate with a suitable optically active base or acid. The invention includes the use of both individually separated isomers, as well as mixtures of isomers.

Also included in the scope of the invention are derivatives of compounds of formula I labeled with radioactive isotopes that are suitable for biological studies. According to a further aspect of the invention, there is provided a compound of formula I, as defined hereinabove, provided that when OY is attached in the meta position to the piperidine ring, Y represents R11, R11 represents 2- (2-methyl) propionamide and the piperidine ring is not in the? / -oxid form, then R3 represents: optionally substituted aryl; C3-? 0 alkenyl or C3-? alkynyl or optionally substituted (these two groups 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; alkyl- C3-, C3-? oo alkenyl or C3-? 0 alkynyl, and these groups 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 alkanoyl C s (the latter group is optionally substituted by one or more halogen atoms)), aril (substituted by one or more substituents selected from nitro, amino and C1-5 haloalkanoyl) or adamantyl (the latter group is optionally substituted by one or more of the related substituents identified hereinbefore); or OR4c, wherein R4c represents C7-10 alkyl, C3-10 alkenyl, C3-10 alkynyl or Het2 (these latter four groups are optionally substituted by one or more of the related substituents identified hereinbefore), or R4c represents C1-10 alkyl, d-4 alkylphenyl, C3-8 cycloalkyl or aryl (these latter four groups are all substituted by one or more of the related substituents identified hereinbefore); -W-A1-N (R5b) (R5c), wherein R5b and / or R5c independently represent C1-4 alkylphenyl (this latter group is optionally substituted by one or more of the related substituents identified hereinbefore), Cpo alkyl, C3-10 alkenyl, C3- [alpha] 0 alkynyl, C3-8 cycloalkyl (these latter four groups are all substituted by one or more of the related substituents identified hereinbefore), or aryl (substituted by one or more substituents selected from nitro, amino and haloalkanoyl ds); these compounds can 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 with respect to the piperidine group; R1 represents alkyl d-2; R 2 represents H or C 1-2 alkyl; R3 represents C6-6 alkyl, C3-6 alkenyl or C3-6 alkyl, said alkyl, alkenyl or alkynyl groups being optionally substituted and / or terminated by one or more substituents selected from OR4c, CN, halo, Het1, or aryl (this latter group is optionally substituted by one or more substituents selected from OH, alkyl d-2, alkoxy d-2 or halo); R4c represents H, alkyl d-6, cycloalkyl C4-6, aryl or Het2; Het1 and Het2 independently represent heterocyclic groups of 5 to 7 members, and these groups contain at least one heteroatom selected from oxygen, sulfur and / or nitrogen, and these groups are optionally substituted by one or more alkyl groups d-2 (these alkyl groups they are optionally substituted by one or more halogen atoms); Y represents C (= E) NR8R9, C (O) R10 or R11; R8 and R9 independently represent H or C1-4 alkyl; R 10 represents C 1-6 alkyl (substituted by one or more phenyl group) or aryl (optionally substituted by one or more substituents selected from OH, halo, C? -3 alkanoyloxy, NH2, C (O) NH2 and C? -3 alkyl (this latter group is optionally substituted by one or more halogen atoms)); R11 represents d5 alkyl (substituted by one or more substituents selected from C (O) NH2, Het8, aryl and aryloxy), C6-? Oo or C3-? 0 alkenyl, and these last two groups are optionally substituted by one or more substituents selected from Het6 and aryl; Het6 and Het8 independently represent 5-6 membered heterocyclic rings, and these rings contain at least one heteroatom selected from oxygen, sulfur and / or nitrogen; these rings are optionally fused to a benzene ring and these rings are optionally substituted on the part of the heterocyclic ring and / or of benzene condensed by one or more substituents selected from OH, = O and C- alkyl); Het6 and Het8 are in the S-oxidized form. More preferred compounds of the invention include those in which: R represents methyl; R 2 represents H or methyl; R3 represents linear saturated d-β-alkyl optionally substituted and / or terminated by one or more substituents selected from OR4c or Het1; R 4c represents C 1-6 alkyl or C 4-6 cycloalkyl; Het1 represents a saturated heterocyclic group of 5 to 6 members, and this group contains a heteroatom selected from oxygen, sulfur or nitrogen; R8 and R9 independently represent H or C? -3 alkyl; R10 represents C- (substituted by one or more phenyl groups) or phenyl (optionally substituted by one or more substituents selected from OH, C? -2 alkanoyloxy, NH 2 and C 1-2 alkyl); R11 represents C- linear or branched alkyl (substituted by one or more substituents selected from C (O) NH2, phenyl and Het8), C6-8 alkyl or C3-5 alkenyl; Het8 represents a five-membered heterocyclic ring, and this ring contains at least one heteroatom selected from oxygen, sulfur and / or nitrogen; this ring is condensed to a benzene ring and this ring is optionally substituted, on the part of the heterocyclic ring and / or condensed benzene, by one or more substituents selected from = O and C-? -4 alkyl); Particularly preferred compounds of the invention include those in which: R1 and R2 represent methyl groups in the trans configuration mutually. Preferred compounds of the invention include the compounds of the examples described below. Therefore, according to a further aspect of the invention, there is provided a compound of the formula I which, apart from any of the above definitions, is: (±) -3- (1-hexyl-trans-3,4-d) methyl-4-p-peridinyl) phenyldimethylcarbamate; (+) - 3- (1-hexyl-frans-3,4-d.methyl-4-piperidinyl) phenylmethylcarbamate; (±) -3- (1-hexyl-trans-3,4-dimethyl-4-piperidinyl) phenolidethylcarbamate; (±) -3- (1-hexyl-urea-3,4-d-methyl-4-p-peridinyl) phenylpivalate; (±) -3- (1-hexyl-frans-3,4-dimethyl-4-piperidinyl) phenyl 2- (acetyloxy) -benzoate; (±) -3- (1-hexyl-rans-3,4-d, methyl-4-piperidinyl) phenylsalicylate; 2-. { [(±) -3- (1-hexyl-fraps-3,4-dimethyl-4-piperidinyl) -phenoxy] methyl} -1H-1, 2-benzoisothiazol-1, 1, 3- (2H) -trione; (±) -3- (1-hexyl-frans-3,4-dimethyl-4-piperidinyl) phenyl 2-methyl-benzoate; (±) -3- (1-hexyl-εpra-3,4-dimethyl-4-p¡peridinyl) phenyl 2-aminobenzoate; (±) -3- (1-hexyl-trans-3,4-d-methyl-4-piperidinyl) phenyl-2,6-dimethyl-benzoate; (±) -3- (1-hexyl-frans-3,4-dimethyl-4-piperidinyl) phenyl 2,2-diphenyl-propionate; (±) -2-. { 3- [1- (3-Tetrahydro-2H-pyran-2-ylpropyl) -., 7S-3,4-dimethyl-4-piperidinyl) phenoxy} -methyl-1 H-1, 2-benzoisothiazol-1, 1, 3- (2H) -trione; (±) -3- [1- (3-tetrahydro-2 H -pyran-2-ylpropyl) -irap7s-3,4-dimethyl-4-piperidinyljphenyl 2- (acetyloxy) benzoate; (±) -2 - [(3- { 1 - [2- (cyclohexyloxy) ethyl] -frans-3,4-dimethyl-4-pyridinyl}. Phenoxy) -methyl] -1 H-1 , 2-benzoisothiazol-1, 1, 3- (2H) -trione; (±) -3-. { 1- [2- (cyclohexyloxy) ethyl] -irae-3,4-dimethyl-4-piperidinol} phenyl 2- (acetyloxy) benzoate; (±) -4- (3- (1-carbamoyl-1-ethoxymethyl) phenyl) -N-hexyl-trans-3,4-dimethylpiperidine; (±) -4- [3- (allyloxy) phenyl] -1-hexyl-trans-3,4-dimethylpiperidine; (±) -O- [3- (1-hexyl-trans-3,4-dimethyl-4-piperidinyl) phenyl] diethylcarbamothioate; or (±) -1-hexyl-trans-3,4-dimethyl-4- [3- (hexyloxy) phenyl] piperidine, and these compounds can also be referred to as "compounds of the invention". According to a further aspect of the invention, methods are provided for the preparation of compounds of the invention, as illustrated below. The following procedures are illustrative of the general synthetic procedures that can be adopted to obtain the compounds of the invention. 1. The compounds of formula I in which R3 represents Ci alkyl optionally substituted by C3-8 cycloalkyl, Het1, aryl, adamantyl (the last two groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, alkyl d-4, C1-4 alkoxy, and alkanoyl d-5 (the last three groups are optionally substituted by one or more halogen atoms)), or R3 represents C2-? alkyl, or C3-? alkenyl (these three groups are all optionally substituted by one or more of the related substituents identified above in the present document with respect to R3), and these alkyl, alkenyl and alkynyl groups are attached to the nitrogen atom of the piperidine via a CH2 group, where Het1 is as defined above, can be prepared by reduction of a corresponding compound of formula II, wherein R31 represents H, C3-8 cycloalkyl, Het1, aryl, adamantyl (the last two groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH 2CN, CONH2, C1-4 alkyl, C---4 alkoxy, and d-5 alkanoyl (the last three groups are optionally substituted by one or more halogen atoms), d2 alkyl, C2-9 alkenyl or C2- alkynyl 9, and these alkyl, alkenyl, and alkynyl groups are optionally substituted and / or terminated by one or more substituents selected from OR4c, S (O) nR4d, CN, halo, C6-C6 alkoxy >; C2-6 alkanoyl, C2-6 alkanoyloxy, C3-8 cycloalkyl, C4-9 cycloalkanoyl, N (R5a) S (O) 2R6, Het1, aryl, adamantyl (the last two groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-4alkyl, alkoxy d-4, and alkanoyl C? -5, (the last three groups are optionally substituted by one or more halogen atoms)), or -W-A1-N (R5) (R5c), and R1, R2, R4c, R4d, R5a, R6, Het1, n, Y, W and A1 are as defined above, using a reducing agent suitable (eg, lithium hydride or a borane derivative), for example with that described hereinabove.

