MXPA00005245A - 4-arylpiperidine derivatives for the treatment of pruritus - Google Patents

Abstract

There is provided a compound of formula I, wherein A, D, R<1>, R<2>, R<3>, X and n have meanings given in the description, which are useful in the prophylaxis and in the treatment of diseases mediated by opiate receptors, such as pruritus.

Description

NEW 4-ARILPIPERIDINE DERIVATIVES FOR THE TREATMENT OF PRURITE This invention relates to pharmaceutically useful compounds, in particular, to compounds that bind opioid receptors (eg, mu, kappa and delta opiate receptors). Compounds that bind to such receptors are likely to be useful in the treatment of diseases mediated by opiate receptors, for example, of irritable bowel syndrome; constipation; sickness; vomiting; and pruritic dermatoses such as allergic dermatitis and atopic dermatitis in animals and in humans. Compounds that bind opioid receptors have also been indicated in the treatment of eating disorders, opioid overdoses, depression, tobacco and alcohol addiction, sexual dysfunction, shock, stroke, spinal injury, and head trauma. There is a particular need for an improved treatment of stinging. Itching, or pruritus, is a common dermatological symptom that can cause considerable discomfort in both humans and animals. Pruritus is often associated with inflammatory skin diseases that can be caused by hypersensitivity reactions, including reactions to insect bites, such as flea bites, and to environmental allergens, such as house dust mites or pollen; for bacterial and fungal infections of the skin; or by infections by ectoparasites. Existing treatments that have been used in the treatment of pruritus include the use of corticosteroids and antihistamines. However, it is known that these two treatments have undesirable side effects. Other therapies that have been used include the use of supplements of essential fatty acids in the diet, although these have the disadvantage of acting slowly and offering only limited efficacy against allergic dermatitis. Various emollients such as soft paraffin, glycerin and lanolin are also employed, but with limited success. Thus, there remains a need for alternative and / or improved treatments for pruritus. In the European patent applications EP 287339, EP 506468, EP 506478 and in J. Med. Chem. 1993, 36, 2833-1850, among other documents, certain compounds based on 4-arylpiperidine are described as opioid antagonists. In addition, International Patent Application WO 95/15327 describes azabicycloalkane derivatives useful as neuroleptic agents. According to the invention, compounds of formula I are provided: wherein A represents a single bond, alkylene d-4, alkenylene Cz ^ to C 2-4 alkynylene, the alkylene, alkenylene or alkynylene groups being optionally substituted with one or more substituents selected from C 1-4 alkyl, C 1 - alkoxy 4, halo or OH; D represents H, OH, CN, N (R4) (R5), N (H) R6, C (0) N (R4) (R5), C (0) OR7, C (0) R8, C (= NR9a) R8 or C (= NOR9b) R8; with the proviso that when A represents alkenylene CZ? Or C2-4 alkynylene, and D represents OH, N (R4) (R5) or N (H) R6, then D is not directly attached to an unsaturated carbon atom; and with the proviso that when A represents a single bond, then D does not represent H, OH, N (R4) (R5) or N (H) R6; R4 and R5 independently represent H, C6-6 alkyl, C3-8 cycloalkyl, keto, alkyl C-? 4-phenyl, the last four groups being optionally substituted with one or more substituents selected from nitro, halo, C- alkyl Or C- alkoxy (the last two groups being optionally substituted with one or more halo atoms), or R4 and R5, together with the N atom to which they are attached, form a 4- to 7-membered heterocyclic ring, containing the ring optionally one or more additional heteroatoms selected from oxygen, nitrogen and sulfur and the ring being optionally substituted with one or more substituents selected from C 1-4 alkyl, C 1-4 alkoxy, OH, = 0, nitro, amino or halo; R6 represents C (O) R10a, C (O) OR10 OR S (O) 2R10c; 1 O 1 O Oc R a R independently represent C-alkyl, C 3-8 cycloalkyl, aryl, C 1 -C 4 alkyl-phenyl (the four groups being optionally substituted with one or more substituents selected from nitro, halo, C 1-4 alkyl or C 4 -alkoxy (the last two groups 10a being optionally substituted with one or more halo atoms), or R represents H; R7 and R8 independently represent H, Ci-β alkyl, C3-8 cycloalkyl, aryl or alkyl d-4-phenyl, the last four groups being optionally substituted with one or more substituents selected from nitro, halo, C1-4alkyl or alkoxy C1-4 (the last two groups being optionally substituted with one or more halo atoms); 9a 9b R and R independently represent C-? -6 alkyl, C3-8 cycloalkyl, aryl, C? -4-phenyl alkyl, the last four groups being optionally substituted with one or more substituents selected from nitro, halo, C- alkyl Α-4 or C-α-4 alkoxy (the last two groups being optionally substituted with 9b one or more halo atoms), or R represents H; each of R1 and R2 is independently H or C- alkyl; R3 represents aryl (optionally substituted with one or more substituents selected from OH, nitro, halo, CN, CH2CN, CONH2, C? -4 alkyl, C? -alkoxy, C? -5 alkanoyl (the last three groups being optionally substituted with one or more halo atoms) and -N (R11a) (R11b)), C-MO alkyl, C3-10 alkenyl or C3-10 alkynyl, said alkyl, alkenyl and alkynyl groups being optionally substituted and / or terminated with one or more 11c 11d substituents selected from OR, S (O) pR, CN, halo, Ci-β-carbonyl alkoxy, Cz-β alkanoyl, C2-6-alkanoyl-oxy, C3-8 cycloalkyl, C4-9 cycloalkanoyl, N (R12a) S (0) 2R13, Het1, aryl, adamantyl (the last two groups being optionally substituted with one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-4 alkyl, C1 alkoxy -4 and C1-5 alkanoyl (the last three groups optionally being substituted with one or more halo atoms)), or -W-A1-N (R12b) (R12c); p is 0, 1 or 2; W represents a single bond, C (O) or S (0) q; A1 represents a single bond or C1-10 alkylene; with the proviso that when W and A represent single bonds, then the group -N (R12b) R12c) is not directly attached to an unsaturated carbon atom; q is 0, 1 or 2; each of R to R independently represents H, C -? - 10 alkyl, C3 -? alkenyl, C3 -? alkynyl, C3-8 cycloalkyl, C? -4 - phenyl alkyl, aryl (the last six groups being optionally substituted with one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, alkyl d-4, alkoxy C- and alkanoyl d-5 (the last three groups being optionally substituted with one or more carbon atoms) halo)) or Het2; with the proviso that when R11d does not represent H then p represents 1 or 2; 12a 12c each of R to R independently represents H, C -? - 10 alkyl, C3 -? Alkenyl, C3 -? Alkynyl, C3-8 cycloalkyl, C - phenyl alkyl, aryl (the last six groups being optionally substituted with one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-4 alkyl, C1-4 alkoxy and C1-5 alkanoyl (the last three groups 3 12b 12c being optionally substituted with one or more halo atoms), Het, or R and R together represent unbranched C2-6alkylene, the alkylene group optionally being interrupted with O, S and / or a N (R) group and optionally being substituted with one or more groups C1-4 alkyl; R 13 represents d-6 alkyl, C 3-8 cycloalkyl, alkyl d-4-phenyl or aryl, the four groups being optionally substituted with one or more substituents selected from C 1-4 alkyl, C 1-4 alkoxy, OH, nitro, amino or halo; R 14 represents H, C 1-6 alkyl, C 3-8 cycloalkyl, A2- (C 3-7 cycloalkyl) or A -aryl; A2 represents alkylene C-i-β; Het1, Het2 and Het3 independently represent heterocyclic groups of 3 to 8 memberssaid groups containing at least one heteroatom selected from oxygen, sulfur and / or nitrogen, said groups optionally being condensed with a benzene ring and said groups being optionally substituted in the part of the heterocyclic ring and / or benzene condensed with one or more substituents selected from OH, = 0, nitro, amino, halo, CN, aryl, C 1-4 alkyl, C 1-4 alkoxy and C 1-5 alkanoyl (the last three groups being optionally substituted with one or more halo atoms); X is H, halo, C? -4 alquiloalkyl or d-4alkoxy (the last two groups being optionally substituted with one or more halo atoms); n is 0, 1 or 2; or the pharmaceutically or veterinarily acceptable derivatives thereof; compounds which are collectively referred to hereafter as "the compounds of the invention". In the definitions used herein, alkyl, alkylene, alkoxy, alkoxycarbonyl, alkanoyl, alkanoyloxy, alkenyl, alkynyl and the alkyl portions of the alkylphenyl and aryl alkoxy groups may, when there is a sufficient number of carbon atoms, be chain linear or branched and / or optionally interrupted by one or more oxygen and / or sulfur atoms. The term "halo" includes fluoro, chloro, bromo or iodo. The term "aryl" includes phenyl, naphthyl and the like, optionally substituted and "aryloxy" includes phenoxy and naphthyloxy and the like, optionally substituted. Unless otherwise indicated, the aryl and aryloxy groups are optionally substituted with one or more (eg, one to three) substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, alkyl d-4. , alkoxy d-4-alkoxy C- -carbonyl and alkanoyl d-5 (the last four groups being optionally substituted with one or more halo atoms). Heterocyclic rings representing Het1, Het2, and Het3 and which may represent N (R4) (R5), may be fully saturated, partially unsaturated and / or may be wholly or partially aromatic in nature.

For the avoidance of doubt, when the heterocyclic groups (ie, Het1, Het2, Het3 and some definitions of N (R4) (R5)) are possible substitution points at least partially saturated, they include the atom (e.g. carbon) at the point of attachment of the heterocyclic group to the rest of the molecule. The Het groups (Het1, Het2 and Het3) can also be linked to the rest of the molecule by a heteroatom. The piperidine moiety present in the compounds of formula I may be in the N-oxidized form. Sulfur atoms that can interrupt substituents (e.g., alkyl) in the compounds of formula I, may be present in oxidized form (e.g., in the form of sulfoxides or sulfones). All heterocyclic groups (ie, Het, Het2, Het3 and some definitions of N (R4) (R5)) may also be in N- or S-oxidized forms. The term "pharmaceutically or veterinarily acceptable derivatives" includes non-toxic salts. Salts that may be mentioned include: acid addition salts, for example, salts formed with sulfuric, hydrochloric, hydrobromic, phosphoric, hydroiodic, sulfamic, organosulfonic, citric, carboxylic (eg, acetic, benzoic, etc.) acids , maleic, malic, succinic, tartaric, cinnamic, ascorbic and related acids; base addition salts; and salts formed with bases, for example, the sodium, potassium and alkyl C -? - 4-ammonium salts. The compounds of the invention can also be in the form of quaternary ammonium salts, for example, in the piperidine moiety, said salts being able to be formed by reaction with a variety of alkylating agents, such as an alkyl halide or a sulfuric acid ester or of an aromatic sulfonic acid. The compounds of the invention may present tautomerism. All tautomeric forms 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 and diastereomers. The diastereomers can be separated using conventional techniques, for example, by fractional crystallization or chromatography. The various stereoisomers can be isolated by separation of a racemic mixture or other mixture of the compounds using conventional techniques, for example, fractional crystallization or HPLC. The desired optical isomers can be prepared by reacting the appropriate optically active starting materials under conditions that do not cause randomization or epimerization. As an alternative, the desired optical isomers can be prepared by resolution, by HPLC of the racemate using a suitable chiral support or, where appropriate, by fractional crystallization of the diastereomeric salts formed by reaction of the racemate with a suitable optically active acid or base. The invention includes the use of the two separate stereoisomers as well as mixtures of such isomers. Also included within the scope of the invention are derivatives of compounds of formula I labeled with radioisotopes which are suitable for biological studies.

Preferred compounds of the invention include those in which: Group A-D is attached in the meta- position relative to the piperidine ring; R1 represents alkyl d-2; R2 represents H or alkyl d-2; R3 represents saturated C-MO alkyl (eg, d-β), optionally substituted with one or more substituents selected from OR11c, CN, halo, C2-4 alkanoyl, d-4-carbonyl alkoxy, N (R12a) SO2R13, Het1 , aryl (the latter group optionally being substituted with one or more substituents selected from OH, C 1-4 alkyl, C 1-4 alkoxy, C 2-5 alkanoyl, halo, n, amino, CN and CONH 2), or -W-A1- N (R12b) (R12c); R11c represents H, d-β alkyl or aryl (the last groups being optionally substituted with one or more substituents selected from OH, d-4 alkyl, C-u alkoxy, C2-5 alkanoyl, halo, n, amino, CN and CONH2); 12a 12c R a R independently represent H, alkyl d-4, alkyl d-2-phenyl or aryl (the last three groups being optionally substituted with one or more substituents selected from halo, Cl-4 alkyl or d-4 alkoxy); R 13 represents C- alkyl, d-2-phenyl alkyl or aryl (the last three groups being optionally substituted with one or more substituents selected from halo, C 1-4 alkyl or C 1-4 alkoxy); W represents C (O); A1 represents a simple link.