Compounds of formula II can be prepared by reaction of the corresponding compound of formula III, wherein R1, R2 and Y are as defined hereinbefore, with a compound of formula IV, R31CO2H IV or a suitable derivative (e.g. carboxylic acid) thereof (e.g., an acid halide or anhydride) ) wherein R31 is as defined above in the present document, 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 shown herein, which describe the production of compounds of formula I. 2. Compounds of formula I can be prepared by reaction of a corresponding compound of formula III, as described hereinabove, 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 in the present document, under conditions that are known to those skilled in the art, including, for example, alkylation at a temperature between room temperature and reflux in the presence of an inert organic solvent (for example? /, V-dimethylformamide) and a suitable base (for example NaHCO3), and arylation at a temperature between room temperature and reflux in the presence of a suitable catalyst system (for example tris (dibenzylideneacetone) palladium (0) combined with tri-o-tolylphosphine), an appropriate strong base (for example sodium tert-butoxide) and an inert solvent (for example toluene). 3. The compounds of formula I wherein R3 represents alkyl d, which instead of being optionally substituted by substituents that have been defined hereinbefore, is optionally substituted, instead, by R31, where R31 is as previously defined herein, can be prepared by reaction of a corresponding compound of formula III, as defined hereinbefore, with a compound of formula VI, R31CHO VI wherein R31 is as defined above in the present document, for example in the presence of a suitable reducing agent (eg sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride) and a suitable solvent (eg methanol). 4. The compounds of formula I wherein R3 is a C-- -10 alkyl, C4-? 0 alkenyl, or C4-? Alkynyl group, which is fully saturated from C1 to C3 (with respect to the N atom of the piperidine), and this group R3 is substituted on the C2 (with respect to the N atom of the piperidine) by S (O) R4d, S (O) 2R4d, alkanoyl, cycloalkanoyano, alkoxycarbonyl, CN, C- (O) - A -N (R5b) (R5c), -S (O) -A1-N (R5b) (R5c), or -S (O) 2-A1-N (R5) (R5c), wherein R4d, R5b and R5c and A1 are as defined hereinabove, they can be prepared by reaction of the corresponding compound of formula III, as defined hereinbefore, with a compound of formula VII, R3a-Z VII in which R3a represents R3 as defined hereinabove except that it does not represent aryl, and that the R3a chain contains an additional carbon-carbon double bond a, β with the substituent Z, and Z represents S (O) R4d , S (O) 2R4d, alkanoyl, cycloalkanoyl or, alkoxycarbonyl, CN, -C- (O) -A-N (R5b) (R5c), -S (O) -A1-N (R5b) (R5c), or -S (O) 2-A1- N (R5b) (R5c), wherein R4d, R5b and R5c and A1 are as defined hereinbefore, for example at a temperature between room temperature and reflux in the presence of an inert solvent (e.g. THF). 5. The compounds of formula I wherein Y represents -C (= E) NR8R9, wherein E, R8 and R9 are as defined hereinbefore, can be prepared by reaction of a corresponding compound of formula VIII, wherein R1, R2 and R3 are as defined hereinabove, with compound of formula IX, HO-C (= E) NR8R9 IX, or a suitable derivative (eg, carboxylic acid) thereof (eg eg, an acid chloride), wherein E, R8 and R9 are as defined hereinbefore, or a compound of formula X, E = C = NR8R9 X wherein E, R8 and R9 are as they have been defined hereinabove, for example (in both cases) at a temperature between room temperature and reflux in the presence of a suitable base (e.g.

KOH, triethylamine and / or pyridine) and optionally in the presence of an appropriate solvent (eg, THF, water, or a suitable mixture thereof). 6. The compounds of formula I wherein Y represents C (O) R10 or C (O) OR10a, wherein R10 and R10a are as defined hereinbefore, can be prepared by reaction of corresponding compound of formula VIII, as defined hereinbefore, with a compound of formula XI, HO-C (O) R10 XI, or a compound of formula XII, HO-C (O) R10a XII respectively or suitable derivatives (e.g. carboxylic acid) thereof (eg, acid halide or anhydride), wherein R10 and R10a are as defined hereinbefore, under coupling conditions which are known to those skilled in the art. 7. The compounds of formula I wherein Y represents C (O) CH (R10b) N (G) (Ga), wherein R10b. G and Ga have been defined hereinabove, they can be prepared by reaction of a corresponding compound of formula VIII, as defined hereinbefore, with a compound of formula XIII, HO-C (O) CH (R10b ) N (G) (Ga) XIII or a suitable derivative thereof (eg carboxylic acid), wherein R10b, G and Ga are as defined hereinbefore, under coupling conditions which are known to those specialized in the technique. 8. The compounds of formula I wherein Y represents C (O) C (R13a) = C (R103b) NH2 or C (O) CH (R13a) CH (NH2) (R13b), wherein R13a and R13b are as have been defined hereinbefore, they can be prepared by reaction of a compound of. Formula VIII, as defined above in the present document, with a compound of formula XIV. wherein the dotted line represents an optional double bond, and R13a and R13b are as defined hereinbefore, for example at a temperature between room temperature and reflux in the presence of a suitable solvent (eg. ,? / - dimethylformamide) and an appropriate base (e.g.? /,? / - d, methyl-4-aminopyridine). 9. The compounds of formula I wherein Y represents C (O) R10, wherein R10 represents phenyl substituted at the ortho position by an amino group, and optionally substituted by one or more additional substituents selected from OH, halo, alkanoyl, FC1-4, alkanoyloxy, N (R8) (R9), C (O) N (R8) (R9), C- alkyl and C? -4 alkoxy, (the last two groups are optionally substituted by one or more carbon atoms) halogen)), and R8 and R9 are as defined hereinabove, can be prepared by reaction of a corresponding compound of formula VIII, as defined hereinbefore, with a compound of formula XV, wherein D represents one to four optional substituents selected from OH, C alca alkanoyl, C C alkanoyloxy, N (R8) (R9), C (O) NN (R8) (R9), C? -4 alkyl and alkoxy d-4 (the last two groups are optionally substituted by one or more halogen atoms), and R8 and R9 are as defined hereinabove, for example at room temperature and reflux in the presence of a solvent suitable (eg? /,? / - dimethylformamide) and an appropriate base (eg, N, N-dimethyl-4-aminopyridine). 10. The compounds of formula I wherein Y represents R11, wherein R11 is as defined above in this document, can be prepared by reaction of a corresponding compound of formula VIII, as defined hereinbefore, with a compound of formula XVI, R11-L2 XVI wherein L2 represents a leaving group such as halo, arenesulfonate, alkanesulfonate, perfluoroalkanesulfonate or diazo, and R11 is as defined hereinbefore, for example under coupling conditions which are known to those skilled in the art (such as those described above in this regard in process 2). 11. 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 hereinabove, can be prepared by reaction of a corresponding compound of formula VIII, as defined above herein, with a compound of formula XVII, L2-CH (R12b) C (O) OR12a XVII a compound of formula XVIII, L2-CH (R12b) OC (O) OR12a XVIII wherein R 2a, R12b, and L2 are as defined above in the present document, for example under coupling conditions known to those skilled in the art (such as those described above in this regard in process 2). 12 '.- The compounds of formula I where Y represents PO (OR14) wherein R14 is as defined hereinbefore, can be prepared by reaction of a compound of formula VIII, as defined above in the present document, with a compound of formula XIX, H-PO (OR14) 2 XIX a compound of formula XX, HO-PO (OR14) 2 XX or a suitable derivative (eg phosphoric acid) thereof (eg a pyrophosphate) , cyanophosphate or chlorophosphate), wherein R14 is as defined hereinbefore, for example at a temperature between -10 ° C and reflux temperature in the presence of a suitable base (eg NaH, triethylamine) and an appropriate organic solvent (eg THF, dichloromethane or carbon tetrachloride).

Compounds of formulas IV to XX, and derivatives thereof, when not commercially available or not described below, can be obtained, either by analogy with the methods described herein, or by conventional synthetic methods according to techniques standard, from readily available starting materials using appropriate reagents and reaction conditions (see, for example, "Comprehensive Organic Transformations -A Guide to Functional Group Preparations," RC Larrok, VCH (1989), or "Advanced Organic Chemistry - Reactions, Mechanism and Structure ", 4th edition, J. March, Wiley-lnterscience (1992)). For example, the compounds of formula VIII can be prepared according to / or by analogy with the methods shown in the aforementioned publications related to compounds based on 4-arylpiperidine. The substituents on alkyl, heterocyclic and aryl groups of the aforementioned compounds can be introduced, removed or interconverted, using techniques that are well known to those skilled in the art. 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 other interconversions and transformations of functional group or standard substituent in which certain compounds of formula I will provide other compounds of formula I. The compounds of the invention can be isolated from their reaction mixtures using conventional techniques. Those skilled in the art will appreciate that, during the course of developing the procedures described above, the functional groups of the intermediate compounds may need to be protected by protecting groups. Functional groups that are desirable to protect include oxo, OH, amino and carboxylic acid. Suitable protective groups for oxo include acetals, ketals (eg, 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 trec-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acid include d-β or benzyl alkyl esters. Suitable protecting groups for terminal alkynes include trialkylsilyl and diarylalkysilyl groups (eg tert-butyldimethylsilyl), tert-butyldiphenylsilyl or trimethylsilyl). The protection and deprotection of functional groups can take place before or after any of the reaction steps described hereinabove. Protective 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, in order to obtain compounds of formula I in an alternative and sometimes more convenient manner, the individual steps of the process mentioned hereinabove can be performed in different order, and / or the individual reactions they may be performed at a different stage of the overall route (ie, substituents may be added to and / or chemical transformations performed on different intermediates to those mentioned hereinabove 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 protective group strategy (if any) that will be adopted. Clearly the type of chemistry involved will influence the choice of reagent used in the synthetic steps mentioned, the need, and type of protecting groups that are used, and the sequence to carry out the synthesis. The methods can be adapted to suit the reactants, reagents and other parameters of the reaction, so that it will be apparent to the skilled person by reference to standard textbooks and to the examples provided later in this document.