More preferred compounds of the invention include those in which: A represents a single bond, C? -4 alkylene, C 2-4 alkenylene or C 2-4 alkynylene, the alkylene, alkenylene or alkynylene groups being optionally substituted with one or more groups OH and / or methyl; D represents H, OH, CN, N (H) R4, N (H) C (O) R10a, N (H) C (O) OR10b, N (H) S (O) 2R10c, C (0) N ( R4) (R5), C (0) OR7, C (0) R8 OC (= NOH) R8; R 4 and R 5 independently represent H, C 1-4 alkyl or C 1 --3-phenyl alkyl (the last two groups being optionally substituted with C 1 - * alkoxy); R7 and R8 independently represent H or C-M alkyl; 1 O 1 O or R R a independently represent C-M alkyl (optionally substituted with one or more halo atoms); R represents methyl; R 2 represents H or methyl; R3 represents saturated C? -7 alkyl, optionally substituted with one or more substituents selected from CN, OR11c or phenyl; R c represents d-β alkyl or phenyl; X represents halo, particularly fluoro; n represents 1 or, preferably, 0. Particularly preferred compounds of the invention include those in which: A represents a single bond, -CH2-, -CH (CH3) -, -C (CH3) 2-, - CH (OH) -, - (CH2) 2-, -CH = CH- or -C = C-; D represents H, OH, CN, NH2, N (H) CH3, CHO, CH (= NOH), C (O) CH3, CO2CH3, CO2H, C (O) NH2, C (O) N (H) CH3, C (O) N (H) Et, C (0) N (H) (2-MeOEt), C (0) N (H) n-Pr, C (0) N (H) / - Pr, C (0) N (H) n-Bu, C (0) N (H) / - Bu, C ( 0) N (H) i-Bu, C (0) N (H) CH2Ph, C (0) N (CH3) 2, C (0) N (Et) 2, N (H) C (0) CH3, N (H) C (0) OCH3, N (H) S (0) 2CH3 or N (H) S (0) 2CF3; R1 and R2 represent methyl groups with a trans configuration therebetween; R3 represents benzyl, 5-cyanopentyl, n-hexyl, 5-methylhexyl, 2-phenoxyethyl or 3-phenylpropyl. Preferred compounds of the invention include the compounds of the Examples described below. In accordance with 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 in order to obtain the compounds of the invention. The compounds of formula I in which A represents C 2-4 alkynylene (group in which the carbon-carbon triple bond is a, β with respect to the benzene ring), said alkynylene group being optionally substituted in the 3- position and / or 4-C (with respect to the benzene ring) with one or more substituents defined hereinbefore in relation to A, and / or one of the groups defined hereinbefore in relation to D, or (when D) it is not attached to the 3- or 4-C position) said substituted alkynylene group being at the 2-C position (with respect to the benzene ring) with CN, C (0) N (R4) (R5), C (0) ) OR7, C (0) R8, C (= NR9a) R8 or C (= NOR9b) R8, can be prepared by the reaction of a corresponding compound of formula wherein L1 is a suitable leaving group such as halogen, preferably bromine or iodine, or a sulfonate such as trifluoromethanesulfonate, and R1, R2, R3, X and n are as defined hereinbefore, with a compound of formula III , M- -A-D lll wherein M represents (where appropriate) H, a residue containing tin (eg, tributyltin), a boron derivative (eg, a boronic acid), a zinc halide, a magnesium halide or an alkali metal (the last three groups can be formed in situ from the corresponding halide), A3 represents a single bond or alkylene d-2 (optionally substituted with one or more substituents selected from C-alkyl, C-α-4 alkoxy, OH or halo ), and D is as defined above in this document, with the proviso that when A3 represents a single bond, then D does not represent H, OH, N (R4) (R5) or N (H) R6, where R4 is , R5 and R6 as defined above, at a temperature varying, for example, between room temperature and reflux temperature, in the presence of a suitable catalyst system (for example, bis (triphenylphosphine) palladium (II) chloride combined with copper iodide (I)) and an appropriate organic base (eg, triethylamine). 2. The compounds of formula I wherein A represents C2-4 alkenylene (a group in which the carbon-carbon double bond is a, ß with respect to the benzene ring), said alkenylene group being optionally substituted at C-2 ( with respect to the benzene ring) with C 1-4 alkyl and also optionally substituted with 3- and / or 4-C (with respect to the benzene ring) with one or more of the substituents defined hereinbefore in relation to A and / or one of the groups defined hereinbefore in relation to D, or said alkenylene group being substituted at C-2 (with respect to the benzene ring) with CN, C (0) N (R4) (R5), C (0) OR7, C (0) R8, C (= NR9a) R8 or C (= NOR9b) R8, can be prepared by the reaction of a corresponding compound of formula II, as defined hereinbefore, with a compound of formula IV, wherein the dashed line represents optional cis or trans geometry, R15 represents H or alkyl CM, and A3, D and M are as defined hereinabove, at a temperature comprised, for example, between room temperature and the reflux temperature, in the presence of a solvent inert to the reaction (for example, 1,4-dioxane or THF), an appropriate catalyst (for example, tetrakis (triphenylphosphine) palladium (0) or bis (triphenylphosphine) palladium acetate (ll)) and (where appropriate) a suitable source of halide ion (e.g., lithium chloride) or a suitable base (e.g., triethylamine). 3. The compounds of formula I in which A represents a single bond and D represents CN, can be prepared by the reaction of a compound of formula V, wherein R1, R2, R3 and X are as defined hereinbefore, with an alkali metal cyanide (eg, potassium cyanide), for example, at elevated temperature, in the presence of a solvent inert to the reaction (e.g., N-methylpyrrolidine) and a suitable catalyst (e.g., palladium acetate (II) combined with 1,1'-bis (diphenylphosphino) ferrocene). The compounds of formula V can be prepared by the reaction of a corresponding compound of formula VI, wherein R1, R2, R3, X and n are as defined above, with an appropriate inflation agent (e.g.,? / - phenyltrifluoromethanesulfonimide), at a temperature comprised, for example, between 0 ° C and room temperature , in the presence of an organic solvent inert to the reaction (e.g., dichloromethane) and a suitable base (e.g., triethylamine). The compounds of formula VI can be prepared by the reaction of a corresponding compound of formula VII, wherein R1, R2, Xi earlier in this document, with a compound of formula Vlll R3-L1 Vlll? 3 .. wherein R and L are as defined above in this document, under conditions that are known to those skilled in the art and include, for example, alkylation at a temperature between room temperature and reflux temperature, in the presence of an organic solvent inert to the reaction (eg,? ,? / - dimethylformamide) and a suitable base (e.g., NaHCOs), and arylation at a temperature between room temperature and reflux temperature, in the presence of a suitable catalyst system (e.g., tr¡s (dibenzyl; denoacetone) palladium (0) combined with tri-o-tolylphosphine), an appropriate strong base (e.g., sodium tert-butoxide) and a reaction inert solvent (e.g., toluene). 4. The compounds of formula I wherein A represents C- alkylene, C2-4-alkenylene or C2-4-alkynylene, said alkylene, alkenylene or alkynylene groups being optionally substituted with one or more substituents selected from C? -4 alkyl, alkoxy C1-4, halo or OH, and D represents NH2 (which is linked to a CH2 group), can be prepared by the reduction of a corresponding compound of formula I wherein A represents (where appropriate) a single bond, C1-alkylene -3, C2-3 alkenylene or C2-3 alkynylene, said alkylene, alkenylene or alkynylene groups being optionally substituted with one or more substituents selected from alkylCal, alkoxy d-4, halo or OH, and D represents CN, at a temperature comprised, for example, between the ambient temperature and the reflux temperature, in the presence of a suitable reducing agent (for example, lithium aluminum hydride) and an appropriate solvent (for example, THF). 5. Compounds of formula I in which D represents C (O) NH2 can be prepared by the controlled hydrolysis of a corresponding compound of formula I in which D represents CN, for example, by reaction with polyphosphoric acid at a temperature comprised between 50 and 150 ° C. 6. The compounds of formula I in which A represents a single bond and D represents C (0) - (alkyl d-β) or C (0) - (alkyl d-4-phenyl), the alkyl and alkylfenyl groups being optionally substituted with one or more of the substituents defined hereinabove with respect to R8 can be prepared by hydrolysis of a corresponding compound of formula IX, wherein R represents alkyl d-6, R represents H, C 1-5 alkyl, phenyl or alkyl d-3-phenyl, the last three groups being optionally substituted with one or more substituents selected from nitro, halo, C 1-4 alkyl or C1-4 alkoxy (the last two groups being optionally substituted with one or more halo atoms), the broken line indicates the optional cis or trans geometry, and R, R2, R3, X and n are as defined above in this document, for example, under conditions known to those skilled in the art (for example, by reaction at a temperature between room temperature and reflux temperature, with an aqueous solution of a mineral acid). The compounds of formula IX can be prepared by the reaction of a compound of formula II, as defined hereinbefore, with a compound of formula X, wherein the dashed line represents the optional cis or trans geometry, and R 5 and R 16 are as defined above in this document, at a temperature comprised, for example, between ambient temperature and reflux temperature, in the presence of a suitable catalyst (e.g., palladium acetate (11) combined with 1,1'-bis (diphenylphosphino) ferrocene), an organic base (e.g., triethylamine) and an appropriate solvent (e.g., N, N-dimethylformamide) ). 7. Compounds of formula I in which D represents C (O) R8, where R8 is as defined hereinabove, with the proviso that it does not represent H, can be prepared by the reaction of a corresponding compound of formula I wherein D represents CN with an organometallic compound capable of releasing an anion containing R8a (for example, an appropriate organolithium or Grignard reagent), R8a being defined as in the case of R indicated above, with the proviso that it does not represent H, at a temperature comprised, for example, between -80 and 10 ° C, in the presence of an organic solvent inert to the reaction (for example, tetrahydrofuran). 8. Compounds of formula I wherein A represents a single bond and D represents C (O) OR7, where R7 is as defined above, with the proviso that it does not represent H, can be prepared by the reaction of a corresponding compound of formula V, as defined hereinabove, with carbon monoxide and an alcohol of formula R7aOH, R7a being defined as in the case of R7 above with the proviso that it does not represent H, for example, in the presence of a system suitable transition metal catalyst (e.g., palladium acetate (11) combined with 1,1'-bis (diphenylphosphino) ferrocene) and a solvent inert to the reaction (e.g., DMF). 9. The compounds of formula I wherein A represents alkylene d-4, C2-4 alkenylene or C2-4 alkynylene, said alkylene, alkenylene or alkynylene groups being optionally substituted with one or more substituents selected from C- alkyl, alkoxy CM , halo or OH, and D represents OH (which is linked to a CH2 group), can be prepared by reduction of a corresponding compound of formula I wherein A represents (where appropriate) a single bond, C-1 alkylene 3, C2-3 alkenylene or C2-3 alkynylene, said alkylene, alkenylene or alkynylene groups being optionally substituted with one or more substituents selected from CM alkyl, d-4 alkoxy, halo or OH, and D represents C (O) OR7a, R7a being as defined above, at a temperature comprised, for example, between 0 ° C and the reflux temperature, in the presence of a suitable reducing agent (for example, lithium aluminum hydride) and an appropriate solvent (e.g. , THF). 10. Compounds of formula I wherein A represents C1-4alkylene, C2-4alkenylene or C2-4alkynylene, said alkylene, alkenylene or alkynylene groups being gem-disubstituted with two C1-4alkyl groups (in position a with with respect to D) and being optionally substituted with one or more additional substituents selected from alkyl d-4, alkoxy Cl-4, halo or OH, and D represents OH, can be prepared by the reaction of a corresponding compound of formula I wherein A represents (where appropriate) a single bond, d-3 alkylene, C 2-3 alkenylene or Cz-3 alkynylene, said alkylene, alkenylene or alkynylene groups being optionally substituted with one or more substituents selected from C 1-4 alkyl, C 1-4 alkoxy, halo or OH, and D represents C (O) OR 7 a, where R 7 a is it has been defined hereinabove, with an organometallic compound releasing appropriate d-4 alkyl (for example, an alkylmagnesium halide), at a temperature comprised, for example, between -10 ° C and the reflux temperature, in the presence of a suitable solvent (e.g., THF). 11. Compounds of formula I wherein D represents C (O) N (R4) (R5), where R4 and R5 are as defined hereinbefore, can be prepared by the reaction of a corresponding compound of formula I in wherein D represents C (0) OR7a, and R7a is as defined hereinabove, with a compound of formula XI, HN (R4) (R5) XI or an acid addition salt (e.g., HCl) thereof, wherein R and R5 are as defined above in this document, at a temperature comprised, for example, between -10 and +150 ° C, and at a pressure comprised between 1 and 10 atmospheres, optionally in the presence ( where appropriate) of a Lewis acid catalyst (eg, trimethylaluminum) and a reaction inert solvent (eg, toluene). 12. Alternatively, the compounds of formula I wherein D represents C (O) N (R4) (R5), where R4 and R5 are as defined hereinbefore, can be prepared by the reaction of a corresponding compound of Formula I wherein D represents C (0) OH with a compound of formula XI, as defined hereinbefore, under coupling conditions known to those skilled in the art. 13. Compounds of formula I in which D represents C (O) OH can be prepared by hydrolysis of a corresponding compound of formula I wherein D represents C (O) OR7a, where R7a is as defined hereinabove. , in conditions that are known to those skilled in the art. 14. Compounds of formula I in which D represents N (H) Rd, where R is as defined hereinabove, can be prepared by the reaction of a corresponding compound of formula I in which D represents NH 2 with a compound of formula XII, R6-L1 XII in which R6 and L1 are as defined above in this document, for example, under conditions that are known to those skilled in the art, including reaction at a temperature between -10 ° C and the reflux temperature, in the presence of a suitable base (for example, triethylamine or pyridine) and, optionally, a solvent inert to the reaction (for example, THF or dichloromethane). 15. Compounds of formula I wherein A represents C1-4 alkyl and D represents N (R4) (R5) or N (H) C (O) R10a attached in the 1, 2 or 3-C position (with respect to to the benzene ring), where R4, R5 and R10a, as defined hereinbefore, can be prepared by the reaction of a corresponding compound of formula I in which A represents alkenylene C? -4 a,? -,? ? - or?, d-unsaturated (respectively) with respect to the benzene ring and D represents H, with a compound of formula XI, as defined hereinbefore, or a compound of formula XIII, NC-R10a XIII 10a wherein R is as defined above, at a temperature comprised, for example, between -10 ° C and room temperature, in the presence of a suitable mercury salt (ll) (eg, acetate, trifluoroacetate, nitrate or mercury perchlorate (ll)), optionally in the presence of a solvent inert to the reaction (eg, THF), and followed by reduction in mercury adduct situ by adding a releasing agent suitable hydride (e.g., sodium borohydride), optionally in the presence of water. 16. Compounds of formula I wherein A represents C2-4 alkylene optionally substituted with one or more substituents selected from C-, C-, halo- or OH-alkoxy, and D represents OH, can be prepared by the oxidation of an adduct of corresponding borane of formula XIV, wherein x is 1, 2 or 3, and is (where appropriate) (3-x) or 1, R17 is (where appropriate) H, halo, an alkyl, or a cycloalkyl group, providing one or two bonds with boron (for example, disiamyl or texil), A represents (where appropriate) C2-4 alkylene optionally substituted with one or more substituents selected from alkyl d-4, C1-4 alkoxy, halo or OH, and R1, R2 , R3, X and n are as defined hereinabove, for example, by reaction with a tertiary amine oxide (eg, trimethylamine N-oxide) at a temperature between room temperature and temperature reflux, in the presence of a solvent inert to the reaction (for example, THF or a mixture of THF / diglyme). A skilled person will appreciate that, in the compounds of formula XIV, bonds between boron atoms and N-atoms of piperidine may be present. Compounds of formula XIV can be prepared by the reaction of a corresponding compound of formula I wherein A represents (where appropriate) C2-4 alkylene optionally substituted with one or more substituents selected from C-, C-, halo- or OH-alkoxy , and D represents H, with borane or a suitable derivative thereof (for example, texil-borane, disiamylborane or 9-borabicyclo [3.3.1] nonane), at a temperature comprised, for example, between -10 ° C and room temperature, in the presence of a suitable solvent (for example, THF or a mixture of THF / diglyme). 17. The compounds of formula I in which A represents a C2-4 alkylene group substituted (at position a with respect to D) with an OH group and D represents OH, can be prepared by the reaction of a corresponding compound of formula I in wherein A represents a C2-4 alkylene group and D represents H, with a suitable dihydroxylation reagent (for example, Os? 4 in a substoichiometric amount together with 4-methylmorpholine? -oxide), at a temperature comprised, for example, , between 0 ° C and the reflux temperature, in the presence of a solvent inert to the reaction (for example, a water / acetone mixture). 18. Compounds of formula I wherein A represents a single bond or an alkylene group C---2 (where appropriate) and D represents C (0) H, can be prepared by the reaction of a corresponding compound of formula I wherein A represents a substituted C2-1 alkylene group (in position with respect to D) with an OH group and D represents OH, with a reagent that performs the oxidative cleavage of 1,2-diol (e.g., sodium periodate) . 19. Compounds of formula I in which D represents C (= NR9a) R8 or C (= NOR9b) R8, where R8, R9a and R9b are as defined hereinabove, can be prepared by the reaction of a corresponding compound of formula I in which D represents C (0) R8 with a compound of formula XV, H2N-R 9a XV or a compound of formula XVI, H2N-OR9b XVI 9a 9b wherein R and R are as defined above in this document, for example, under conditions that are known to those skilled in the art, including reaction at a temperature between room temperature and reflux temperature, in the presence of a suitable solvent (eg, an alkyl alcohol) lower such as methanol or ethanol). 20. Compounds of formula I in which A represents C? -4 alkylene substituted (in position a with respect to D) with an OH group and D represents N (H) CH3 (at the end of the alkylene chain), can prepared by the reduction of a corresponding compound of formula XVII, wherein r is 0, 1 or 2, L represents H or a capable group, when attached to a C2 alkylene unit, of undergoing 1, 2-elimination (with with respect to the group L2, for example, an alkyl or aryl sulfoxide or sulfone), and R1, R2, R3, X and n are as defined hereinabove, at a temperature comprised, for example, between -10 ° C and the reflux temperature, in the presence of a suitable reducing agent (e.g., lithium aluminum hydride) and a solvent inert to the reaction (eg, THF). Compounds of formula XVII can be prepared by the reaction of a corresponding compound of formula I in which A represents a single bond or alkylene C? -2 and D represents C (0) H, with a compound of formula XVIII, CN-CH2 -L2 XVIII in which L2 is as defined above in this document, at a temperature comprised, for example, between 0 ° C and the reflux temperature, in the presence of a suitable solvent (for example, ethanol) and an amount catalytic of a cyanide salt (for example, sodium cyanide). 21. The compounds of formula I wherein R3 represents alkyl d optionally substituted with C3-8 cycloalkyl, Het1, aryl, adamantyl (the last two groups being optionally substituted with one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, d-4 alkyl, C1-4 alkoxy and d-5 alkanoyl (the last three groups being optionally substituted with one or more halo atoms)), or R3 represents C2-? Alkyl, C3-alkenyl Or C3-10 alkynyl (the last three groups being optionally substituted with one or more of the relevant substituents identified hereinabove with respect to R3), said alkyl, alkenyl or alkynyl groups being attached to the piperidine nitrogen atom by a CH2 group, being Het1 as defined above, can be prepared by reduction of a corresponding compound of formula XIX, wherein R31 represents H, C3-8 cycloalkyl, Het1, aryl, adamantyl (the last two groups being optionally substituted with one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, alkyl d-4 , C 4 alkoxy and C 5 alkanoyl (the last three groups being optionally substituted with one or more halo atoms), C 1-9 alkyl, C 2-9 alkenyl or C 2-9 alkynyl, said alkyl groups being , alkenyl or alkynyl optionally substituted and / or terminated with one or more substituents selected from OR11c, S (0) pR11d, CN, halo, C6-6-carbonyl alkoxy, C2-6 alkanoyl, C2-oxo alkanoyl, 12a 13 C3-8 cycloalkyl, C4-9 cycloalkanoyl, N (R) S (22) R, Het, aryl, adamantyl (the last two groups being optionally substituted with one or more substituents selected from OH, nitro, amino, halo , CN, CH2CN, CONH2, C- alkyl, C1-4 alkoxy and C? -5 alkanoyl (the last three groups being optionally substituted with one or more atoms halo)), or -W-A1-N (R12b) (R12c), where R1, R2, R11c, R11d, R12a to R12c, R13, Het1, n, p, W, X, A1, A and D as defined hereinbefore, using a suitable reducing agent (eg, lithium aluminum hydride or a borane derivative), for example, as described above. A specialist will appreciate that this reduction can be done simultaneously with other reduction steps described in this document (see, for example, procedures 4, 9 and 16). The compounds of formula XIX can be prepared by the reaction of a corresponding compound of formula XX, wherein R "1, r R-? 2, A, D, X and n are as defined above, with a compound of formula XXI, R31C02H XXI or a suitable derivative (e.g., carboxylic acid) of the same (for example, a halide or acid anhydride), wherein R31 is as defined above, using coupling conditions known to those skilled in the art. The compounds of formulas XIX and XX can be prepared from suitable precursors by analogy with the methods described hereinabove describing the preparation of the compounds of formula I. 22. The compounds of formula I can be prepared by reaction of a corresponding compound of formula XX, as defined above in this document, with a compound of formula Vlll, as defined hereinbefore, under conditions which are well known to those skilled in the art, for example, as described above in this document with respect to the production of compounds of formula VI. 23. Compounds of formula I wherein R3 represents Ci-alkyl which, instead of being optionally substituted with the substituents defined hereinbefore, is optionally substituted with R31, where R31 is as defined hereinabove, can be prepared by reacting a corresponding compound of formula XX, as defined hereinabove, with a compound of formula XXII, R31CHO XXII wherein R is as defined hereinabove, in the presence of a suitable reducing agent (for example, sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride) and an appropriate solvent (for example, methanol). 24. Compounds of formula I wherein R3 is a C? -? Or C, C4-10 alkenyl or C4-10 alkynyl group which is fully saturated at 1- to 3-C (with respect to the N atom of piperidine ), and the group R3 being substituted in 2-C (with respect to the N atom of piperidine) with S (0) R11d, S (0) 2R11d, alkanoyl, cycloalkanoyl, alkoxycarbonyl, CN, -C (0) -A1 -N (R12b) (R12c), -S (0) -A1-N (R12b) (R12c) or -S (0) 2-A1-N (R12b) (R12c), where R11d, R12b, R12c and A1 as defined hereinbefore, can be prepared by the reaction of a corresponding compound of formula XX, as defined hereinbefore, with a compound of formula XXIII, R3a-Z XXIII 33 3 wherein R represents R as defined above, with the exception that it does not represent aryl and that the R3a chain contains an additional carbon-carbon double bond a, β with respect to the substituent Z, and Z represents S (0) R11d, S ( 0) 2R11d, alkanoyl, cycloalkanoyl, alkoxy carbonyl, CN, -C (0) -A1-N (R12b) (R12c), -S (0) -A1-N (R12b) (R12c) or -S (0) 2-A1-N (R12b) ( R12c), being 11b 12b 12c 1 R, R, R and A as defined above, for example, at a temperature comprised between room temperature and reflux temperature, in the presence of a reaction inert solvent (for example, THF).

. The compounds of formula I wherein A represents Cz-4 alkylene substituted (at position a with respect to D) with an OH group, D represents N (R4) (R5) (at the end of the alkylene chain), and R4 and R5 are as defined above in this document, can be prepared by the reaction of a compound of formula XXIV, wherein R1, R2, R3, X, nyr are as defined above, with a compound of formula XI, as defined hereinbefore, at a temperature comprised, for example, between room temperature and temperature reflux, in the presence of a suitable base (e.g., potassium carbonate) and an appropriate solvent (e.g., N, N-dimethylformamide). The compounds of formula XXIV can be prepared by dehydration of a corresponding compound of formula I wherein A represents a substituted C2-4 alkylene (at position a with respect to D) with an OH group and D represents OH (at the terminus of the alkylene chain), under conditions well known to those skilled in the art (for example, by heating in concentrated sulfuric acid). Alternatively, compounds of formula XXIV can be prepared by the oxidation of a corresponding compound of formula I wherein A represents a C 2-4 alkylene group terminal and D represents H, under conditions well known to those skilled in the art (e.g. , by reaction with mefa-chloroperbenzoic acid). 26. Compounds of formula I in which D represents N (H) R4, where R4 is as defined above with the proviso that it does not represent aryl, can be prepared by reduction of a corresponding compound of formula XXV, wherein R4 and R4c, together with the carbonyl group to which they are attached, form a C1-6 alkano group, C3-6 alkanone, C3-8 cycloalkanone, phenyl (C? -4) -alkanal or phenyl (C2-4) ) -alkanone, the five groups being optionally substituted with one or more substituents selected from nitro, halo, C 1-4 alkyl or C 1-4 alkoxy (the last two groups being optionally substituted with one or more halo atoms) and R 1, R 2 , R3, A, X and n are as defined above (with the proviso that the group -N = C (R4b) (R4c) is not directly bonded to an unsaturated carbon atom), at a temperature included, for example , between the ambient temperature and the reflux temperature, in the presence of a mild reducing agent (for example, sodium borohydride) and a suitable solvent (for example, a lower alkyl alcohol such as methanol or ethanol). The compounds of formula XXV can be prepared by the reaction of a corresponding compound of formula I in which D represents NH2, with a compound of formula XXVI, R4bC (0) R4c XXVI wherein R4b and R4c are as defined above in this document, at a temperature comprised, for example, between the ambient temperature and the reflux temperature, in the presence of a reaction inert solvent (for example, a lower alkyl alcohol such as methanol or ethanol) and, optionally, in the presence of a Lewis acid catalyst. 27. Compounds of formula I wherein A represents C? -4 alkylene, C 2-4 alkenylene or C 2-4 alkynylene, the alkylene, alkenylene or alkynylene groups being optionally substituted with one or more substituents selected from C 1-4 alkyl, CM alkoxy, halo or OH, and D represents N (R4) (R5) (attached to a CH2 group), where R4 and R5 as defined hereinbefore, can be prepared by reduction of a corresponding compound of formula I wherein A represents (where appropriate) a single bond, C? -3 alkylene, C2-3 alkenylene or C2-3 alkynylene, said alkylene groups being, alkenylene or alkynylene optionally substituted with one or more substituents selected from C 1-4 alkyl, C 1-4 alkoxy, halo or OH, and D represents C (0) N (R 4) (R 5), for example, in the presence of a suitable reducing agent (for example, lithium aluminum hydride or a borane derivative) and a solvent inert to the reaction (for example, THF). The compounds of formulas II, III, VII, X, R7aOH, XI, XII, XIII, XV, XVI, XVIII, XXI, XXII, XXIII, XXVI and their derivatives, when not available on the market or not described below , can be obtained by analogy with the processes described herein or by conventional synthesis procedures, according to conventional techniques, from readily available starting materials, using the appropriate reagents and reaction conditions. The substituents of the alkyl, heterocyclic and aryl groups in the aforementioned compounds can also be introduced, removed and interconverted using techniques that are well known to those skilled in the art. For example, nitro can be reduced to amino, OH can be alkylated to alkoxy, alkoxy can be hydrolyzed to OH, alkenes can be hydrogenated to alkanes, halo can be hydrogenated to H, etc. In some cases, it is possible to introduce other substituents directly into the compounds of formula I. For example, the chlorination of the phenyl group of the compounds of formula I can be carried out by reaction with a solution of chlorine in acetic acid. A specialist will also appreciate that various other conventional substituents or interconversions and transformations of functional groups with 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, in the course of performing the procedures described above, it may be necessary to protect the functional groups of the intermediates with protecting groups. The functional groups that it is desirable to protect include oxo, OH, amino and carboxylic acid. Suitable protecting groups include acetals, ketals (for example, ethylene ketals) and dithynes. Suitable protecting groups for OH include trialkylsilyl and diarylalkysilyl groups (for example, ferd-butyldimethylsilyl, urea-butyldiphenylsilyl or trimethylsilyl) and tetrahydropyranyl. Suitable protecting groups for amino include tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acid include d-β or benzyl alkyl esters. Suitable protecting groups for terminal alkynes include trialkylsilyl and diarylalkylsilyl groups (for example, tert-butyldimethylsilyl, urea-butyldiphenylsilyl or trimethylsilyl). The protection and deprotection of the functional groups can be carried out before or after any of the reaction steps described hereinabove. The protecting groups can be removed according to techniques that are well known to those skilled in the art. The use of protective groups is described in detail in "Protective Groups in Organic Chemistry", edited by JWF McOmie, Plenum Press (1973), and in "Protective Groups in Organic Synthesis", 2nd Edition, TW Greene and 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, on some occasions, more convenient, the individual steps of the aforementioned processes can be performed in a different order, and / or individual reactions can performed at a different stage of the overall route (i.e. substituents can be added and / or chemical transformations performed on intermediates other than those mentioned hereinabove in relation to a particular reaction). This will depend, among other things, on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the strategy of protective groups (if applicable) to be adopted. Obviously, the type of chemistry involved will influence the choice of reagent used in said synthesis steps, the need and the type of protective groups that are used, and the sequence of reactions necessary to achieve the synthesis. The methods may be adapted, where appropriate, to the reagents and other parameters of the reaction, in a manner that is apparent to the specialists by reference to conventional textbooks and to the examples provided later in this document. Those skilled in the art will appreciate that certain protected derivatives of the compounds of formula I, which can be obtained prior to a final deprotection step, may not possess a pharmacological activity as such, but, in certain cases, may be administered orally or parenterally. and subsequently metabolized in the body to form compounds of the invention that are pharmacologically active. Therefore, such derivatives can be described as "prodrugs". In addition, certain compounds of formula I can act as prodrugs of other compounds of formula I. Those skilled in the art will also appreciate that certain moieties, known to those skilled in the art as "pro-moieties", for example, as described in "Design of Produgs", by H. Bundgaard, Elseiver, 1985 (whose description is incorporated herein by reference), can be put into proper 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 the invention. The pharmaceutically acceptable acid addition salts of the compounds of formula I containing a basic center can be prepared in a conventional manner. For example, a solution of the free base can be treated with the appropriate acid, either in its pure state or in a suitable solvent, and the resulting salt can then be isolated by filtration or by evaporation under vacuum of the reaction solvent. The pharmaceutically acceptable base addition salts can be obtained in an analogous manner by treating a solution of a compound of formula I with the appropriate base. The two types of salt can be formed or interconverted using ion exchange resin techniques. When appropriate, the above procedures can be adapted to the particular reagents and groups involved, and other variants will occur to the specialist chemist, by reference to conventional textbooks and to the examples provided below, which allow the preparation of all the compounds of the invention. Formula I. The compounds of the invention are useful because they possess pharmacological activity in animals, especially mammals, including humans. Therefore, they are indicated as pharmaceutical compounds and, in particular, for use as animal medicaments. According to another aspect of the invention, the compounds of the invention are provided for use as medicaments, such as pharmaceutical compositions and animal medicaments. The term "treatment" includes both therapeutic (curative) treatment and prophylactic treatment. In particular, it has been found that the compounds of the invention are useful in the treatment of diseases mediated by opioid receptors, said diseases including irritable bowel syndrome.; constipation; sickness; vomiting; pruritus; and conditions characterized by pruritus as a symptom. Thus, according to another 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 a disease mediated by an opioid receptor. In addition, the use of the compounds of the invention in the manufacture of a medicament for the treatment of irritable bowel syndrome is provided; constipation; sickness; vomiting; itching or a medical condition characterized by pruritus as a symptom. Therefore, the compounds of the invention are expected to be useful for the curative or prophylactic treatment of pruritic dermatoses, including allergic dermatitis and atopy in animals and in humans. Other diseases and conditions that may be mentioned include contact dermatitis, psoriasis, eczema and insect bites. Thus, the invention provides a method for the treatment or prevention of a disease mediated by an opioid receptor. In addition, a method of treating irritable bowel syndrome is provided; constipation; sickness; vomiting; 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 the animal in need of such treatment. The compounds of the invention will normally be administered orally or by any parenteral route, in the form of pharmaceutical preparations comprising the active ingredient, optionally in the form of an organic or inorganic non-toxic acid or base addition salt, in a pharmaceutically acceptable dosage form. Depending on the disorder and the patient to be treated, as well as the route of administration, the compositions may be administered in varying doses (see below). Although it is possible to administer a compound of the invention directly without any formulation, the compounds are preferably employed in the form of a pharmaceutical or veterinary formulation comprising a pharmaceutically or veterinarily acceptable carrier, diluent or excipient, and a compound of the invention. The vehicle, diluent or excipient may be selected with respect to the desired route of administration and conventional pharmaceutical and / or veterinary practice. The pharmaceutical compositions comprising the compounds of the invention may contain from 0.1 weight percent to 90.0 weight percent of the active ingredient. The methods by which the compounds can be administered for veterinary use include oral administration by capsules, boluses, tablets or potions, topical administration in the form of an ointment, a pouring, local application, immersion, spray, cream formulation, shampoo, collar or powder, or, alternatively, such compounds may be administered by injection (eg, subcutaneous, intramuscular or intravenous) or as an 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 they contain, depending on the species of animal to be treated, the severity and type of infection and the animal's body weight. For parenteral, topical and oral administration, typical dosage ranges of the active ingredient are from 0.01 to 100 mg per kg of body weight of the animal. Preferably, the range is 0.1 to 10 mg per kg. The compositions are preferably formulated in a unit dosage form, each dose containing from about 1 to about 500 mg, more usually from about 5 to about 300 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unit doses for humans and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier. In any case, the veterinarian, or the specialist, will be able to determine the most appropriate real dose 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 middle case; but, of course, there may be individual cases where larger or smaller dosage intervals are required, and such ranges are within the scope of this invention. For veterinary use, the compounds of the invention are particularly valuable for the treatment of pruritus in domestic animals such as cats and dogs, and in horses. As an alternative for the treatment of animals, the compounds can be administered with the feed of the animal and, for this purpose, a concentrated additive or premix can be prepared for the food, to be mixed with the normal feed of the animal. For human use, the compounds are administered as a pharmaceutical formulation containing the active ingredient together with a pharmaceutically acceptable diluent or carrier. Such compositions include preparations of conventional tablets, capsules and ointments, which are formulated in accordance with conventional pharmaceutical practice. The compounds of the invention can be administered 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 are not to be construed as limiting) include antiparasitics, for example, fipronil, lufenuron, imidacloprid, avermectins (e.g., abamectin, ivermectin, doramectin), milbemycins, organophosphates, pyrethroids; antihistamines, for example, chlorpheniramine, trimeprazine, diphenhydramine, doxylamine; antifungals, for example, fluconazole, ketoconazole, traconazole, griseofulvin, amphotericin B; antibacterials, for example, enroflaxacin, marbofloxacin, ampicillin, amoxicillin; anti-inflammatories, for example, prednisolone, betamethasone, dexamethasone, carprofen, ketoprofen; diet 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 diseases mediated by opioid receptors. The skilled artisan will also appreciate that the compounds of the invention can be taken as a single dose or on a "when required" basis (ie, when necessary or desired). Thus, according to another 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 carrier. The compounds of the present invention may also have the advantage that, in the treatment of human and / or animal patients, they may be more effective, may be less toxic, may have a wider range of activity, may be more potent, may producing fewer side effects, they can be absorbed more easily or they can have other pharmacological properties, in comparison with the compounds known in the prior art. The biological activities of the compounds of the present invention were determined by the following test procedure.