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 alone or in a suitable solvent, and the resulting salt can then be isolated either by filtration or by vacuum evaporation of the reaction solvent. Pharmaceutically acceptable base 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 techniques with ion exchange resins. The above procedures can be adapted as appropriate to the particular reactants and groups involved and other variants will be apparent to the skilled chemist by reference to standard textbooks and the examples provided hereinafter to allow the preparation of all compounds of formula I The compounds of the invention may possess pharmacological activity as such. Other compounds of formula I may 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. This may include compounds in which, instead of the group Y, a group H is present. Therefore, such compounds (which also include compounds that may possess some pharmacological activity, but this activity is appreciably less than the compounds active in the which are metabolized), can be described as "prodrugs". Furthermore, it will be appreciated by those skilled in the art that certain protected derivatives of the compounds of formula I, which can be obtained before a final deprotection phase, may not possess pharmacological activity as such, but may, in certain cases, be administered orally or parenterally and then metabolized in the organism 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 of said document being incorporated herein by reference), can be placed in appropriate functionalities, when such functionalities are present within the compounds of Formula I. All protected derivatives and prodrugs of the compounds of formula I are included within the scope of this 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 drugs and, in particular, for their use as animal medicaments. According to a further aspect of the invention, the compounds of the invention are provided for use as medicaments, such as pharmaceutical drugs and animals. In 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. Thus, 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 a non-toxic addition salt or base, organic or inorganic, in a pharmaceutically acceptable dosage form . Depending on the disorder and the patient in question, as well as the route of administration, the compositions may be administered at varying doses (see below): Although it is possible to administer a compound of the invention directly without any formulation, the compounds are preferably used 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 respect to the desired administration route and standard 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 capsule, bolus, tablet or portion, topical administration as an ointment formulation, prepared for continuous anointing, prepared for spot anointing, bath, aerosol, foam , shampoo, collar or powder or, alternatively, can be administered by injection (eg, subcutaneously, intramuscularly or intravenously), or with a simple implant. Such formulations can be prepared in a conventional manner in accordance with standard veterinary practice. The formulations will vary with respect to the weight of the active compound contained therein, depending on the animal species concerned, the severity and type of infection and the animal's body weight. For parenteral, topical and oral administration, typical 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, each dose containing 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 amount of active material calculated to produce the desired therapeutic effect, in association with a pharmaceutically suitable carrier. In any case, the veterinarian, or the expert, can determine the actual dose that will be most appropriate for an individual patient, which may vary with the species, age, weight and response of the particular patient. The above doses are examples of the average case; Of course, there may be individual cases where larger or smaller dosage intervals are needed, and these are within the scope of this invention. For veterinary use, the compounds of the invention are of particular value in the treatment of pruritus in domestic animals such as cats and dogs, and in horses. As an alternative for the treatment of animals, the compounds can be administered with animal feed and for this purpose a concentrated feed additive or 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 compound together with a pharmaceutically acceptable diluent or carrier. Such compositions include conventional tablet, capsule and ointment preparations which are formulated in accordance with standard 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 illustration and should not be construed as limiting) include antiparasitics, for example, 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. Therefore, 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 on an "as required" basis (ie, 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 in admixture with a pharmaceutically or veterinarily acceptable adjuvant, diluent or vehicle. The compounds of the invention may also have the advantage that, in the treatment of human and / or animal patients, they may be, or may be metabolized to form compounds that may be, more effective, less toxic, have a wider range of activity , be more potent, produce fewer side effects, be absorbed more easily, or may have other useful pharmacological properties with respect to 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 assay The compounds of the invention are evaluated for their activity as antipruritic agents by measuring their ability to inhibit the scratching behavior with 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 the European Journal of Pharmacology, 1991, 194, 201. The assay is carried out as follows: Male Wistar rats (approximately 150 g body weight) are inoculated with a pruritogen by subcutaneous injection of 5-methoxytryptamine hydrochloride (4 mg / 3 ml / kg) dissolved in physiological saline solution in the back of the neck. With this dose, a constant and quantifiable 90-minute back-scratching response was obtained. 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, tween 89, 17, benzyl alcohol, 1.5 and purified water to 100), then seven parts of purified water are added to three parts of the previous vehicle giving the aqueous micelle formulation. The compounds can be administered pre- or post-inoculation or can be administered at the same time as the pruritogenic inoculation. After inoculation of the pruritogen is administered, scratching with the hind legs is scored for each animal by registering the presence or absence of scratching during each 30-second interval as a score of 1 or 0, respectively. The score of 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 are used: APCI = chemical ionization at atmospheric pressure a (in relation to NMR) = width DMF =? / -? / - dimethylformamide DMSO = dimethylsulfoxide d (in relation to time) = day d (in relation to NMR) = double dd (in relation to NMR) = doublet of doublets EtOAc = ethyl acetate EtOH = ethanol H = hour (s) M (relative to NMR) = multiplet MeOH = methanol min = minute q (relative to NMR) = quadruplet s (relative to NMR) = singlet t (relative to NMR) = triplet THF = tetrahydrofuran TSI = ionization by thermospray When reference is made to column chromatography usually refers to a glass column packed with silica gel (40 μm - 63 μm). Generally a pressure of about 165 kPa is applied and the ratio of crude product: silica gel which is required for the purification is typically 50: 1. Alternatively, an SPE column (solid phase extraction) lsolute.RTM. Or a Waters Sep-PakR cartridge packaged with silica gel, under atmospheric pressure, may be used. The ratio of crude product to silica gel required for purification is typically 100: 1. The hydrochloride salt can be obtained by methods commonly known to those skilled in the synthetic chemistry art. Typically, to a solution of the product in diethyl ether (10 ml / mmol) was added ethereal hydrogen chloride (1 M solution, 1 eq) to give a precipitate which was collected by filtration and dried in vacuo. The acetate salts can be prepared by similar procedures, of which a typical example is given below. To a solution of the product in methanol (5 ml / mmol) was added acetic acid (1 mol, eq.), After which the reaction mixture was concentrated in vacuo to give the product. The spectral data of the nuclear magnetic resistance (NMR) were obtained using a Varian Unity 300 or 400 spectrometer, in which the observed chemical shifts (d) are compatible with the proposed structures. Mass spectrometry (MS) data were obtained on a Fisons Instruments Trio 1000 spectrometer, or in a Fisons Instruments Trio 1000 APCI, or in a Finnigan Navigator MS, or in Micromass Platform LC. The calculated and observed cited ones refer to the lower mass isotopic composition. HPLC means high performance liquid chromatography. Ambient temperature means from 20 ° C to 25 ° C.

EXAMPLES EXAMPLE 1 Dimethylcarbamate of (±) -3- (1 -hexyl-frans-3,4-d-methyl-4-p-peridinyl) phenyl To a stirred solution of (±) -1-hexyl-fra /? S-3,4-dimethyl-4- (3-hydroxyphenyl) piperidine (preparation 1, 0.289 g, 1.00 mmol) and dimethylcarbamyl chloride (0.101 ml, 1.1 mmol) in tetrahydrofuran (2 ml) and pyridine (2 ml) was added triethylamine (0.279 ml, 2 mmol). After 24 h, 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 (Na2SO4), filtered and concentrated in vacuo to give the crude product which was purified by chromatography on silica gel, eluting with a gradient of methanol: dichloromethane: 0.0880 ammonia (10: 989: 1 to 30: 967: 3), giving the title compound as a yellow oil (0.329 g, 91%). NMR (CeD6, data selected for 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), 2.61 (s, 3H), 2.55 (s, 3H), 2.63 (m, 1 H), 7.04-7.12 (m, 2H), 7.24 (m, 1 H). MS (APCI +): M / Z [MH +] 361.3; C22H36N2? 2 + H requires 361.3.

EXAMPLE 2 (±) -3- (1-Hexyl-frans-3,4-dimethyl-4-pperidinyl) phenyl methylcarbamate To a stirred solution of (±) -1-hexyl-trans-3,4-dimethyl-4- (3-hydroxyphenyl) piperidine (preparation 1, 0.029 g, 0.10 mmol) and methyl isocyanate (7 μl, 0.11 mmoles) triethylamine (28 μm, 0.2 mmol) was added and the reaction was allowed to stir under reflux. After 5 h, methyl socianate (7 μl, 0.11 mmol) and additional triethylamine (28 μl, 0.2 mmol) were added and the stirring was continued at reflux for 14 h. Under cold, the reaction mixture was concentrated in vacuo to give the crude product which was purified by chromatography 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 pale yellow oil (0.019 g, 55%). NMR (CßDβ, data selected for the free base): 0.86 (t, 3H), 0.91 (d, 3H), 1.18 (s, 3H), 1.24-1.43 (m, 9H), 1.78 (m, 1 H), 2.06-2.42 (m, 9H), 2.65 (m, 1 H), 4.05 (a, 1 H), 6.94 (m, 1 H), 7.04-7.12 (m, 2H), 7.26 (m, 1 H). MS (APCI +): M / Z [MH +] 347.2; C2iH34N2? 2 + H requires 347.3.

EXAMPLE 3 (±) -3- (1-Hexyl-frans-3,4-dimethyl-4-piperidinyl) phenyl dimethylcarbamate To a stirred solution of (±) -1-hex? -ffa / 7s-3,4-d.methyl-4- (3-hydroxyphenyl) piperidine (preparation 1, 0.145 g, 0.50 mmole) in pyridine ( 2 ml) was added diethylcarbamyl chloride (76 μl, 0.6 mmol). After 24 h, the reaction mixture was diluted with water (10 ml) and extracted with dichloromethane (3 x 20 ml). The combined extracts were washed with brine (30 ml), dried (Na2SO), filtered and concentrated in vacuo to give the crude product which was purified by chromatography on silica gel, eluting with a gradient of methanol: dichloromethane: 0.880 ammonia (10: 988: 2 to 20: 978: 2), giving the title compound as a yellow oil (0.110 g, 57%). NMR (CßD ?, data selected for the free base): 0.78-0.92 (m, 12H), 1.17 (s, 3H), 1.20-1.41 (m, 9H), 1.77 (m, 1 H), 2.03-2.40 ( m, 6H), 2.63 (m, 1 H), 3.02-3.11 (m, 4H), 6.94 (m, 1 H), 7.04-7.12 (m, 2H), 7.24 (m, 1 H). MS (APCI +): M / Z [MH +] 389.3; C24H40N2O2 + H requires 389.3.