Biological Assay It has been found that the compounds of the present invention exhibit activity in selective binding assays for the mu opiate receptor in the brain of dogs. The tests were carried out by the following procedure.

As a source of dog brain tissue, laboratory-trained bloodhounds were used. The animals were sacrificed, the brains were removed and the cerebellum was discarded. The rest of the brain tissue was sectioned into small pieces weighing approximately 3 g and homogenized in 50 mM Tris buffer, pH 7.4, at 4 ° C, using a Kinematica Polytron ™ tissue homogenizer. The resulting homogenate was centrifuged at 48,400 x g for 10 minutes and the supernatant discarded. The pellet was resuspended in Tris buffer and incubated at 37 ° C for 10 minutes. The centrifugation, resuspension and incubation steps were repeated two more times and the final pellet was resuspended in Tris buffer and stored at -80 ° C. The membrane material prepared in this way could be stored for up to four weeks before use. For the mu receptor assays, increasing concentrations of experimental compound (5 x 10 ~ 12 to 10"5 M), Tris buffer and 3H ligand were combined ([D-Ala2, N-Me-Phe4, Gly-ol5] - Encefalina, DAMGO) in polystyrene tubes.The reaction was initiated by the addition of tissue and the mixture was incubated at room temperature for 90 minutes.The reaction was terminated by rapid filtration using a Brandel Cell Harvester ™ through fiber filters. Betaplate ™ GF / A glass pre-immersed in 50 mM Tris buffer, pH 7.4, and 0.1% polyethyleneimine The filters were then washed three times with 0.5 ml of ice-cold Tris pH 7.4 buffer. The washed filters were bagged and Starscint scintillation fluid was added.The bags containing the filters and the scintillation liquid were thermally sealed and the counts were performed with a beta Bletaplate ™ 1204 counter. Samples were tested in duplicate for each compound experiment al and the generated data were analyzed using an IC50 analysis software from Graphpad Prism. The Ki values were calculated using the Graphpad Prism software according to the following formula: Ki = IC 50/1 [ligand 3H] / KD where IC 50 is the concentration at which 50% of the H 3 ligand is displaced by the compound of assay and KD is the dissociation constant for the 3H ligand at the receptor site. The invention is illustrated by the following Preparations and Examples, in which the following abbreviations can be 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) = doublet dd (in relation to NMR) = doublet of doublets EtOAc = ethyl acetate EtOH = ethanol h = hour (s) m (in relation to NMR) = multiplet MeOH = methanol min = minute q (in relation to NMR) = quadruplet s (in relation to NMR) = singlet t (in relation to NMR) = triplet THF = tetrahydrofuran. When the reversed phase HPLC is mentioned in the text, the 2 series of conditions indicated below were used. Condition 1: A Phenomenex Magellen ™ column, 150 x 21 mm, loaded with silica Cie 5m, eluting with a gradient of acetonitrile: aqueous ammonium acetate 0.1 M (30:70 to 95: 5 for 10 minutes, flow 20 ml per minute). Condition 2: A Dynamax ™ column, 42 x 250 mm, loaded with silica Cie 8μ, eluting with acetonitrile: 0.1 M aqueous ammonium acetate (30:70) at 45 ml per minute. In both cases, the combination and evaporation of the appropriate fractions, determined by analytical HPLC, provided the desired compounds in the form of acetate salts. The analytical HPLC conditions used to highlight the appropriate fractions were a Phenomenex Magellan ™ column, 4.6 x 150 mm, loaded with C-5μ silica, eluting with a gradient of acetonitrile: 0.1 M aqueous heptane sulfonic acid (10:90 at 90:10 for 30 minutes, followed by minutes more at 90:10) at 1 mi per minute. The heating temperature of the column was 40 ° C, and ultraviolet detection of the components was performed at 220 nM. When column chromatography is mentioned, reference is usually made to a glass column loaded with silica gel (40-63 μm). Generally a pressure of ~ 165 kPa is applied and the ratio of crude product: silica gel necessary for purification is typically 50: 1. Alternatively, an Isolute ™ SPE column (solid phase extraction) or a Waters Sep-Pak ™ cartridge loaded with silica gel at atmospheric pressure can be used. The ratio between the crude product and the silica gel necessary for purification is typically 100: 1. The hydrochloride salt can be obtained by methods commonly known to those skilled in the art of synthesis chemistry. Typically, to a solution of the free base in dichloromethane (1 g: 100 ml) was added ethereal hydrochloric acid (1.0 M, 1.2 equivalents), the excess solvent was removed by decanting and the remaining precipitate was washed three times. times with ether and then dried under vacuum. The melting points were determined using a Gallenkamp melting point apparatus and are uncorrected. The data of the 1H nuclear magnetic resonance spectrum (NMR) were obtained using a Varian Unity 300 or 400 spectrometer, the observed chemical shifts (d) being coherent with the proposed structures. The mass spectrum (MS) data were obtained on a Fisons Instruments Trio 1000 spectrometer, Fisons Instruments Trio 1000 APCI, Finnigan Navigator MS, or Micromass Platform LC. The calculated and observed ions quoted refer to the lower mass isotopic composition. HPLC means high performance liquid chromatography. Ambient temperature means 20 to 25 ° C.

EXAMPLES EXAMPLE 1 1-Hexyl-3,4-dimethyl-4- (3-cyanophenyl) piperidine A solution of 1-hexyl-3,4-dimethyl-4- (3-trifluoromethanesulfonyloxy-phenyl) piperidine (Preparation 1, 500 mg, 1.19 mmol) in 1-methyl-2-pyrrolidinone (2.5 ml) was added to a flask containing potassium cyanide (115 mg, 2.38 mmol). The solution was deoxygenated by evacuation and washing with nitrogen three times. Catalytic amounts of palladium (ll) acetate and 1,1'-bis (d-phenylphosphino) ferrocene were added and the reaction mixture was heated to 60 ° C, at which temperature it was stirred for 3 hours. The reaction mixture was cooled to room temperature and poured into a saturated aqueous sodium hydrogen carbonate solution (50 ml). The product was extracted into ethyl acetate (3 x 30 mL). The combined organic extracts were dried (Na 2 S 4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (15 g), eluting with a gradient of ethyl acetate: hexane: 0.880 ammonia (20: 79: 1 to 50: 49: 1), giving the title compound in form of an oil (346 mg).

NMR (CDCl 3): 0.75 (d, 3H), 0.9 (m, 3H), 1, 2-1, 4 (m, 9H), 1, 4-1, 55 (m, 2H), 1 , 6 (m, 1 H), 2.0 (m, 1 H), 2.2-2.45 (m, 4H), 2.45-2.65 (m, 2H), 2.8 (m) , 1 H), 7.35-7.6 (m, 4H). MS (electrospray): M / Z (MH +) 299.2; C20H30N2 + H requires 299.2.