EXAMPLE 4 Pivalate of (±) -3- (1-hexyl-frans-3,4-dimethyl-4-piperidinyl) phenyl To a stirred solution of (±) -1-hexyl-trans-3,4-dimethyl-4- (3-hydroxyphenyl) piperidine (preparation 1, 0.081 g, 0.30 mmol) in triethylamine (1.2 ml) and dichloromethane (1.8 ml) under nitrogen at 0 ° C was added pivaloyl chloride (41 μl, 0.33 mmol) dropwise. The reaction mixture was stirred at room temperature overnight before being partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The aqueous layer was further extracted with dichloromethane. The combined organic extracts were dried (Na2SO), concentrated and subjected to purification on silica gel by flash column chromatography, eluting with ethyl acetate: hexane: 0.880 ammonia solution (30: 70: 1) to give the title (0.10 g, 89%) which was subsequently transformed into the hydrochloride salt. NMR (CDCI3, data selected for the hydrochloride salt): 0.9 (m, 3H), 1.35 (s, 9H), 6.9-7.4 (m, 4H), 11.55 (a, 0.5H), 12.3 (a, 0.5H). MS (TSI +): M / Z [MH +] 374.5; C24H39N? 2 + H requires 374.3.

EXAMPLE 5 2- (Acetyloxy) benzoate of (±) -3- (1-hexyl-frans-3,4-dimethyl-4-piperidinyl) phenyl To a stirred solution of (±) -1-hexyl-trans-3,4-dimethyl-4- (3-hydroxyphenyl) piperidine (preparation 1, 0.211 g, 0.728 mmol) in triethylamine (2.8 ml) and dichloromethane (4.2 ml. ) under nitrogen at 0 ° C was added 2- (chloro-carbonyl) phenyl acetate (0.159 g, 0.80 mmol) in portions. The reaction mixture was allowed to warm to room temperature overnight before being partitioned between the aqueous 1M sodium hydroxide solution and dichloromethane. The aqueous layer was then extracted further with dichloromethane. The combined organic extracts were dried (Na 2 S 4), concentrated and subjected to purification on silica gel using flash column chromatography, eluting with ethyl acetate: hexane: 0.880 ammonia solution (15: 85: 1). The title compound was obtained as a clear oil (0.217 g, 66%) which was subsequently transformed into the hydrochloride salt. NMR (CDCI3, data selected for the hydrochloride salt): 0.85 (m, 3H), 1.8-2.0 (m, 2H), 2.3 (s, 3H), 7.0-7.4 (m, 6H), 7.7 (m, 1 H ), 8.2 (m, 1 H), 11.5 (a, 0.4H), 12.25 (a, 0.6H). MS (TSI +): M / Z [MH +] 452.3; C28H37NO4 + H requires 452.3.

EXAMPLE 6 (±) -3- (1-Hexyl-frans-3,4-dimethyl-4-piperidinyl) phenyl salicylate A solution of 3- (1-hexyl-trans-3,4-dimethyl-4-piperidinyl) phenyl-2- (acetyloxy) benzoate (example 5, 0.146 g, 0.3 mmol) in concentrated hydrochloric acid (0.5 ml) and methanol (9.5 ml) was stirred at room temperature overnight. The reaction mixture was concentrated, partitioned between dichloromethane (50 ml) and water (15 ml), and the resulting aqueous layer was adjusted to pH 8 with 0.880 ammonia solution. The phases were separated and the aqueous layer was further extracted with dichloromethane (2x15 ml). The combined organic extracts were washed with water (20 ml), dried (Na2SO) and concentrated to give a crude oil. The crude oil was purified using flash column chromatography, eluting with ethyl acetate: hexane: 0.880 ammonia solution (25: 75: 1), yielding an oil which was transformed into its hydrochloride salt (110 mg, 82%). NMR (CDCI3, data selected for the hydrochloride salt): 0.9 (m, 3H), 1.8-2.0 (m, 2H), 2.2 (m, 1 H), 6.9-7.6 (m, 7H), 8.05 (d, 1 H), 11.55 (a, 0.8H), 12.3 (a, 0.2H). MS (TSI +): M / Z [MH +] 410.7; C26H35NO3 + H requires 410.3.

EXAMPLE 7 2-M +) - 3- (1 -hexyl-frans-3,4-dimethyl-4-piperidinyl) phenoxymethyl > -1 H-1.2- bencisothiazol-1, 1, 3 (2H) -trione A mixture of (±) -1-hexyl-frans-3,4-dimethyl-4- (3-hydroxyphenyl) piperidine (preparation 1, 0.122 g, 0.42 mmol), sodium iodide (0.063 g, 0.42 mmol), carbonate of potassium (0.06 g, 0.42 mmol) and N- (chloromethyl) saccharin (reference 1.98 mg, 0.42 mmol) in acetone (4 ml) was stirred under nitrogen at room temperature overnight. The reaction mixture was filtered through a plug of cotton wool, concentrated and directly subjected to flash chromatography on silica gel, eluting with ethyl acetate: hexane: 0.880 ammonia solution (30: 70: 1), giving the title compound as a clear oil which was subsequently converted to the hydrochloride salt (125 mg, 57%). NMR (CDCI3, data selected for the hydrochloride salt): 0.8 (m, 6H), 1.8-2.0 (m, 2H), 2.2 (m, 1 H), 5.8 (a, 2H), 7.0-7.4 (m, 4H), 7.8-8.2 (m, 4H), 11.45 ( a, 0.33H), 12.1 (a, 0.67H). MS (TSI +): M / Z [MH +] 485.3; C27H36N2? 4S + H requires 485.2.

EXAMPLE 8 2-methyl benzoate of (±) -3- (1-hexyl-frans-3,4-dimethyl-4-piperidinyl) phenyl To a stirred solution of (±) -1-hexyl-trans-3,4-dimethyl-4- (3-hydroxyphenyl) piperidine (preparation 1, 0.089 g, 0.307 mmol) in dichloromethane (1.8 ml) and triethylamine (1.2 ml ) at 0 ° C under nitrogen, 0-toluoyl chloride (45 μl, 0.34 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 21/2 days. The reaction mixture was diluted with water (25 ml) and extracted with dichloromethane (50 ml followed by 2 x 25 ml). The organic extracts were washed with water (20 ml), dried (Na2SO) and subjected to flash column chromatography, eluting with ethyl acetate: hexane: 0.880 ammonia solution (30: 70: 1), giving the title as an oil (0.095 g, 76%) which was subsequently transformed into the hydrochloride salt.

NMR (CDCI3, data selected for the hydrochloride salt): 0.85 (m, 3H), 1.8-2.0 (m, 2H), 2.2 (m, 1H), 2.6 (s, 3H), 7.0-7.6 (m, 7H) , 8.15 (d, 1H), 11.65 (a, 0.4H), 12.4 (a, 0.6H). MS (TSI +): M / Z [MH +] 408.6; C27H37NO2 + H requires 408.3 EXAMPLE 9 2-aminobenzoate of (±) -3- (1 -hexyl-frans-3,4-dimethyl-4-piperidinyl) phenyl A stirred solution of (±) -1-hexyl-frans-3,4-dimethyl-4- (3-hydroxyphenyl) piperidine (preparation 1, 0.069 g, 0.238 mmol), 4- (dimethylamino) pyridine (0.032 g, 0.262 mmoles) and isatoic anhydride (0.043 g, 0. 262 mmoles) in? /,? / - dimethylformamide (2 ml) was heated for 12 hours at 80 ° C under nitrogen. The reaction mixture was diluted with water (25 ml) and the product was extracted with dichloromethane (50 ml followed by 2 x 25 ml). The combined organic extracts were washed with water (20 ml), dried (Na2SO4) and concentrated in vacuo. The crude residue thus obtained was subjected to flash column chromatography, eluting with ethyl acetate: hexane: 0.880 ammonia solution (25: 75: 1), giving the title compound as an oil (77 mg, 79%) which subsequently It was transformed into the hydrochloride salt. NMR (CDCI3, data selected for the hydrochloride salt): 0.8 (m, 3H), 1.8-2.0 (m, 2H), 2.25 (m, 1 H), 5.6-5.8 (m, 2H), 6.65-6.7 (m , 2H), 7.0-7.2 (m, 3H), 7.3-7.4 (m, 2H), 8.05 (m, 1 H), 11.6 (a, 0.35H), 12.3 (a, 0.65H).

MS (TSI +): M / Z [MH +] 408.7; C26H36N2? 2 + H requires 409.3 EXAMPLE 10 2,6-dimethylbenzoate of (±) -3- (1-hexyl-frans-3,4-dimethyl-4-piperidinyl) phenyl To a solution of 2,6-dimethylbenzoic acid (0.092 g, 0.612 mmol) in dichloromethane (3.6 ml) stirred under nitrogen at 0 ° C, oxalyl chloride (54 μl, 0.612 mmol) was added followed by a catalytic amount of? /,? / - dimethylformamide (1 drop). This reaction mixture was stirred for 11 2 hours before being added to a solution of (±) -1-hexyl-trans-3,4-dimethyl-4- (3-hydroxyphenyl) piperidine (preparation 1, 0.161 g, 0.556 mmol). ) in dichloromethane (1.5 ml). The combined reaction mixture was stirred under nitrogen at room temperature overnight. The reaction mixture was diluted with water (15 ml) and extracted with dichloromethane (2 x 20 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate: hexane: 0.880 ammonia solution (30: 70: 1), giving the title compound as a clear oil (0.157 g, 68% ) which was subsequently transformed into the hydrochloride salt. NMR (CDCI3, data selected for the hydrochloride salt): 0.75-0.9 (m, 6H), 1.8-1.9 (m, 2H), 2.2 (m, 1 H), 2.4 (s, 6H), 7.0-7.4 (m , 7H), 11.6 (a, 0.45H), 12.3 (a, 0.55H). MS (TSI +): M / Z [MH +] 422.0; C28H39N? 2 + H requires 22.3.

EXAMPLE 11 2,2-Diphenylpropionate of (±) -3- (1-hexyl-frans-3,4-dimethyl-4-piperidinyl) phenyl To a stirred mixture of 2,2-diphenylpropionic acid (0.161 g, 0.711 mmol) in dichloromethane (4.2 ml) under nitrogen at 0 ° C, oxalyl chloride (62 μl, 0.711 mmol) was added followed by? / -? / - Catalytic dimethylformamide (1 drop). After 1 hour,? / -? / - dimethylformamide (1 drop) was added and the reaction mixture was heated to 10 ° C to improve the solubility of the acid. This reaction mixture was added to a solution of (±) -1-hexyl-trans-3,4-dimethyl-4- (3-hydroxyphenyl) p-peridine (preparation 1, 0.187 g, 0.646 mmol) in triethylamine (2.8 ml) and dichloromethane (1.75 ml) at 0 ° C, and stirred under nitrogen overnight. The reaction mixture was diluted with water (15 ml) and extracted with dichloromethane (3 x 20 ml). The combined organic extracts were dried (Na2SO), and concentrated in vacuo. The crude residue was purified on silica gel by flash column chromatography, eluting with ethyl acetate: hexane: ammonia solution 0. 880 (25: 75: 1), giving the title compound as a clear oil (121 mg, 38%) that was subsequently transformed into the hydrochloride salt. NMR (CDCI3, data selected for the hydrochloride salt): 0.85 (m, 3H), 1.8-2.0 (m, 2H), 2.0 (s, 3H), 6.8-6.95 (m, 4H), 7.05-7.20 (m, 2H), 7.25-7.4 (m, 8H), 11.65 (a, 0.33H), 12.35 (a, 0.67H). MS (TSI +): M / Z [MH +] 498.4; C34G43NO2 + H requires 498.3.

EXAMPLE 12 (±) -2 3-p- (3-Tetrahydro-2H-pyran-2-ylpropin-trans-3,4-dimethyl-4-piperidinopfenoxi.) Methyl-1 H-1,2-benzisothiazole -1.1, 3 (2H) -triona To a stirred solution of 3- [1- (3-tetrahydro-2H-pyran-2-ylpropyl) -trans-3,4-dimethyl-4-piperidinyl] phenol (preparation 2, 7.589 g, 22.86 mmol) and iodide sodium (0.41 g, 2.74 mmol) in anhydrous acetone (100 ml) under nitrogen was added potassium carbonate (3.79 g, 27.43 mmol) followed by N- (chloromethyl) saccharin (reference 1, 6.41 g, 27.43 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through Celite® and the filtrate was concentrated in vacuo. The crude residue thus obtained was purified by flash column chromatography on silica gel, eluting with dichloromethane: ethanol: 0.880 ammonia solution (200: 8: 1), yielding the title compound as an oil which solidified under reduced pressure (5.51). g, 46%). The hydrochloride salt was subsequently prepared as a white solid (5.62 g, 44%). NMR (CDCI3, data selected for the hydrochloride salt): 1.0 (m 3H), 1.9-2.1 (m, 2H), 3.95 (m, 1 H), 5.75-5.85 (a, 2H), 6.9-7.1 (m, 3H), 7.25 (m, 1 H), 7.8-7.95 (m, 3H), 8.1 (m, 1 H), 11.4 (a, 0.7H), 12.1 (a, 0.3H). MS (TSI +): M / Z [MH +] 527.7; C29H38N2O5S + H requires 527.3 EXAMPLE 13 2- (Acetyloxy) benzoate of (±) -3-EI - (3-tetrahydro-2H-pyran-2-ylpropyl) -trans-3,4-dimethyl-4-piperidinylphenyl To a stirred solution of 3- [1- (3-tetrahydro-2H-pyran-2-ylpropyl) -trans-3,4-d, methyl-4-piperidinyl] phenol (preparation 2, 8.22 g, 24.75 mmol) in triethylamine (20 ml) and dichloromethane (80 ml) at 0 ° C under nitrogen was added 2- (chlorocarbonyl) phenyl acetate (5.90 g, 29.71 mmole) in portions. After 3 hours, the reaction mixture was quenched with ice (100 g), and after an additional 1 hour, the organic and aqueous phases were separated. The aqueous layer was back extracted with dichloromethane and the combined organic layers were dried (Na2SO) and concentrated to give a crude oil. The title compound was then obtained by purification by flash column chromatography on silica gel, eluting with dichloromethane: ethanol: 0.880 ammonia solution (97: 3: 1). The hydrochloride salt (8.72 g, 66%) was subsequently prepared as a white solid (mp 79 ° C-80 ° C). NMR (CDCI3, data selected for the hydrochloride salt): 1.1 (m, 3H), 1.4 (s, 3H), 2.0-2.1 (m, 2H), 2.3 (s, 3H), 3.65 (m, 1 H), 3.95 (m, 1 H), 7.0-7.4 (m, 6H), 7.6 (m, 1 H), 8.2 (m, 1 H), 11.5 (a, 0.8H), 12.2 (a, 0.2H) EM ( TSI +): M / Z [MH +] 494.7; C3oH39NO5 + H requires 494.3.

EXAMPLE 14 (±) -2-r (3- { 1-r2- (Cyclohexyloxy) et.n-trans-3,4-dimethyl-4-pyridinyl) phenoxy) met.p-1 H- 1, 2-benzisothiazol-1, 1, 3 (2H) -trione A solution of 3-. { 1- [2-cyclohexyloxy) ethyl] -trans-3,4-dimethyl-4-piperidinyljphenol (preparation 6, 0.80 g, 2.41 mmol) and sodium iodide (0.43 g, 2.9 mmol) in anhydrous acetone (25 ml) were added. it stirred under nitrogen. Potassium carbonate (1.66 g, 13.2 mmol) was added, followed by N- (chloromethyl) saccharin (Reference 1, 0.67 g, 2.9 mmol), and the reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was filtered through a plug of Celite® and then concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel, eluting with dichloromethane: 0.880 ammonia (99: 1), yielding the title compound (0.3 g, 24%). NMR (CDCI3, data selected for the free base): 0.75 (d, 3H), 1.15-2.35 (m, 9H), 2.8 (m, 1 H), 3.2 (m, 1 H), 3.55-3.65 (m, 2H), 6.9-7.0 (m, 2H), 7.05 (s, 1 H), 7.25 (m, 1 H), 7.8-8.0 (m, 3H), 8.1 (m, 1 H). MS (TSI +): M / Z [MH +] 527.2; C29H38N2O5S + H requires 527.3.

EXAMPLE 15 2- (Acetyloxy) benzoate of (±) -3-f 1 -r 2 - (cyclohexyloxy) ethyp-trans-3,4-dimethyl-4-piperidine D-phenyl A solution of 3-. { 1- [2-cyclohexyloxy) ethyl] -trans-3,4-dimethyl-4-piperidinyljphenol (preparation 6, 0.80 g, 2.41 mmol) and sodium iodide (0.43 g, 2.9 mmol) in anhydrous acetone (25 ml) were added. it stirred under nitrogen. Potassium carbonate (1.66 g) was added, 13.2 mmol), followed by 2- (chlorocarbonyl) phenyl acetate (o.67 g, 2.9 mmol) and pyridine (9 ml), the reaction mixture was allowed to stir for 5 h at room temperature. The reaction mixture was diluted with dichloromethane (30 ml) and washed with water (30 ml), and the organic extract was washed with brine (20 ml), dried (MgSO4), and concentrated in vacuo to give a yellow foam. . This crude residue was partially purified by flash column chromatography on silica gel, eluting with CH2Cl2: 0.880 ammonia (99: 1) and then with CH2Cl2: ethanol: 0.880 ammonia (75: 25: 1). Further purification of the product was carried out by flash column chromatography on silica gel, eluting with CH2Cl2: 0.880 ammonia (99: 1) and then with CH2Cl2: ethanol: 0.880 ammonia (75: 25: 1). Further purification of the product was performed by flash column chromatography on silica gel, eluting with a gradient of ethyl acetate: hexane: 0.880 ammonia (10: 90: 1 and then 30: 70: 1), yielding the title compound (0.09 g, 8%). NMR (CDCI3, data selected for the free base): 0.8 (d, 3H), 1.4 (s, 3H), 2.3 (s, 3H), 2.85 (m, 1 H), 3.25 (m, 1 H), 3.55 -3.65 (m, 2H), 7.0 (d, 1 H), 7.1 (s, 1 H), 7.15-7.25 (m, 2H), 7.3-7.4 (m, 2H), 7.6 (m, 1 H), 8.2 (d, 1 H). MS (TSI +): M / Z [MH +] 494.3; C3oH39NO5 + H requires 494.3.

EXAMPLE 16 (±) -4- (3- (1-Carbamoyl-1-methylethoxy) phenyl) -? -hexyl-frans-3,4-methylmethoxydine To a solution of (±) -1-hexyl-frans-3,4-dimethyl-4- (3-hydroxyphenyl) piperidine (preparation 1, 20 g, 69.2 mmol), in 1,4-dioxane (250 ml) under a nitrogen atmosphere was added cesium carbonate (32.5 g, 100 mmol) followed carefully by sodium hydride (60% dispersion in mineral oil, 4 g, 100 mmol) in four portions for 30 minutes.

The resulting mixture was stirred for 30 minutes before 2-bromo-2-methyl-propionamide (reference 2, 16.6 g, 100 mmol) was added and the mixture was heated under reflux overnight. The reaction mixture was cooled, filtered and concentrated in vacuo to give the crude product was purified by flash column chromatography on silica gel (600 g), eluting with a gradient of ethyl acetate: hexane: 0.880 ammonia (30: 70: 1 to 50: 50: 1), giving the initial phenol recovered (5.9 g, 30%), followed by the title compound as a white solid (14.3 g, 55%). NMR (CDCI3, data selected for the free base): 0.75 (d, 3H), 0.85 (m, 3H), 2.0 (m, 1 H), 2.3 (m, 4H), 2.5 (m, 2H), 2.8 ( m, 1 H), 5.45 (ss, 1 H), 6.65 (ss, 1 H), 6.75-7.2 (m, 4H). MS (TSI +): M / Z [MH +] 375.4; C23H38N2O2 + H requires 375.3.

EXAMPLE 17 (±) -4-r3- (allyloxy) phenan-1-hexyl-fra /? -3,4-dimethyl-piperidine To a stirred solution of (±) -1-hexyl-fra / 7s-3,4-dimethyl-4- (3-hydroxyphenyl) piperidine (preparation 1, 0.043 g, 0.15 mmol) and allyl bromide ( 15 μl, 0.17 mmol) in acetonitrile (3 ml) was added cesium carbonate (0.098 g, 0.3 mmol) and the reaction was heated under reflux for 6 h. Under cold, the reaction mixture was diluted with saturated aqueous sodium bicarbonate (20 ml) and extracted with dichloromethane (3 x 20 ml). The combined organic extracts were washed with brine (25 ml), dried (Na2SO), filtered and concentrated in vacuo to give the crude product which was purified by chromatography on silica gel, eluting with a gradient of methanol: CH2Cl2: ammonia 0.880 (10: 989: 1 to 30: 967: 3), giving the title compound as a yellow oil (0.031 g, 63%). NMR (C6D6, data selected for the free base): 0.86 (t, 3H), 0.94 (d, 3H), 1.23 (s, 3H), 1.21-1.33 (m, 6H), 1.39-1.46 (m, 3H) , 1.84 (m, 1 H), 2.10-2.47 (m, 6H), 2.69 (m, 1 H), 4.17-4.22 (m, 2H), 5.01 (m, 1 H), 5.23 (m, 1 H) , 5.78-5.87 (m, 1 H), 6.63 (dd, 1 H), 6.83 (d, 1 H), 6.99 (m, 1 H), 7.14 (m, 1 H). MS (APCI +): M / Z [MH +] 330.2; C22H35NO + H requires 330.3.