EXAMPLE 2 1-Hexyl-3,4-dimethyl-4- (3-amidophenyl) piperidine A mixture of polyphosphoric acid (160 mg) and 1-hexyl-3,4-dimethyl-4- (3-cyanophenyl) piperidine (Example 1.19 mg, 0.064 mmol) was heated at 115 ° C for one hour. Then, the reaction mixture was cooled to room temperature and diluted with ice-cold water (0.4 ml). An aqueous sodium hydroxide solution (2 N) was added until the pH was 7. The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were dried (Na 2 SO 4) and the solvent was evaporated in vacuo to give a white solid. Purification by column chromatography on silica gel (1 g), eluting with a mixture of ethyl acetate: ethanol: 0.880 ammonia (89: 10: 1) gave the product as a white solid (6 mg). NMR (CDCI3, data selected): 0.75 (d, 3H), 0.9 (m, 3H), 1, 2-1, 4 (m, 9H), 1, 4-1, 55 (m, 2H ), 1.65 (m, 1 H), 2.05 (m, 1 H), 2.2-2.45 (m, 4H), 2.45-2.6 (m, 2H), 2.8 (m, 1 H), 7.35 (t, 1 H), 7.45 (d, 1 H), 7.55 (d, 1 H), 7.8 (s, 1 H). MS (electrospray): M / Z (MH +) 317.3; C2oH32N20 + H requires 317.3.

EXAMPLE 3 1-Hexyl-3,4-dimethyl-4- (3-methoxycarbonylphenyl) -piperidine To a solution of 1-hexyl-3,4-dimethyl-4- (3-trifluoromethanesulfonyloxyphenyl) piperidine (Preparation 1, 500 mg, 1.19 mmol) in anhydrous? /,? / - dimethylformamide (6 ml) was added triethylamine (1.7 mL, 12.2 mmol) and anhydrous methanol (1.0 mL, 24.7 mmol). The solution was deoxygenated by evacuation and flushing with nitrogen five times. Palladium (II) acetate (27 mg, 0.12 mmol) and 1,1'-bis (diphenylphosphino) ferrocene (67 mg, 0.12 mmol) were added and the mixture was deoxygenated again, using the same procedure that has been described above. Carbon monoxide gas was bubbled through the mixture for 5 minutes and then stirred under a carbon monoxide atmosphere and heated at 120 ° C overnight. The solvent was removed in vacuo to give a brown oil (0.7 g), which was purified by column chromatography on silica gel (35 g), eluting with a gradient of ethyl acetate: hexane: 0.880 ammonia (10: 190 : 1 to 10: 90: 1 to 25: 72: 1). This gave the title compound as a yellow oil (250 mg). NMR (CDCl 3): 0.75 (d, 3H), 0.9 (m, 3H), 1, 2-1, 4 (m containing s, 9H), 1, 4-1, 55 (m, 2H ), 1, 7 (m, 1 H), 2.1 (m, 1 H), 2.2-2.45 (m, 4H), 2.45-2.6 (m, 2H), 2, 8 (m, 1 H), 3.9 (s, 3H), 7.35 (t, 1 H), 7.5 (d, 1 H), 7.85 (d, 1 H), 8.0 (s, 1 H). MS (APCI): M / Z (MH +) 332.4; C 21 H 33 NO 2 + H requires 332.3.

EXAMPLE 4 1-Hexyl-3,4-dimethyl- - (3 - (/ V-isopropyl) amidophenyl) -piperidine In an airtight Wheaton ™ vial, 1-hexyl-3,4-dimethyl-4- (3-methoxycarbonylphenyl) piperidine (Example 3, 40 mg, 0.12 mmol) and isopropylamine (5 ml, 59 mmol) were heated together 150 ° C for two days. Then, the reaction mixture was cooled to room temperature and the excess amine was removed by evaporation in vacuo. The residue was purified by column chromatography on silica gel (5 g), eluting with a mixture of ethyl acetate: ethanol: 0.880 ammonia (50:49: 1), to give the title compound as an oil (32). mg). NMR (CDCI3, data selected): 0.75 (d, 3H), 0.9 (m, 3H), 1, 2-1, 4 (m, 15H), 1, 4-1, 55 (m, 2H ), 1.65 (m, 1 H), 2.05 (m, 1 H), 2.2-2.45 (m, 4H), 2.45-2.65 (m, 2H), 2, 85 (m, 1 H), 4.3 (m, 1 H), 7.3-7.5 (m, 3H), 7.75 (s, 1 H). MS (electrospray): M / Z (MH +) 359.3; C23H38N2O + H requires 359.3.

EXAMPLE 5 1-Hexyl-3,4-dimethyl-4- (3- (A-butyl) amidophenyl) -p.peridine In an airtight Wheaton ™ vial, 1-hexyl-3,4-dimethyl-4- (3- (methoxycarbonylphenyl) piperidine (Example 3, 30 mg, 0.09 mmol) and n-butylamine (4 ml, 40 ml) were heated together. , 5 mmol) at 140 ° C for 2 days.Then, the reaction mixture was cooled to room temperature and the excess amine was removed by evaporation in vacuo.The residue was purified by column chromatography on silica gel (5 g. ), eluting with a mixture of ethyl acetate: hexane: 0.880 ammonia (40: 49: 1), giving the title compound as an oil (20 mg). NMR (CDCI3, data selected): 0.75 ( d, 3H), 0.9 (m, 3H), 0.95 (t, 3H), 1, 2-1, 8 (m, 16H), 2.05 (m, 1H), 2.2- 2.45 (m, 4H), 2.45-2.65 (m, 2H), 2.85 (m, 1 H), 3.45 (m, 2H), 7.3-7.55 (m , 3H), 7.75 (s, 1 H), MS (electrospray): M / Z (MH +) 373.3, C24H40N2O + H requires 373.3.

EXAMPLE 6 1-Hexyl-3,4-dimethyl-4- (3 - (? / - prop.pamidophenyl) -piperidine In an airtight Wheaton ™ vial, 1-hexyl-3,4-dimethyl-4- (3- (methoxycarbonylphenyl) piperidine (Example 3, 30 mg, 0.09 mmol) and n-propylamine (4 ml, 94 g) were heated together. mmoles) at 140 ° C for two days, then the reaction mixture was cooled to room temperature and the excess amine was removed by evaporation in vacuo.The residue was purified by column chromatography on silica gel (5 g), eluting with a mixture of ethyl acetate: ethanol: 0.880 ammonia (50:49: 1) to give the title compound as an oil (3.5 mg).

NMR (CDC, data selected): 0.75 (d, 3H), 0.9 (m, 3H), 1.0 (t, 3H), 1, 25-1, 4 (m, 9H), 1, 4-1, 55 (m, 2H), 1, 6-1, 75 (m, 3H), 2.05 (m, 1H), 2.2-2.45 (m, 4H), 2.45- 2.65 (m, 2H), 2.8 (m, 1 H), 3.45 (m, 2H), 7.3-7.5 (m, 3H), 7.75 (s, 1 H) . MS (electrospray): M / Z (MH +) 359.3; C23H38N2O + H requires 359.3.

EXAMPLE 7 1-Hexyl-3,4-dimethyl-4- (3- (β-benzopomphophenyl) -pperidine In an airtight Wheaton ™ vial, 1-hexyl-3,4-dimethyl-4- (3- (methoxycarbonylphenyl) piperidine (Example 3, 30 mg, 0.09 mmol) and benzylamine (3 mL, 27.5 mmol) were heated together. mmoles) at 100 ° C for 76 hours.Then, the reaction mixture was cooled to room temperature, concentrated and the residue was purified by column chromatography on silica gel, eluting with a gradient of hexane: ethyl acetate (20 ml). : 80 to 50:50.) The title compound was obtained as a pale oil (13 mg). NMR (CDCb, data selected): 0.75 (d, 3H), 0.9 (t, 3H). , 1, 2-1, 4 (m, 9H), 1, 6-1, 55 (m, 2H), 1, 65 (m, 1 H), 2.05 (m, 1 H), 2.2 -2.45 (m, 4H), 2.45-2.65 (m, 2H), 2.85 (m, 1 H), 4.65 (m, 2H), 7.3-7.4 (m, 2H), 2.85 (m, 1 H), 4.65 (m, 2H), 7.3-7.4 ( m, 6H), 7.45 (d, 1 H), 7.55 (d, 1 H), 7.8 (s, 1 H), MS (electrospray): M / Z (MH +) 407.3; C27H38N2O + H requires 407.3.

EXAMPLE 8 1-Hexyl-3,4-dTMTtl-4- (3 - (? / - ethyl) amidophene-piperidine In an airtight Wheaton ™ vial, 1-hexyl-3,4-dimethyl-4- (3- (methoxycarbonylphenyl) piperidine (Example 3, 30 mg, 0.09 mmol) and ethylamine (3 mL, 45 mL) were heated together. , 8 mmol) at 100 ° C for 60 hours.The ethylamine was observed to evaporate, so that the reaction mixture was transferred to an airtight autoclave and heated to 100 ° C and to 690 kPa for an additional 16 hours. The reaction mixture was cooled to room temperature, concentrated and then purified by column chromatography on silica gel eluting with a gradient of hexane: ethyl acetate (20:80 to 50:50) .The title compound was obtained in a of a pale oil (11 mg) .NMR (CDCI3) data selected): 0.75 (d, 3H), 0.9 (m, 3H), 1, 2-1, 4 (m, 12H), 1, 4-1, 55 (m, 2H), 1, 65 (m, 1 H), 2.05 (m, 1 H), 2.2-2.45 (m, 4H), 2.45-2, 65 (m, 2H), 2.85 (m, 1 H), 3.5 (m, 2H), 7.35 (t, 1 H), 7.4 (d, 1 H), 7.5 ( d, 1 H), 7.75 (s, 1 H). MS (thermospray): M / Z (MH +) 345.1 C22H36N2O + H requires 345.3.

EXAMPLE 9 1-Hexyl-3,4-dimethyl-4- (3- (α-isobutyl) amidophenyl) -piperidine The title compound was prepared by the procedure of Example 7, substituting benzylamine with isobutylamine (3 mL, 30.18 mmol). This gave the title compound as a pale oil (9 mg). NMR (CDCI3, data selected): 0.75 (d, 3H), 0.9 (t, 3H), 1.0 (d, 6H), 1, 2-1, 35 (m, 9H), 1, 4-1, 55 (m, 2H), 1, 65 (m, 1 H), 1, 9 (m, 1 H), 2.05 (m, 1 H), 2.2-2.45 (m , 4H), 2.45-2.65 (m, 2H), 2.8 (m, 1 H), 3.3, (t, 2H), 7.35 (t, 1 H), 7.45 (d, 1 H), 7.5 (d, 1 H), 7.75 (s, 1 H). MS (electrospray): M / Z (MH +) 373.3; C24H40N2O + H requires 373.3.

EXAMPLE 10 1-Hexyl-3,4-dimethyl-4-l3-r? - (2-methoxyethyl-1-amidophenyl) piperidine In an airtight Wheaton vial, 1-hexyl-3,4-dimethyl-4- (3- (methoxycarbonylphenyl) piperidine (Example 3, 30 mg, 0.09 mmol) and 2-methoxy-ethylamine (3 mL, 34.5 mmoles) at 130 ° C for 120 hours, then the reaction mixture was cooled to room temperature, concentrated and purified by column chromatography on silica gel, eluting with a gradient of hexane: ethyl acetate: ammonia 0.880 (10: 89: 1 to 49: 50: 1) This gave the title compound as a pale oil (8 mg).

NMR (CDC, data selected): 0.75 (d, 3H), 0.9 (m, 3H), 1, 2-1, 4 (m, 9H), 1, 4-1, 55 (m, 2H ), 1.65 (m, 1H), 2.05 (m, 1H), 2.2-2.45 (m, 4H), 2.45-2.65 (m, 2H), 2.8 ( m, 1 H), 3.3-3.7 (m, 7H), 7.35 (t, 1 H), 7.4 (d, 1 H), 7.5 (d, 1 H), 7 75 (s, 1 H). MS (APCI): M / Z (MH +) 374.5; C23H38N2O2 + H requires 374.3.

EXAMPLE 11 1-Hexyl-3,4-dimethyl-4- (3- (-methyl) amidophenyl) -pperiodine To a suspension of anhydrous methylamine hydrochloride (17 mg, 0.25 mmoles) in anhydrous toluene (0, 5 ml) stirred under a nitrogen atmosphere and cooled in an ice bath was added a solution of trimethylaluminum (2.0 M in toluene, 0.12 ml, 0.24 mmol). The mixture was allowed to warm to room temperature while stirring for 4 hours, then treated with a solution of 1-hexyl-3,4-dimethyl-4- (3-methoxycarbonylphenyl) piperidine (Example 3, 40 mg, 0.12 mmoles) in anhydrous toluene (1.5 ml). The resulting mixture was heated to reflux overnight, then quenched with dilute hydrochloric acid (10 mL of 2 N) and extracted with diethyl ether (10 mL). The aqueous phase was basified to pH 13 with aqueous sodium hydroxide solution (2 N) and extracted with dichloromethane (3 x 20 mL). The combined dichloromethane extracts were dried (Na 2 S 4) and concentrated in vacuo to give an orange oil (31 mg), which was purified by column chromatography on silica gel (1.2 g), eluting with an acetate mixture of ethyl: hexane: 0.880 ammonia (50: 50: 1). This gave the title compound as a colorless residue (17 mg). NMR (CDCb, data selected): 0.75 (d, 3H), 0.9 (m, 3H), 1.2-1.4 (m, 9H), 1.4-1.55 (m, 2H) ), 1.65 (m, 1H), 2.05 (m, 1H), 2.2-2.45 (m, 4H), 2.45-2.65 (m, 2H), 2.8 ( m, 1H), 3.0 (d, 3H), 7.35 (t, 1H), 7.4 (d, 1H), 7.5 (d, 1H), 7.75 (s, 1H). MS (APCI): M / Z (MH +) 331.1; C 21 H 34 N 2 O + H requires 331.3.