EXAMPLE 18 Diethylcarbamothioate of (+) - O-r3- (1-hexyl-frans-3,4-dimethyl-4-piperidine D-phenyl) To a stirred solution of (±) -1-hexyl-frans-3,4-dimethyl-4- (3-hydroxyphenyl) piperidine (preparation 1, 0.710 g, 2.45 mmol) and potassium hydroxide (0.137 g) , 2.45 mmol) in water (5 ml) and tetrahydrofuran (5 ml) was added diethylthiocarbamyl chloride (0.485 g, 3.2 mmol). After 24 h, additional potassium hydroxide (0.137 g, 2.45 mmol) and diethyl thiocarbamyl chloride (0.485 g, 3.2 mmol) were introduced. After an additional 24 h, the reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (3 x 25 ml). The combined extracts were washed with brine (30 ml), dried (Na2SO), filtered and concentrated in vacuo to give the crude product which was purified by chromatography on silica gel, eluting with a gradient of methanol: dichloromethane: ammonium. 0.880 (10: 989: 1 to 30: 967: 3), giving the title compound as a yellow oil (0.627 g, 63%). NMR (C6D6, data selected for 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 (q, 2H), 3.55 (q, 2H), 6.91 (m, 1 H), 6.98 (m, 1 H) , 7.05-7.13 (m, 1 H), 7.19 (m, 1 H). MS (APCI +): M / Z [MH +] 405.3; C24H40N2OS + H requires 405.3.

EXAMPLE 19 (±) -1-Hexyl-frans-3,4-dimethyl-4-r3- (hexyloxy) pheninpiperidine To a solution of the acetate salt of (±) -3- (frans-3,4-dimethylpiperidinyl) -phenol (reference 3), 45 g, 170 mmol) in N, N-dimethylformamide (250 ml) and bromohexane (71.6 ml, 510 mmol) was added potassium carbonate (70.5 g, 510 mmol). The reaction mixture was stirred overnight at 50 ° C. The reaction mixture was diluted with water (500 ml) and extracted with ethyl acetate (3 x 200 ml), the combined extracts were washed with water (100 ml), dried (MgSO4) and concentrated in vacuo. The crude residue contained two products which were separated by flash column chromatography on silica gel, eluting with ethyl acetate: hexane: 0.880 ammonia solution (10: 90: 1 and then 40: 60: 1). The title compound was obtained first, (1.2 g, 2%) followed by (±) -1-hexyl-frans-3,4-dimethyl-4- (3-hydroxyphenyl) piperidine (13.6 g, 28%). MS (TSI +): M / Z [MH +] 374.4; C25H43NO + H requires 374.3.

EXAMPLE 20 It was found that the compounds according to the present invention, for example the compound of Example 2, exhibit anti-pruritic activity when tested according to the above procedure.

Preparation of starting materials PREPARATION 1 (±) -1-Hexyl-frans-3,4-dimethyl-4- (3-hydroxyphenyl) piperidine To a stirred solution of (±) -3- (trans-3,4-dimethylpiperidinyl) phenol (reference 3, 2.0 g, 9.8 mmol) in N, N-dimethylformamide (50 ml) was added sodium bicarbonate (1.76 g, 20.95 mmoles) and bromohexane (1.64 g, 9.9 mmoles). The reaction mixture was heated under reflux for 3 h 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 (MgSO), filtered and concentrated in vacuo to give the crude product. This was purified by chromatography on a silica column (50 g), eluting with ethyl acetate: hexane: 0.880 ammonia (30: 70: 1), to give the title compound as a light brown oil (2.68 g, 91%). NMR (CDCI3, data selected for 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), 6.55-7.2 (m, 4H). MS (TSI +): M / Z [MH +] 290.2; C19H3? NO + H requires 290.3.

PREPARATION 2 (±) -3-p-f3-Tetrahydro-2-A-pyran-2-ylpropin-frans-3,4-dimethyl-4- piperidinylphenol To a stirred solution of (±) -1- [Irans-3,4-dimethyl-4- (3-hydroxyphenyl) -1-piperidinyl] -3-tetrahydro-2 / -piran-2-yl-1-propanone (Preparation 3, 0.470 g, 1.36 mmol) in diethyl ether (6.6 ml) at room temperature was added lithium aluminum hydride (2.72 ml of 1.0 M in diethyl ether, 2.72 mmol). After 2 hours, the reaction was quenched with 2 × V aqueous sodium hydroxide solution (0.2 μl) and water (0.3 μl) and diluted with diethyl ether (15 ml). The solid was then removed by filtration through Celite®, washing with ethyl acetate (5 x 50 ml). The filtrate was dried (Na2SO), filtered and concentrated in vacuo to give the title compound (396 mg, 88%) as a pale yellow oil. NMR (CDCI3, data for the free base): 0.78 (d, 3H), 1.38 (s, 3H), 1. 80 (m, 1 H), 1.95 (m, 1 H), 2.20-2.70 (m, 5H), 2.78-2.90 (m, 1 H), 3.25 (m, 1 H), 3.41 (m, 1 H) , 3.98 (m, 1 H), 6.65 (d, 1 H), 6.75 (s, 1 H), 6.82 (d, 1 H), 7.18 (t, 1 H). MS (TSI +): M / Z [MH +] 332.1; C2? H33NO2 + H requires 332.3.

PREPARATION 3 (±) -1-rfra / 7S-3,4-Dimethyl-4- (3-hydroxy-thienyl) -1-pyrimidin-3-tetrahydro-2H-pyran-2-yl-1-propanone To a solution of 3- (tetrahydro-2 / - -pyran-2-yl) propionic acid (Preparation 4, 0.243 g, 1.54 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.42 g, 2.19 mmol) and 1-hydroxybenzotriazole (0.223 g, 1.65 mmol) in? /,? / - dimethylformamide (55 ml) at room temperature was added (±) -3- (7ra-3,4-dimethylpiperidinyl) phenol (reference 3, 0.338 g, 1.65 mmol): The mixture was stirred at room temperature for 48 hours and then added water (50 ml). The aqueous layer was extracted with diethyl ether (2 x 150 ml) and the combined organic layers were washed with brine (50 ml), dried (Na SO), filtered and concentrated in vacuo to give a clear residue. This was purified by chromatography on silica gel, eluting with a gradient of ethyl acetate and hexane (66:44 to 75:25) to give the title compound (0.473 g, 90%) as a colorless oil. NMR (CDCI3, data selected for the free base (approximately a mixture of 1: 1 isomers)): 0.59-0.68 (m, 3H), 1.38-1.41 (m, 3H), 2.87 (m, 0.5H), 3.15 ( m, 0.5H), 3.50-3.70 (m, 1 H), 3.90-4.02 (m, 1.5H), 4.35 (m, 0.5H), 4.70 (m, 0.5H), 6.68 (d, 1 H), 6.72-6.80 (m, 2H), 7.18 (t, 1 H). MS (TSI +): M / Z [MH +] 346.3; C2? H31NO3 + H requires 346.2.

PREPARATION 4 3- (Tetrahydro- / V-pyran-2-yl) propionic acid An aqueous solution of lithium hydroxide (4 ml of 2 M) was added to a solution of methyl 3- (tetrahydro-2 - / - pyran-2-yl) propionate (preparation 5)., 0.46 g, 2.67 mmoles) in tetrahydrofuran (16 ml) and the reaction mixture was heated under reflux for 10 h. The cooled reaction mixture was acidified with 2 / V aqueous hydrochloric acid to pH 1, and then extracted with ethyl acetate (3 x 50 ml). The combined extracts were washed with brine (30 ml), dried (MgSO 4) and concentrated in vacuo to give the title product as a colorless oil (460 mg, 67%). NMR (CDCl 3): 1.10-1.20 (m, 1 H), 1.40-1.60 (m, 4H), 1.70-1.90 (m, 3H), 2.50 (dt, 2H), 3.25-3.25 (m, 1 H), 3.40 (m, 1 H) and 3.95 (d, 1 H). MS (TSI +): M / Z [MH +] 159.2; C8H14O3 + H requires 159.1.

PREPARATION 5- 3- (Tetrahydro-2H-pyran-2-yl) methyl propionate A mixture of methyl (E) - and (Z) -3- (tetrahydro-2 / - / - pyran-2-yl) propionate (Reference 4, 0.537 g, 3.15 mmol) was dissolved in methanol (10 ml) which it contained 10% palladium on charcoal (0.050 g) and was subjected to hydrogenation at 415 KPa and at room temperature overnight. The reaction mixture was filtered through Celite®, the residue was washed with methanol and the combined filtrates were concentrated in vacuo. The crude product was purified by silica gel column chromatography 830 g), eluting with diethyl ether: hexane (1: 4), to give the title compound as a colorless oil (470 g, 87%). NMR (CDCl 3: 1.21 (q, 1H), 1.50-1.60 (m, 4H), 1.70-1.80 (m, 3H), 2. 40 (m, 2H), 3.15-3.25 (m, 1 H), 3.35 (t, 1 H), 3.62 (s, 3H) and 3.90 (d, 1 H).

PREPARATION 6 (±) -3- (1-r2- (cyclohexyloxy) etn-frans-3,4-dimethyl-4-piperidinyl > phenol A solution of (±) -3- (rans-3,4-dimethyl-4-piperidinyl) phenol (Reference 3, 2.43 g, 12 mmol) in 1,2-dimethoxyethane (100 mL) was stirred under nitrogen. Sodium bicarbonate (1.41 g, 16.7 mmol) was added followed by 2- (cyclohexyloxy) ethyl 4-bromobenzenesulfonate (preparation 7.4.3 g, 12 mmol) and the reaction mixture was heated to 85 ° C for 24 hours. The reaction mixture was cooled to room temperature and then further cooled with stirring to 0 ° C for 15 minutes. The solid was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel, eluting with hexane: ethyl acetate (2: 1), to give the title compound (2.5 g, 64%). NMR (CDCI3, data selected for the free base): 0.8 (d, 3H), 1.3 (s, 3H), 2.8-2.9 (m, 1 H), 3.2-3.3 (m, 1 H), 3.5-3.65 ( m, 2H), 6.6 (d, 1 H), 6.75 (s, 1 H), 6.85 (d, 1 H). 7.15 (t, 1 H).

MS (TSI +): M / Z [MH +] 332.2; C2? H33NO2 + H requires 332.3.

PREPARATION 7 2- (cyclohexyloxy) ethyl 4-bromobenzenesulfonate A solution of 2-cyclohexyloxyethanol (4.56 g, 32 mmol) and triethylamine (22 ml, 160 mmol) in dichloromethane (225 ml) was stirred under nitrogen. A saturated solution of 4-bromobenzenesulfonyl chloride (9.0 g, 35 mmol) in dichloromethane was added dropwise at 0 ° C, and the reaction mixture was stirred overnight under nitrogen. The reaction mixture was then washed with 1N aqueous hydrochloric acid (2 x 200 ml) and the organic layer was separated. The organic layer was washed sequentially with water (200 ml) and brine (200 ml), dried (MgSO) and then concentrated in vacuo to give a white solid. The crude solid was dissolved in the minimum amount of dichloromethane and purified by passing it through a plug of silica, which was eluted with ethyl acetate: hexane (50:50), ethyl acetate (100%) and finally methanol: ethyl acetate (10:90). The title compound was obtained as a yellow oil (4.3 g, 41%). NMR (CDCI3, selected data): 3.1-3.35 (M, 2H), 4.1-4.3 (t, 2H), 7.7 (d, 2H). 7.8 (d, 2H). MS (TSI +): M / Z [MNH4 +] 379.9; C14H19BrO4S + NH4 requires 380.1.

REFERENCES 1. - J. U. Patel, R. J. Prankerd and K. B. Sloan, J. Pharmaceutical Sciences, 1994, 83, 10, 1477. 2.- I. G. Coults, N. R. Southcott, J. Chem. Soc, Perkin 1, 1990, 767. 3.- a) J A Werner et al, J Org. Chem., 1996, 61, 587; b) C. H. Mitch, D. M. Zimmerman, J. D. Snoddy, J. K. Reel, and B. E. Cantrell, J. Org. Chem, 1991, 56, 1660. 4.- H. Priepke and R. Brückner, Chem. Ber., 1990, 123, 153.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula I, wherein R1 and R2 are each independently H or C1_alkyl; R3 represents aryl (optionally substituted by one or more substituents selected from OH, nitro, halo, CN, CH2CN, CONH2, d- alkyl, C-alco4 alkoxy, C1-5 alkanoyl, (the last three groups being optionally substituted by one or more halo atoms) and -N (R4a) (R4b)), d-, C3-? 0 alkenyl or C3-? alkynyl, or said alkyl, alkenyl or alkynyl groups optionally substituted and / or terminated by one or more substituents selected from OR4c, S (O) nR4d, CN, halo, d6-carbonyl alkoxy, C2-6 alkanoyl, C2-6 alkanoyloxy, C3-8 cycloalkyl, C4-9 cycloalkanoyl, N (R5a) S (O ) 2R6, Het1, aryl, adamantyl, (the last two groups being optionally substituted by one or more substituents selected from OH, nitro, halo, CN, CH2CN, CONH2, C? -4 alkyl, C? - alkoxy and C1- alkanoyl) 5, (the last three groups being optionally substituted by one or more halo atoms)) and -N (R4a) (R4b)) or -W-A1-N (R5b) (R5c); n is 0, 1 or 2; W represents a simple bond, C (O) or S (O) p; AVepresents a single bond or alkenyl d-io; as long as both W and A1 represent simple bonds, then the group -N (R5b) (R5c) is not directly to an unsaturated carbon atom; p is 0, 1 or 2; R4a to R4b each independently represent H, C-MO alkyl, C3-? 0 alkenyl, C3-? Alkynyl, C3-8 cycloalkyl, d-alkyl alkyl, aryl (the last six groups being optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, alkyl d-4, alkoxy d-4 and alkanoyl d-5, (the last three groups being optionally substituted by one or more halo atoms)) or Het2; provided that R4d does not represent H when n represents 1 or 2; R5aR5c each independently represents H, alkyl d.-io, C3-? Alkenyl or C3-? Alkynyl, C3-8 cycloalkyl, C? - alkylphenyl, aryl (the last six groups being optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2) alkyl d-4, alkoxy C1-4 and alkanoyl d-5 (the last three groups being optionally substituted by one or more halo atoms), Het3, or R5b and R5c together represent unbranched C2-6alkylene, alkylene group which is optionally interrupted by O, S and / or a group N (R7) and is optionally substituted by one or more C4-4 alkyl groups; R6 represents alkyl d-6, cycloalkyl C3-8, alkylphenyl C? - or aryl, the four groups being optionally substituted by one or more substituents selected from alkyl d-4, alkoxy d-4, OH, nitro, amino or halo; R7 represents H, d-β alkyl, C3-8 cycloalkyl, A2- (C3-8 cycloalkyl) or A2-aryl; A2 represents alkyl d-β; Het1, Het2 and Het3 independently represent 3 to 8 membered heterocyclic groups, said groups containing at least one heteroatom selected from oxygen, sulfur and / or nitrogen, said groups optionally being fused to a benzene ring, and said groups being optionally substituted in 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, alkyl d-4, alkoxy C? -4 and alkanoyl d-5 (the last three groups being optionally substituted by one or more halo atoms); and represents -C (= E) NR8R9, C (O) R10, C (O) OR10, C (O) CH (R10b) 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; R > H.H . and, D R9 independently represent H, alkyl d '1-10. C3-? 0 alkenyl (the latter two groups being optionally substituted by one or more C4-7 aryl or cycloalkyl groups (the two groups being optionally substituted by one or more substituents selected from halo, C? - alkyl, C-? - alkoxy) 4, C? -4 haloalkyl or C? -4) haloalkoxy), aryl, C- cycloalkyl (optionally substituted by one or more substituents selected from halo, C? -4 alkyl and C 1-4 alkoxy (the last two groups being optionally substituted by one or more halo atoms), or R8 and R9, together with the N atom to which both are bound, 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 d- alkyl groups; R10 represents H, C4-7 cycloalkyl (optionally substituted by one or more C4-4 alkyl groups), d-n alkyl (substituted by one or more substituents selected from aryl (optionally substituted by one or more substituents selected from

OH, halo, alkanoyl d.4, C 1-4 alkanoyloxy, C 1-4 alkyl, C 1-4 alkoxy, haloalkyl d 4 and haloalkoxy d 4) or cycloalkyl C- (the latter group being optionally substituted by one or more alkyl groups d-)) or aryl (optionally substituted by one or more substituents selected from OH, halo, C 1-4 alkanoyl, C 1-4 alkoxyloxy, N (R 8) (R 9), C (O) N (R 8 ) (R9), alkyl d-4 and alkoxy d.4 (the last two groups being optionally substituted by one or more halo atom groups)); R10a represents C7 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 , C 1-4 alkanoyl, C 1-4 alkanoyloxy, N (R 8) (R 9), C (O) N (R 8) (R 9), d- alkyl, C 1- alkoxy, d- haloalkyl and C 1-4 haloalkoxy) O cycloalkyl d-7 (the latter group optionally being substituted by one or more C 1-4 alkyl groups), aryl (optionally substituted by one or more substituents selected from OH, halo, d-4 alkanoyl, d-4 alkanoyloxy, N ( R8) (R9), C (O) N (R8) (R9), d4 alkyl and C4-4 alkoxy (the latter two groups being optionally substituted by one or more halo atoms) or Het5; R10 represents H, C-cycloalkyl, d -ioalkyl (optionally substituted by one or more substituents selected from aryl or C4-7 cycloalkyl, aryl, or R10b (optionally, together with Ga) represents a naturally occurring amino acid substituent; Ga independently represent H, an amino protecting group, or Ga, together with R10b, represents a naturally occurring amino acid substituent, R11 represents C4-7 cycloalkyl (optionally substituted by one or more C- alkyl groups), aryl (optionally substituted by one or more substituents selected from OH, halo, d-4 alkanoyl, C 1-4 alkanoyloxy, N (R 8) (R 9), C (O) N (R 8) (R 9), d 4 alkyl and d-alkoxy, ( the latter two groups being optionally substituted by one or more halo atoms), C 1 -io alkyl, C 3 - 0 alkenyl, said alkyl or alkenyl group being optionally substituted by one or more substituents selected from C (O) NH 2) Het 6, cycloalkyl d-7 (optionally substituted by one or more C1-4 alkyl groups), aryl, aryloxy or arylalkoxy C? - (the last three groups being optionally substituted by one or more substituents selected from OH, halo, d-4 alkanoyl, d-4 alkanoyloxy, N (R8) (R9); C (O) N (R8) (R9), C4-4alkyl and d-4alkoxy (the latter two groups being optionally substituted by one or more halo atoms)), or R11 represents Het7 or d-5 alkyl substituted by one or more substituents selected from C (O) NH 2, Het 8, cycloalkyl d-7 (optionally substituted by one or more C 1-4 alkyl groups), aryl, aryloxy or C 1-4 arylalkoxy (the last three groups being optionally substituted by one or more substituents selected from OH, halo, d-4 alkanoyl, C 1-4 alkanoyloxy, N (R 8) (R 9), C (O) N (R 8) (R 9), C 1 -alkyl and C 1-4 alkoxy (the last two groups optionally substituted by one or more halo atoms)); Het5 to Het8 independently represent 4- to 6-membered heterocyclic rings, said rings containing at least one heteroatom selected from oxygen, sulfur and / or nitrogen, said rings optionally fused to a benzene ring, and said rings being optionally substituted in the part of the heterocyclic ring and / or the benzene ring condensed by one or more substituents selected from OH, = 0, nitro, amino, halo, CN, aryl, C -? - 4 alkyl, C -? - 4 alkoxy, C3 - cycloalkyl 6 and C3-6 alkanoyl and C? -5 alkanoyl (the last four groups being optionally substituted by one or more halo atoms); R12a and R12b independently represent H, cycloalkyl d- (optionally substituted by one or more alkyl groups d-4), C? -10 alkyl (optionally substituted by one or more substituents selected from aryl or C4-7 cycloalkyl (the last group being optionally substituted by one or more C- or aryl-alkyl groups (optionally substituted by one or more substituents selected from OH, halo, C 1-4 alkanoyl, C 1-4 alkanoyloxy, C 1-4 alkyl and d-4-alkoxy (the last two being groups optionally substituted by one or more halo atoms)); R13a and R13 independently represent H, C4-7 cycloalkyl (optionally substituted by one or more C? - alkyl groups), C1-10 alkyl. C2-? o alkenyl (alkyl or alkenino groups which are optionally substituted by one or more substituents selected from aryl or C7 cycloalkyl (the latter group being optionally substituted by one or more C-? 4 alkyl groups) or aryl (optionally substituted by one or more substituents selected from OH, halo, d-4 alkanoyl, C 1-4 alkanoyloxy, C 1-4 alkyl and C 1-4 alkoxy (the last two groups being optionally substituted by one or more halo atoms)); R 14 represents H, cycloalkyl C - (optionally substituted by one or more alkyl groups d-), CMO alkyl (optionally substituted by one or more substituents selected from aryl or cycloalkyl -7 (the latter group being optionally substituted by one or more C-alkyl groups) )), or aryl (optionally substituted by one or more substituents selected from OH, halo, d-4 alkanoyl, C- alkanoyloxy, d-4 alkyl and C- alkoxy (the last two groups being optionally substituted by a or more halo atoms)); or a pharmaceutically or veterinarily acceptable derivative thereof. 2. A compound according to claim 1, wherein the group OY is attached to the benzene ring in the meta- position relative to the piperidine group.