EXAMPLE 12 1-Hexyl-3,4-dimethyl-4- (3 - (? /.? / - dimethyl) amidophenyl) -pperidine The title compound was prepared as for Example 11, except that anhydrous dimethylamine hydrochloride (20 mg, 0.25 mmol) was used in place of methylamine hydrochloride. This gave a pale yellow oil (38 mg). NMR (CDCb): 0.75 (d, 3H), 0.9 (m, 3H), 1.2-1.4 (m, 9H), 1.4-1.55 (m, 2H), 1.65 (m, 1H), 2.0 (m, 1H), 2.2-2.45 (m, 4H), 2.45-2.65 (m, 2H), 2.8 (m, 1H), 2.95 (sa, 3H), 3.1 (sa, 3H), 7.15-7.25 (m, 1H), 7.25-7.4 (m, 3H). MS (thermospray): M / Z (MH +) 345.2; C 22 H 36 N 2 O + H requires 345.3.

EXAMPLE 13 1-Hexy-3,4-dimethyl-3 - (? /,? -diet ~ pamidrophenyl) -piperidine To a suspension of anhydrous diethylamine hydrochloride (30 mg, 0.27 mmol) in anhydrous toluene (0.5 ml) stirred under a nitrogen atmosphere and cooled in an ice bath was added a solution of trimethylaluminium (2.0 M in. toluene, 0.14 ml, 0.28 mmol). The mixture was allowed to warm to room temperature while stirring for 2 hours, then treated with a solution of 1-hexyl-3,4-dimethyl-4- (3-methoxycarbonylphenyl) piperidine (Example 3.44 mg, 0.13 mmoles) in anhydrous toluene (1 ml). The resulting mixture was heated to reflux for 2.5 days, then quenched with dilute hydrochloric acid (10 ml of 2 N) and extracted with diethyl ether (10 ml). The aqueous phase was basified to pH 13 with an aqueous sodium hydroxide solution (2 N) and extracted with dichloromethane (3 x 20 mL). The combined dichloromethane extracts were dried (Na 2 SO 4) and concentrated in vacuo to give an orange oil (52 mg), which was purified by column chromatography on silica gel (1.5 g), eluting with a gradient of ethyl acetate. : hexane: 0.880 ammonia (10: 90: 1 to 20: 40: 1).

This gave the title compound as a yellow oil (34 mg). NMR (CDCb): 0.75 (d, 3H), 0.9 (m, 3H), 1.0-1.4 (m, 15H), 1, 4-1, 55 (m, 2H), 1 , 65 (m, 1 H), 2.0 (m, 1 H), 2.2-2.45 (m, 4H), 2.45-2.65 (m, 2H), 2.8 (m) , 1 H), 3.25 (ma, 2H), 3.55 (ma, 2H), 7.1-7.2 (m, 1 H), 7.2-7.35 (m, 3H). MS (APCI): M / Z (MH +) 373.1; C24H40N2O + H requires 373.3.

EXAMPLE 14 1-Hexyl-3,4-dimethyl-4- (3 - (? - ferc-butyl) amidophenippepperidine A solution of 1-hexyl-3,4-dimethyl-4- (3-methoxycarbonylphenyl) -piperidine (Example 3, 40 mg, 0.12 mmol) in dilute hydrochloric acid (5 ml. 2 N) was heated to reflux overnight. The solvent was removed in vacuo and the residue was taken up in methanol and concentrated again in vacuo to give a brown oil (40 mg), which was dissolved in dichloromethane (1 ml) and treated with 1- (3-dimethylaminopropyl) hydrochloride. ) -3-ethylcarbodiimide (25 mg, 0.13 mmol),? / - methyl-morpholine (27 μl, 0.25 mmol) and tert-butylamine (14 μl, 0.13 mmol).

The resulting mixture was stirred at room temperature overnight, then poured into a saturated aqueous sodium hydrogen carbonate solution. (5 ml) and extracted with dichloromethane (3 x 5 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give a brown residue which was purified by column chromatography on silica gel (2.5 g), eluting with a gradient of ethyl acetate: hexane: 0.880 ammonia ( 5: 95: 1 to 10: 90: 1 a : 80: 1 to 30: 70: 1). This gave the title compound as a colorless residue (10 mg). NMR (CDCb, data selected): 0.75 (d, 3H), 0.9 (m, 3H), 1, 2-1, 4 (m, 9H), 1, 4-1, 55 (m, 11 H), 1.65 (m, 1 H), 2.05 (m, 1 H), 2.2-2.45 (m, 4H), 2.45-2.6 (m, 2H), 2 , 8 (m, 1 H), 7.3-7.45 (m, 3H), 7.75 (s, 1 H). MS (APCI): M / Z (MH +) 373.1; C24H40N2O + H requires 373.3.

EXAMPLE 15 1-Benzyl-3,4-dimethyl-4- (3-methoxycarbonylphenyl) -piperidine A stirred solution of 1-benzyl-3,4-d-methyl-4- (3-trifluoromethanesulfonyloxyphenyl) piperidine (Preparation 2, 506 mg, 1.18 mmol), triethylamine (1.6 ml, 11.8 mmol) ) and anhydrous methanol (1.9 mL, 46.8 mmol) in anhydrous? /,? / - dimethylformamide (6 mL) was deoxygenated by evacuation and flushing with nitrogen five times. Palladium acetate (ll) (30 mg, 0.13 mmol) and l .l'-bisidiphenylphosphino-ferrocene (63 mg) were added., 0.11 mmol) and the mixture was deoxygenated again, using the same procedure as described above. Carbon monoxide gas was bubbled through the mixture for about 5 minutes and then heated to 80 ° C in a carbon monoxide atmosphere overnight. Then, the mixture was poured into water (100 ml) and extracted with diethyl ether (3 x 100 ml). The combined extracts were dried (Na 2 S 4) and concentrated in vacuo to give an orange oil (250 mg). A remaining black residue in the reaction flask, insoluble in diethyl ether, was dissolved in dichloromethane and transferred to the separatory funnel containing the aqueous layer and this was extracted again with dichloromethane (3 x 50 mL). The combined organic extracts were filtered through Celite® removing residual palladium, dried (Na 2 S 4) and concentrated in vacuo to give a brown oil (270 mg). The combined oils were purified by silica column chromatography (25 g), eluting with a gradient of hexane: ethyl acetate: 0.880 ammonia (140: 10: 1 to 90: 10: 1), giving the title compound in the form of a colorless oil (335 mg). NMR (CDCb): 0.75 (d, 3H), 1.35 (s, 3H), 1.65 (m, 1 H), 2.05 (m, 1 H), 2.3-2.5 (m, 2H), 2.5-2.65 (m, 2H), 2.85 (m, 1 H), 3.45 (d, 1 H), 3.6 (d, 1 H), 3 , 9 (s, 3H), 7.2-7.4 (m, 6H), 7.5 (d, 1 H), 7.85 (d, 1 H), 8.0 (s, 1 H) . MS (thermospray): M / Z (MH +) 338.2; C22H27NO2 + H requires 338.2.

EXAMPLE 16 1-Benzyl-3,4-dimethyl-4- (3 - (? / - ethyl) amidophenyl) -piperidine A stirred suspension of ethylamine hydrochloride (880 mg, 10.8 mmol) in anhydrous toluene (10 ml) was deoxygenated by evacuation and washing with nitrogen three times. It was stirred under a nitrogen atmosphere, cooled in an ice bath and treated with a solution of trimethylaluminum (2.0 M in toluene, 5.4 ml, 10.8 mmol) by means of a syringe. The mixture was allowed to warm to room temperature while stirring for 1.25 hours. A solution of 1-benzyl-3,4-dimethyl-4- (3-methoxycarbonylphenyl) piperidine (Example 15, 1.81 g, 5.36 mmol) in anhydrous toluene (20 ml) was added via syringe. the reaction mixture was heated to reflux overnight. After cooling, aqueous hydrochloric acid (100 ml of 2 N) was added and the mixture was extracted with diethyl ether (100 ml). The organic extract was washed again with aqueous hydrochloric acid (50 ml of 2 N). The combined aqueous phases were basified to pH 13 with aqueous sodium hydroxide solution (2 N) and then extracted with dichloromethane (300 ml followed by 2 x 100 ml). The combined dichloromethane extracts were washed with water (150 ml) followed by a saturated aqueous sodium chloride solution (150 ml), dried (Na 2 SO 4) and concentrated in vacuo to a brown oil (2.0 g). . Purification by silica column chromatography (100 g), eluting with a gradient of ethyl acetate: hexane: 0.880 ammonia (20: 80: 1 to 30: 70: 1 to 40: 60: 1) gave the title compound in the form of a cream colored foam (805 mg). NMR (CDCb, data selected): 0.75 (d, 3H), 1.25 (t, 3H), 1.35 (s, 3H), 1.65 (m, 1 H), 2.05 (m , 1 H), 2.35-2.45 (m, 2H), 2.5-2.6 (m, 2H), 2.85 (m, 1 H), 3.4-3.55 (m , 3H), 3.6 (d, 1 H), 7.2-7.35 (m, 6H), 7.4 (d, 1 H), 7.5 (d, 1 H), 7.75 (s, 1 H). MS (APCI): M / Z (MH +) 351.3; C23H30N2O + H requires 351, 2.

EXAMPLE 17 1- (2-Phenoxyethyl-3-4-dimethyl-4- (3- (α-ethyl) -amidophenyl) piperidine A stirred mixture of 3,4-dimethyl-4- (3 - (? / - ethyl) amidophenyl) piperidine (Preparation 3, 50 mg, 0.19 mmol), 2-bromoethyl phenyl ether (42 mg, 0.20 mmol. ) and sodium hydrogen carbonate (19.1 mg, 0.22 mmol) in anhydrous? /,? / - dimethylformamide (1 mL) was heated at 100 ° C for 2 hours. Then, the solvent was removed in vacuo to give a brown oil which was purified by column chromatography on silica gel (4 g), eluting initially with CH 2 Cl 2, changing increasingly to CH 2 Cl 2: MeOH (25: 1), giving the compound of the title in the form of a yellow oil (55 mg). NMR (CDCb, data selected): 0.75 (d, 3H), 1.25 (t, 3H), 1.35 (s, 3H), 1.65 (m, 1 H), 2.05 (m , 1 H), 2.35 (m, 1 H), 2.55 (m, 1 H), 2.6-2.8 (m, 3H), 2.8-2.95 (m, 2H) , 3.5 (m, 2H), 4.1 (m, 2H), 6.9-7.0 (m, 3H), 7.3 (m, 2H), 7.35 (m, 1 H) , 7.4 (m, 1 H), 7.5 (d, 1 H), 7.75 (s, 1 H). MS (thermospray): M / Z (MH +) 381.2; C 24 H 32 N 2 O 2 + H requires 381, 3.

EXAMPLE 18 1- (5-Met.lhex¡0-3,4-dimethyl-4- (3- (α-ethyl) -amidophenyl) p.peridine A stirred mixture of 3,4-dimethyl-4- (3 -? / - ethyl) amidophenyl) piperidine (Preparation 3, 50 mg, 0.19 mmol), 1-bromo-5-methylhexane (37 mg, 0.20 mmoles) and sodium hydrogen carbonate (19.1 mg, 0.22 mmol) in anhydrous N, N-dimethylformamide (1 mL) was heated at 100 ° C for 2.5 hours. Then, the solvent was removed in vacuo to give a brown oil which was purified by column chromatography on silica gel (4 g), eluting initially with CH 2 Cl 2, changing increasingly to CH 2 Cl 2: MeOH (25: 1), giving the compound of the title in the form of a yellow oil (58 mg). NMR (CDCb, data selected): 0.75 (d, 3H), 0.85 (d, 6H), 1.15 (m, 2H), 1, 2-1, 35 (m, 8H), 1, 35-1, 6 (m, 3H), 1.65 (m, 1 H), 2.05 (m, 1 H), 2.2-2.45 (m, 4H), 2.45-2, 65 (m, 2H), 2.85 (m, 1 H), 3.5 (m, 2H), 7.35 (t, 1H), 7.4 (d, 1 H), 7.5 (d , 1 H), 7.75 (s, 1 H). MS (thermospray): M / Z (MH +) 359.5; C23H38N2O + H requires 359.3.

EXAMPLE 19 1- (3-Phenylpropyl) -3,4-d-methyl-4 - (? / - etl) -amidophenol) piperidine A stirred mixture of 3, 4-dimethyl-4- (3 - (? / - ethyl) amidophenyl) piperidine (Preparation 3, 50 mg, 0.19 mmol), 1-bromo-3-phenylpropane (32 μl, 0.21 mmol) and carbonate Sodium acid (19.1 mg, 0.22 mmol) in? /,? / -dimethylformamide anhydrous (1 mL) was heated at 100 ° C for 2 hours. Then, the solvent was removed in vacuo to give a brown oil which was purified by column chromatography on silica gel (4 g), eluting initially with CH 2 Cl 2, changing increasingly to CH 2 Cl 2: MeOH (25: 1), followed by purification Additional by column chromatography on silica gel (4 g), eluting with a gradient of CH2Cl2: MeOH (50: 1 to 50: 2). This gave the title compound as a yellow oil (55 mg). NMR (CDCb, data selected): 0.75 (d, 3H), 1.25 (t, 3H), 1.3 (s, 3H), 1.65 (m, 1 H), 1.8 (m , 2H), 2.05 (m, 1 H), 2.25-2.45 (m, 4H), 2.45-2.7 (m, 4H), 2.85 (m, 1 H), 3.5 (m, 2H), 7.15-7.2 (m, 3H), 7.25 (m, 2H), 7.35 (t, 1 H), 7.4 (d, 1 H) , 7.5 (d, 1 H), 7.75 (s, 1 H). MS (thermospray): M / Z (MH +) 379.0; C 25 H 34 N 2 O + H requires 379.3.