3. A compound according to claim 1 or claim 2, wherein R1 represents alkyl d-2.

4. A compound according to any of claims 1 to 3, wherein R2 represents H or alkyl d-2.

5. A compound according to any of claims 1 to 4, wherein R3 represents C6-6 alkyl, C3-6 alkenyl or C3-4 alkynyl, said alkyl, alkenyl or alkynyl groups being optionally substituted and / or terminated by one or more substituents selected from OR4c, CN, halo, Het1 or aryl (the latter group being optionally substituted by one or more substituents selected from OH, d-2 alkyl, alkoxy-? -2 or halo).

6. - A compound according to any of claims 1 to 5, wherein R4c represents H, alkyl d-6, cycloalkyl C4-6, aryl or Het2.

7. A compound according to any of claims 1 to 6, wherein Het1 and Het2 independently represent 5- to 7-membered heterocyclic groups, said groups containing at least one heteroatom selected from oxygen, sulfur and / or nitrogen, said groups being optionally substituted by one or more alkyl groups d-2 (alkyl groups which are optionally substituted by one or more halo atoms).

8. A compound according to any of claims 1 to 7, wherein Y represents C (= E) NR8R9, C (O) R10 or R11.

9. A compound according to any of claims 1 to 8, wherein R8 and R9 independently represent H or C1- alkyl; R 10 represents C 1-6 alkyl (substituted by one or more phenyl groups) or aryl (optionally substituted by one or more substituents selected from OH, halo, C? -3 alkanoyloxy, NH2, C (O) NH2 and C? -3 alkyl (the last group being optionally substituted by one or more halo atoms)); and / or R11 represents d-5 alkyl (substituted by one or more substituents selected from C (O) NH2, Het8, aryl and aryloxy), C6-? oo alkyl or C3-? 0 alkenyl, the last two groups being optionally substituted by one or more substituents selected from Het6 and aryl.

10. A compound according to any of claims 1 to 9, wherein Het6 and Het8 independently represent 5-6 membered heterocyclic rings, said rings containing at least one heteroatom selected from oxygen, sulfur and / or nitrogen, being said rings optionally condensed to a benzene ring, and said rings being optionally substituted on the part of the heterocyclic ring and / or the benzene ring condensed by one or more substituents selected from OH, = O and C? -4 alkyl).

11. A compound according to any of claims 1 to 10, wherein Het6 and Het8 are in the S-oxidized form.

12. A compound as defined in any of claims 1 to 11, for use as a medicament.

13. A compound as defined in any of claims 1 to 11, for use as an animal medicament.

14. A formulation comprising a compound as defined in any of claims 1 to 11, in admixture with a pharmaceutically or veterinarily acceptable adjuvant, diluent or vehicle.

15. A formulation according to claim 14, which is a veterinary formulation.

16. The use of a compound according to any one of claims 1 to 11, in the manufacture of a medicament for the curative or prophylactic treatment of pruritus.

17. A method for the treatment or prevention of pruritus, comprising the administration of a therapeutically effective amount of a compound as defined in any one of claims 1 to 11, to a patient in need of such treatment.

18. - A process for the preparation of a compound as defined in claim 1, comprising: a) for the compounds of formula I wherein R3 represents Ci alkyl optionally substituted by C3-8 cycloalkyl, Het1, aryl, adamantyl (wherein the last two groups optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C? - alkyl, C? - alkoxy and d-5 alkanoyl (the last three groups being optionally substituted by one or more halo atoms)), or R3 represents C2-? o alkyl. C3-? oo alkenyl c3-? 0 alkenyl (the three groups all being optionally substituted by one or more of the corresponding substituents identified in claim 1 with respect to R3), the alkyl, alkenyl or alkynyl groups being attached to the nitrogen atom of piperidine by a CH2 group > Het1 being as defined in claim 1, the reduction of a corresponding compound of formula II, wherein R31 represents H, C3-8 cycloalkyl, Het1, aryl, adamantyl (the last two groups being optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, alkyl d-4 , alkoxy C -? - 4 and alkanoyl d-5 (the last three groups being optionally substituted by one or more halo atoms), C? -9 alkyl, C2-9 alkenyl or C2-9 alkynyl, said alkyl groups being, alkenyl or alkynyl 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, cycloalkanoyl C -9, N (R5a) S (O) 2R6, Het1, aryl, adamantyl (the last two groups being optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C-alkyl ? -, alkoxy d- and alkanoyl d-5 (the last three groups being optionally substituted by one or more halo atoms)), or -W-A1N (R5b) (R5c), and R1, R2, R4c, R14d, R5a, aR5c, R6, Het1, n, Y, W and A1 are as defined in claim 1; b) the reaction of a corresponding compound of formula III, wherein R1, R2, and Y are as defined in claim 1, as a compound of formula V, R3-L1 V wherein L1 represents a leaving group and R3 is as defined in claim 1; c) for compounds of formula I in which R3 represents Ci-alkyl, which, instead of being optionally substituted by substituents as defined in claim 1, is instead optionally substituted by R31, where R3 is as defined above, the 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 C1-10 alkyl group, C -? 0 alkenyl which is completely saturated with C1 to C3 (relative to the N atom of piperidine), and said R3 group being substituted in C2 (relative to the N atom of piperidine) by S (O) R4d, S (O) 2 R4d, 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), wherein R4d, R5b, R5c and A1 are as defined in claim 1, the reaction of a corresponding compound of formula III, as defined above, with a compound of formula VII, R3a-Z VII wherein R3a represents R3 as defined in claim 1 except that it does not represent aryl, and that the R3a chain contains an additional carbon-carbon double bond, ß to the Z substituent, and Z represents S (O) 2 R4d, alkanoyl, cycloalkanoyl, alkoxy carbonyl, CN, -C (O) -A1-N (R5b) (R5c), -S (O) -A1-N (R5b) (R5c), or -S (O) 2 -A1-N (R5b) (R5 °), in the that 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, the reaction of a corresponding compound of formula VIII, wherein R1, R2 and R3 are as defined in claim 1, with a compound of formula IX, or a suitable derivative thereof, wherein E, R8 and R9 are as defined in claim 1, or a compound of formula X, E = C = NR8R9 X 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) OR10a, in which R10 and R10a are as defined in claim 1, the reaction of a corresponding compound of formula VIII, as defined above, with a compound of formula XI, HO-C (O) R10 XI, or a compound of formula XII, HO-C (O) OR10a XII, respectively, or suitable derivatives thereof, wherein R10 and R10a are as defined in claim 1; g) for the compounds of formula I wherein Y represents C (O) CH (R10b) N (G) (Ga), wherein R10b, G and Ga are as defined in claim 1, the reaction of a corresponding compound of formula VIII, as defined above, with a compound of formula XIII, OH-C (O) CH (R10b) N (G) (Ga) XIII or a suitable derivative thereof (carboxylic acid), in the that R10b, G and Ga are as defined in claim 1; h) for the compounds of formula I in which Y represents C (O) C (R13a) = C (R13b) NH2 or C (O) CH (R13a), in which R13a and R13b are as defined in the claim 1, the reaction of a corresponding compound of formula VIII, as defined above, with a compound of formula XIV, 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) R10, wherein R10 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 4 alkanoyl, C 4 alkanoyloxy, N (R 8) (R 9), C (O) N (R 8) (R 9), C 4 alkyl, and C 1-4 alkoxy (the latter two groups being optionally substituted by one or more atoms halo), and R8 and R9 are as defined in claim 1, the reaction of a corresponding compound of formula VIII, as defined above, with a compound of formula XV, wherein D represents one to four optional substituents selected from OH, halo, C1-4 alkanoyl, C1-4 alkanoyloxy, N (R8) (R9), C (O) N (R8) (R9), Cr4 alkyl, and C 1-4 alkoxy (the last two groups being optionally substituted by one or more halo atoms), and R 8 and R 9 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, the reaction of a corresponding compound of formula VIII, as defined above, with a compound of formula XVI , R11-L2 XVI wherein L2 represents a leaving group and R11 is as defined in claim 1; k) for 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 in claim 1, the reaction of a corresponding compound of formula VIII, as defined above, with a compound of formula XVII, L2-CH (R12b) C (O) OR12a XVII or a compound of formula XVIII, L2-CH (R12b) OC (O) OR12a XVI 11 wherein R12a and R12b are as defined in claim 1 and L2 is as defined above; I) for compounds of formula I in which Y represents PO (OR14) 2, in which R14 is as defined in claim 1, the reaction of a compound of formula VIII, as defined above, with a compound of formula XIX, H-PO (OR14) 2 XIX or a compound of formula XX, HO-PO (OR 14) 2 XX or a suitable derivative thereof, wherein R 14 is as defined in claim 1; m) the conversion of a functional group into an alkyl, heterocyclic or aryl group in a compound of formula I into another.

19. A compound of formula II, as defined in claim 18.

20. A compound of formula III, as defined in claim 18.