EXAMPLE 20 1- (5-Cyanopentyl) -3,4-dimethyl-4- (3 -? / - ethyl) -amidophenyl) piperidine A stirred mixture of 3,4-dimethyl-4- (3 - (? / - ethyl) amidophenyl) piperidine (Preparation 3, 50 mg, 0.19 mmol), 6-bromohexanonitrile (28 μl, 0.20 mmol. ) and sodium hydrogen carbonate (19.1 mg, 0.22 mmol) in? /,? / - anhydrous dimethylformamide (1 mL) was heated at 100 ° C for 4 hours. Then, the solvent was removed in vacuo to give a brown oil which was purified by column chromatography on silica gel (4 g), eluting initially with CH 2 Cl 2, changing increasingly to CH 2 Cl 2: MeOH (25: 1), giving an oil yellow (82 mg), followed by further purification by column chromatography on silica gel (4 g), eluting with a gradient of CH2Cl2: MeOH (50: 1 to 50: 2). This gave the title compound as a yellow oil (54 mg). NMR (CDCb, data selected): 0.8 (d, 3H), 1, 25 (t, 3H), 1.35 (s, 3H), 1, 5 (m, 2H), 1, 55-1, 8 (m, 5H), 2.15 (m, 1 H), 2.35 (t, 2H), 2.4 -2.6 (m, 4H), 2.6-2.75 (m, 2H), 2.95 (m, 1 H), 3.5 (m, 2H), 7.3-7.45 ( m, 2H), 7.5 (d, 1 H), 7.75 (s, 1 H). MS (thermospray): M / Z (MH +) 356.4; C 22 H 33 N 3 O + H requires 356.3.

EXAMPLE 21 1-Hexyl-3,4-dmethyl-4- (3-aminomethylphenyl) piperidine To a stirred solution of 1-hexyl-3,4-dimethyl-4- (3-cyanophenyl) piperidine (Example 1, 800 mg, 2.68 mmol) in anhydrous tetrahydrofuran (40 ml) at 0 ° C under nitrogen , lithium aluminum hydride (1.0 M in tetrahydrofuran, 4.0 ml, 4.0 mmol) was added. The reaction mixture was allowed to warm to room temperature, before heating to 37 ° C during minutes. Subsequently, diethyl ether (50 ml) was added, then aqueous sodium hydroxide (0.3 ml, 15% w / v solution) and finally water (0.45 ml). The white solid formed was removed by filtration. The filtrate was washed with a saturated aqueous sodium hydrogen carbonate solution (2 x 50 mL). The aqueous phases were extracted again with diethyl ether (50 ml). The combined organic extracts were dried (MgSO 4) and concentrated in vacuo to give the title compound as an oil (770 mg). NMR (CDCb, data selected): 0.75 (d, 3H), 0.9 (m, 3H), 1, 2-1, 4 (m, 9H), 1, 4-1, 55 (m, 2H ), 1.65 (m, 1 H), 2.0 (m, 1 H), 2.2-2.45 (m, 4H), 2.45-2.6 (m, 2H), 2, 8 (m, 1 H), 3.85 (s, 2H), 7.1-7.35 (m, 4H). MS (APCI): M / Z (MH +) 303.4; C20H34N2 + H requires 303.3.

EXAMPLE 22 1-Hexyl-3,4-dimethyl-4- (3 - (? / - methoxycarbonyl) amine-methylphenyl) piperidine To a stirred solution of 1-hexyl-3,4-dimethyl-4- (3-aminomethylphenyl) -piperidine (Example 21, 100 mg, 0.33 mmol) in pyridine (2 mL, dried over basic alumina) at 0 °. C in methyl atmosphere was added methyl chloroformate (40 μl, 0.52 mmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere overnight.

Subsequently, ice was added followed by aqueous sodium hydroxide (5 N solution), giving a pH of 11. The mixture was extracted with diethyl ether (3 x 25 mL). The combined organic phases were dried (MgSO 4) and then concentrated in vacuo at 70 ° C, giving an oil (104 mg) which was purified by column chromatography on silica gel (2.9 g), eluting with a gradient of ethyl acetate: hexane (1: 2 to 2: 1). This gave the title compound as an oil (65 mg). NMR (CDCb, data selected): 0.75 (d, 3H), 0.9 (m, 3H), 1, 2-1, 35 (m, 9H), 1, 4-1, 55 (m, 2H ), 1, 6 (m, 1 H), 2.0 (m, 1 H), 2.2-2.4 (m, 4H), 2.4-2.6 (m, 2H), 2, 8 (m, 1 H), 3.7 (s, 3H), 4.35 (d, 2H), 7.1 (d, 1 H), 7.15-7.35 (m, 3H). MS (thermospray): M / Z (MH +) 361.4; C 22 H 36 N 2 O 2 + H requires 361, 3.

EXAMPLE 23 1-Hexyl-3,4-dimethyl-4- (3 - (/ V-acetyl) aminomethylphenyl) -piperidine This preparation was carried out using the procedure described for Example 22, except that acetyl chloride (35 μl, 0.49 mmol) was used in place of methyl chloroformate. This gave the title compound as an oil (100 mg). NMR (CDCb, data selected): 0.75 (d, 3H), 0.9 (m, 3H), 1, 2-1, 4 (m, 9H), 1, 4-1, 55 (m, 2H ), 1, 6 (m, 1 H), 1, 95-2.05 (m, 4H), 2.2-2.4 (m, 4H), 2.4-2.6 (m, 2H) , 2.8 (m, 1 H), 4.4 (d, 2H), 7.1 (d, 1 H), 7.15-7.35 (m, 3H). MS (APCI): M / Z (MH +) 345.3; C 22 H 36 N 2 O + H requires 345.3.

EXAMPLE 24 1-Hexyl-3,4-dmethyl-4- (3- (? -methanes? Lfonyl) am.no-methylphenyl) p.peridine This preparation was carried out using the procedure described for Example 22, except that methanesulfonyl chloride (40 μl, 0.52 mmol) was used in place of methyl chloroformate. This gave the title compound as an oil (94 mg). NMR (CDCb, data selected): 0.75 (d, 3H), 0.9 (m, 3H), 1, 2-1, 4 (m, 9H), 1, 4-1, 55 (m, 2H ), 1, 6 (m, 2H), 2.0 (m, 1 H), 2.2-2.4 (m, 4H), 2.4-2.65 (m, 2H), 2.75 -2.9 (m, 4H), 4.3 (s, 2H), 7.15 (d, 1 H), 7.2-7.35 (m, 3H). MS (APCI): M / Z (MH +) 381.6; C 21 H 36 N 2 O 2 S + H requires 381.3.

EXAMPLE 25 1-Hexyl-3,4-dimethyl-4- (3 - (? / - trifluoromethanesulfonyl) -aminomethylphenyl) piperidine To a solution of 1-hexyl-3,4-dimethyl-4- (3-aminomethylphenyl) piperidine (Example 21, 100 mg, 0.33 mmol) in pyridine (1.5 ml, dried over basic alumina) stirred under an atmosphere of nitrogen was added trifluoromethanesulfonyl chloride (0.3 ml, 0.28 mmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere overnight. Aqueous sodium hydroxide (20 ml of 2 N) was added and the mixture was extracted with dichloromethane (3 x 20 ml). The aqueous layer was treated with dilute aqueous hydrochloric acid (20 ml of 1 N) and then extracted with dichloromethane (2 x 20 ml). The organic phases were combined, dried (MgSO 4) and concentrated in vacuo to give an orange oil (40 mg) which was purified by column chromatography on silica gel (1.2 g), eluting with a gradient of ethyl acetate. ethyl: hexane: triethylamine (20: 80: 1) to ethyl acetate: triethylamine (100: 1). This gave the title compound as an oil (30 mg). NMR (CDCb, data selected): 0.75 (d, 3H), 0.9 (m, 3H), 1, 2-1, 4 (m, 9H), 1, 4-1, 55 (m, 2H ), 1.65 (m, 1 H), 2.05 (m, 1 H), 2.2-2.75 (m, 6H), 2.8 (m, 1 H), 4.4 (s) , 2H), 7.15 (d, 1 H), 7.2-7.35 (m, 3H). MS (thermospray): M / Z (MH +) 435.1; C 21 H 33 F 3 N 2 O 2 S + H requires 435.2.

EXAMPLE 26 1-Hexyl-3,4-dimethyl-4- (3-vinylphenyl) piperidine A solution of 1-hexyl-3,4-dimethyl-4- (3-trifluoromethanesulfonyloxy-phenyl) piperidine (Preparation 1, 1.5 g, 3.6 mmol) in 1,4-dioxane (17 ml) it was deoxygenated by evacuation and flushing with nitrogen five times. Vinyl tributyl tin (1.06 ml, 3.71 mmol) was added with stirring, followed by lithium chloride (456 mg, 10.76 mmol), tetrakis (triphenylphosphine) palladium (0) (catalytic) and 2,6- di-tert-butyl-4-methylphenol (2 crystals). The suspension was stirred under a nitrogen atmosphere and heated to reflux for ten hours. After cooling to room temperature, the reaction mixture was quenched with an aqueous ammonium hydroxide solution (50 ml, 1.0 M) and further diluted with ethyl acetate (50 ml). The phases were separated and the aqueous layer was further extracted with ethyl acetate (3 x 25 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The residual oil was purified by column chromatography on silica gel (120 g), eluting with a mixture of ethyl acetate: hexane: 0.880 ammonia (39: 60: 1), to give the title compound as an oil ( 890 mg). NMR (CDCb): 0.75 (d, 3H), 0.85 (m, 3H), 1, 2-1, 4 (m, 9H), 1, 4-1, 55 (m, 2H), 1 , 65 (m, 1 H), 2.05 (m, 1 H), 2.2-2.45 (m, 4H), 2.45-2.65 (m, 2H), 2.85 (m , 1 H), 5.25 (d, 1 H), 5.75 (d, 1 H), 6.7 (dd, 1 H), 7.1-7.35 (m, 4H). MS (thermospray): M / Z (MH +) 300.4; C21H33N + H requires 300.3.

EXAMPLE 27 1 -Hexyl-3,4-dimethyl-4- (3- (1,2-dihydroxyethyl) phenyl) -piperidine 1-Hexyl-3,4-dimethyl-4- (3-vinylphenyl) piperidine was dissolved (Example 26, 200 mg, 0.67 mmol) in a mixture of water (2 ml) and acetone (18 ml). 4-Methylmorpholine oxide (172 mg, 1.47 mmol) was added with stirring followed by osmium tetroxide (200 μl, 2.5% w / w in tert-butanol). The reaction mixture was stirred at room temperature for 4 hours before the solvent was removed by evaporation in vacuo. The residue was partitioned between dichloromethane (25 ml) and water (25 ml). The organic phase was separated and dried (Na 2 S 4). Concentration in vacuo gave a residue that was purified by column chromatography on silica gel (10 g), eluting with a gradient of ethyl acetate: hexane: ammonium hydroxide solution (50: 49: 1 to 60: 33: 1), followed by ethyl acetate: methanol: ammonium hydroxide solution (94: 5: 1). The combination of the appropriate fractions and evaporation to dryness in vacuo gave the product as a yellow oil (145 mg). NMR (CDCb, data selected): 0.75 (d, 3H), 0.9 (m, 3H), 1, 2-1, 4 (m, 9H), 1, 4-1, 55 (m, 2H ), 1, 6 (m, 1 H), 2.05 (m, 1 H), 2.2-2.45 (m, 4H), 2.45-2.65 (m, 2H), 2, 8 (m, 1 H), 3.7 (m, 2H), 4.80 (m, 1 H), 7.1-7.4 (m, 4H). MS (thermospray): M / Z (MH +) 334.5; C 21 H 35 NO 2 + H requires 334.3.

EXAMPLE 28 1-Hexyl-3,4-dimethyl-4- (3-formylphenolpiperidine 1-Hexyl-3,4-dimethyl-4- (3-vinylphenyl) piperidine was dissolved (Example 26, 200 mg, 0.67 mmol) in a mixture of water (2 ml) and acetone (18 ml). Osmium tetroxide (200 μl, 2.5% w / w in tert-butanol) was added, followed by sodium periodate (572 mg, 2.68 mmol) which was added in portions. The reaction mixture was stirred at room temperature for 26 hours, then filtered off with the precipitate, and the solvent was removed by evaporation in vacuo. The residue was partitioned between dichloromethane (25 ml) and saturated sodium chloride solution (25 ml). The organic phase was separated, dried (Na 2 SO 4) and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (50 g), eluting with a mixture of ethyl acetate: hexane: 0.880 ammonia (74: 25: 1). The title compound was obtained in the form of an oil (80 mg). NMR (CDCb): 0.75 (d, 3H), 0.9 (m, 3H), 1, 2-1, 4 (m, 9H), 1, 4-1, 6 (m, 2H), 1 , 65 (m, 1 H), 2.05 (m, 1 H), 2.2-2.45 (m, 4H), 2.45-2.65 (m, 2H), 2.85 (m , 1 H), 7.5 (t, 1 H), 7.55 (d, 1 H), 7.7 (d, 1 H), 7.8 (s, 1 H), 10.0 (s) , 1 HOUR). MS (electrospray): M / Z (MH +) 302.0; C20H31NO + H requires 302.2.

EXAMPLE 29 1-Hexyl-3,4-dimethyl-4- (3- (α-hydroxyl) iminomethyl-phenylpiperidine A solution of 1-hexyl-3,4-dimethyl-4- (3-formylphenyl) piperidine (Example 28, 80 mg, 0.27 mmol) in a mixture of pyridine (1 ml) and ethanol (1 ml) was treated with hydroxylamine hydrochloride (22 mg, 0.32 mmol) and the resulting mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the residual orange oil was purified by column chromatography on silica gel (10 g), eluting with a gradient of dichloromethane: methanol: 0.880 ammonia (98: 1: 1 to 94: 5: 1) . This gave the title compound as an oil (18 mg). NMR (CDCb, data selected): 0.8 (d, 3H), 0.85 (m, 3H), 1, 2-1, 4 (m, 9H), 1, 4-1, 6 (m, 2H ), 1, 7 (m, 1 H), 2.1 (m, 1 H), 2.2-2.75 (m, 6H), 2.95 (m, 1 H), 7.2-7 , 4 (m, 3H), 7.6 (s, 1 H), 8.1 (s, 1 H). MS (thermospray): M / Z (MH +) 317.6; C20H32N2O + H requires 317.3.

EXAMPLE 30 1-Hexyl-3,4-dimethyl-4- (3-acetylphenyl) piperidine To a solution of 1-hexyl-3,4-d, methyl-4- (3-cyanophenyl) piperidine (Example 1, 791 mg, 2.65 mmol) in anhydrous tetrahydrofuran (6 mL) at 0 ° C was added methyl. lithium (2.46 ml, 3.45 mmol) and the mixture darkened. Then, the solution was warmed to room temperature and stirred under a nitrogen atmosphere for 1 hour before being poured into water (10 ml). The basic aqueous layer was extracted with a mixture of diethyl ether: ethyl acetate (1: 1, 3 x 10 mL). The combined organic extracts were dried (MgSO 4) and concentrated in vacuo. This gave the crude title compound as a colorless oil (720 mg, 86%). NMR (CDCb): 0.75 (d, 3H), 0.9 (m, 3H), 1, 2-1, 4 (m, 9H), 1, 4-1, 55 (m, 2H), 1 , 65 (m, 1 H), 2.05 (m, 1 H), 2.2-2.45 (m, 4H), 2.45-2.6 (m, 2H), 2.6 (s) , 3H), 2.85 (m, 1 H), 7.4 (t, 1 H), 7.5 (d, 1H), 7.75 (d, 1 H), 7.95 (s, 1 H). MS (thermospray): M / Z (MH +) 316.3; C21H33NO + H requires 316.3.

EXAMPLE 31 1-Hexyl-3,4-dimethyl-4- (3-ethynylphenyl) piperidine A solution of 1-hexyl-3,4-dimethyl-4-. { 3- [2- (Trimethylsilyl) ethynyl] -phenyljpiperidine (Preparation 4, 150 mg, 0.40 mmol) in tetrahydrofuran (2 mL) was cooled to -70 ° C and tetrabutylammonium fluoride (1.0 M) was added slowly THF, 0.41 mL, 0.41 mmol). The reaction mixture was allowed to warm to room temperature gradually before being diluted with dichloromethane (10 ml) and water (10 ml). The phases were separated and the aqueous layer was further extracted with dichloromethane (2 x 10 mL). The combined organic extracts were dried (Na 2 SO 4) and the solvent was evaporated in vacuo. The oily yellow residue was purified by column chromatography on silica gel (10 g), eluting with a mixture of ethyl acetate: hexane: 0.880 ammonia (10: 89: 1), giving the title compound as an oil (100 mg). NMR (CDCb): 0.75 (d, 3H), 0.9 (m, 3H), 1, 2-1, 35 (m, 9H), 1.35-1.55 (m, 2H), 1 , 6 (m, 1 H), 2.0 (m, 1 H), 2.2-2.6 (m, 6H), 2.8 (m, 1 H), 3.05 (s, 1 H) ), 7.2-7.35 (m, 3H), 7.45 (s, 1 H). MS (APCI): M / Z (MH +) 298.6; C21H31N + H requires 298.3.

EXAMPLE 32 1 -Hexyl-3,4-dimethyl-4- (3- (1,1-dimethylphydroxymethyl-phenyl) piperidine A solution of 1-hexyl-3,4-dimethyl-4- (3-methoxycarbonylphenyl) -piperidine (Example 3, 50 mg, 0.15 mmol) in anhydrous tetrahydrofuran was deoxygenated by evacuation and washing with nitrogen three times. Then, the solution was cooled to 0 ° C and treated dropwise with methylmagnesium chloride (0.5 ml, 1.5 mmol, 3.0 M in tetrahydrofuran). The reaction mixture was stirred at 50 ° C for 2 hours and then a saturated aqueous ammonium chloride solution (20 ml) was added followed by saturated aqueous sodium hydrogen carbonate (20 ml). The mixture was extracted with ethyl acetate (3 x 15 mL) and the combined organic phases were dried (MgSO 4) and concentrated in vacuo to give an oil (39 mg). The residue was purified by column chromatography on silica gel (1 g), eluting with a gradient of ethyl acetate: hexane: ammonia (50: 50: 1 to 25: 75: 1), giving the title compound in the form of a colorless oil (30 mg). NMR (CDCb, data selected): 0.75 (d, 3H), 0.9 (m, 3H), 1, 25-1, 4 (m, 9H), 1, 4-1, 55 (m, 2H ), 1, 6 (s, 6H), 1, 65 (m, 1 H), 2.05 (m, 1 H), 2.2-2.45 (m, 4H), 2.45-2, 65 (m, 2H), 2.8 (m, 1H), 7.15 (m, 1H), 7.2-7.3 (m, 2H), 7.45 (s, 1 H). MS (APCI): M / Z (MH +) 332.4; C22H37NO + H requires 332.3.

EXAMPLE 33 1-Hexyl-3,4-dimethyl-4- (3-hydroxymethylphenyl) -piperidine A stirred solution of 1-hexanoyl-3,4-dimethyl-4- (3-methoxycarbonylphenyl) piperidine (Preparation 7, 80 mg, 0.23 mmol) in anhydrous tetrahydrofuran (1 ml) under a nitrogen atmosphere was treated with anhydrous hydride. lithium and aluminum (1.0 M in ether, 0.70 ml, 0.70 mmol) and the mixture was stirred at room temperature for 3 hours. Then, the reaction mixture was quenched with water (7.5 ml) and extracted with ethyl acetate (7 ml). The phases were separated and the aqueous layer was further extracted with ethyl acetate (2 x 5 mL). The combined organic extracts were dried (Na 2 S 4) and the solvent was removed in vacuo to give the title compound as a pale oil (30 mg). NMR (CDCb, data selected): 0.75 (d, 3H), 0.9 (m, 3H), 1, 2-1, 4 (m, 9H), 1, 4-1, 55 (m, 2H ), 1.65 (m, 1 H), 2.0 (m, 1 H), 2.2-2.45 (m, 4H), 2.45-2.65 (m, 2H), 2, 8 (m, 1 H), 4.7 (s, 2H), 7.1-7.35 (m, 4H).

MS (thermospray): M / Z (MH +) 304.3; C20H33NO + H requires 304.3.

EXAMPLE 34 1-Hexyl-3,4-dimethyl-4- (3- (2-hydroxyethyl) fenip-piperidine To a stirred solution of 1-hexanoyl-3,4-dimethyl-4- (3-vinylphenyl) -piperidine (Preparation 8, 50 mg, 0.16 mmol) in bis (2-methoxyethyl) ether (1.5 mi) at 0 ° C under nitrogen atmosphere was added dropwise borane (1.0 M in tetrahydrofuran, 0.35 ml, 0.35 mmol). The reaction mixture was stirred at 0 ° C for 30 minutes and then at room temperature for 2 hours. Subsequently,? / - trimethylamine oxide (48 mg, 0.64 mmol) was added and the reaction mixture was heated to reflux under a nitrogen atmosphere for 2 hours. Then, to the cooled reaction were added diethyl ether (10 ml) and a saturated aqueous sodium chloride solution (10 ml). The phases were separated and the aqueous layer was further extracted with diethyl ether (10 ml). The combined organic extracts were dried (MgSO 4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (1.5 g), eluting with a mixture of ethyl acetate: hexane (50:50), to give the title compound as an oil (30 mg). NMR (CDCb, data selected): 0.75 (d, 3H), 0.9 (m, 3H), 1, 25-1, 4 (m, 9H), 1, 4-1, 55 (m, 2H ), 1, 6 (m, 1 H), 2.0 (m, 1 H), 2.2-2.45 (m, 4H), 2.45-2.6 (m, 2H), 2, 8 (m, 1 H), 2.85 (t, 2H), 3.85 (t, 2H), 7.05 (d, 1 H), 7.1-7.35 (m, 3H). MS (APCI): M / Z (MH +) 318.6; C21H35NO + H requires 318.3.

EXAMPLE 35 1-Hexyl-3,4-dimethyl-4- (3- (1-hydroxy-2-methylamino) -etl-phenyl) piperidine To a solution of 1-hexanoyl-3,4-dimethyl-4-. { 3- [4- (4-methylphenyl) -sulfonyl-4,5-dihydro-1,3-oxazol-5-yl] phenyl} piperidine (Preparation 10, 345 mg, 0.68 mmol) in anhydrous tetrahydrofuran (5 ml) at room temperature was added dropwise lithium aluminum hydride (solution 1), 0 M in tetrahydrofuran, 0.74 ml, 0.74 mmol) for five minutes. The solution was stirred at room temperature under a nitrogen atmosphere for 2 hours and then cooled to 0 ° C. The reaction was carefully quenched by the addition of an aqueous sodium hydroxide solution (1.0 ml, 1.0 N) and then ethyl acetate (20 ml) and solid sodium carbonate (excess) were added. The mixture was stirred vigorously for 30 minutes and then filtered through Celite®, washing with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with pure ethyl acetate and then with a mixture of ethyl acetate: methanol: 0.880 ammonia (70: 30: 1), giving the compound of the title in the form of a transparent gum (120 mg). NMR (CDCb, data selected): 0.75 (d, 3H), 0.9 (t, 3H), 1, 2-1, 4 (m, 9H), 1, 4-1, 55 (m, 2H ), 1, 6 (m, 1 H), 2.0 (m, 1 H), 2.2-2.6 (m, 9H), 2.65-2.85 (m, 3H), 4, 75 (m, 1 H), 7.1-7.35 (m, 4H). MS (thermospray): M / Z (MH +) 347.3; C 22 H 38 N 2 O + H requires 347.3.

Preparation of the Starting Materials PREPARATION 1 1-Hexyl-3,4-dimethyl-4- (3-trifluoromethanesulfonyloxyphenyl) piperidine To a solution of 1-hexyl-3,4-dimethyl-4- (3-hydroxyphenyl) piperidine (3.5 g, 12 mmol, J. Med. Chem., 1993, 36, 2833) in dichloromethane (15 ml) was added in portions triethylamine (3 ml) followed by? / - phenyltrifluoro-methanesulfonimide (6.1 g). , 18 mmol). The reaction mixture was stirred under nitrogen at room temperature for 18 hours and then washed with a solution of aqueous sodium hydroxide (60 ml of 2 N). The separated aqueous layer was washed again with dichloromethane (2 x 30 ml), after which the combined organic extracts were dried (Na 2 SO 4) and the solvent was removed in vacuo to give a yellow oil. This was purified by column chromatography on silica gel (150 g), eluting with a mixture of hexane: ethyl acetate: 0.880 ammonia (66: 33: 1), giving the title compound as a yellow oil (4). , 22 g). NMR (CDCb): 0.75 (d, 3H), 0.9 (m, 3H), 1, 2-1, 4 (m, 9H), 1, 4-1, 7 (m, 3H), 2 , 0 (m, 1 H), 2.2-2.45 (m, 4H), 2.45-2.65 (m, 2H), 2.8 (m, 1 H), 7.1 (d) , 1 H), 7.15 (s, 1 H), 7.25-7.45 (m, 2H). MS (thermospray): M / Z (MH +) 422.3; C20H30F3NO3S + H requires 422.2.

PREPARATION 2 1-Benzyl-3,4-dimethyl-4- (3-trifluoromethanesulfonyl-oxyphenyl) pperidine To a stirred solution of 1-benzyl-3,4-dimethyl-4- (3-hydroxyphenyl) -piperidine (10.16 g, 34.4 mmol, J. Med. Chem., 1993, 36, 2833) in dichloromethane Anhydrous (100 ml) was added triethylamine (8 ml) and the resulting solution was deoxygenated by evacuation and washing with nitrogen three times. ? / - Phenyltrifluoromethanesulfonimide (18.43 g, 51.6 mmol) was added and the mixture was deoxygenated again, using the same procedure as described above, and stirred overnight at room temperature under nitrogen atmosphere. Then, the reaction mixture was diluted with dichloromethane (200 ml) and washed with an aqueous sodium hydroxide solution (200 ml of 1 N). The aqueous phase was washed again with dichloromethane (2 x 100 mL). The combined organic extracts were dried (Na 2 S 4) and concentrated in vacuo to give an orange oil (approximately 20 g), which was purified by column chromatography on silica gel (700 g), eluting with a gradient of ethyl acetate. : hexane: 0.880 ammonia (10: 190: 1 to 10: 90: 1). This gave the title compound as a colorless oil (13.98 g). NMR (CDCb): 0.75 (d, 3H), 1.35 (s, 3H), 1.55 (m, 1H), 1.95 (m, 1 H), 2.25-2.5 ( m, 2H), 2.5-2.65 (m, 2H), 2.85 (m, 1 H), 3.45 (d, 1 H), 3.6 (d, 1 H), 7, 1 (d, 1H), 7.15 (s, 1 H), 7.2-7.45 (m, 7H). MS (thermospray): M / Z (MH +) 428.0; C21H24F3NO3S + H requires 428.2.

PREPARATION 3 3,4-Dimethyl-4 - (? / - ethyl) amidophenol) piperidine To a solution of 1-benzyl-3,4-dimethyl-4- (3 - (? / - ethyl) amidophenyl) piperidine (Example 16, 800 mg, 2.3 mmol) in methanol (40 mL) was added palladium on Activated carbon (150 mg, type Degussa E101 NE / W, Pd at 10% dry weight, approximately 50% water). The resulting suspension was stirred at room temperature under a hydrogen atmosphere at 415 kPa for 1, 5 days. Then, it was filtered through Celite® removing the catalyst residues and concentrated in vacuo to give a foam (610 mg). Purification by column chromatography on silica gel (30 g), eluting with a mixture of CH 2 Cl 2: EtOH: 0.880 ammonia (50: 8: 1) gave the title compound as thick gum (557 mg). NMR (CDCb, data selected): 0.7 (d, 3H), 1, 25 (t, 3H), 1, 4 (s, 3H), 1.95 (m, 1 H), 2.15 (m , 1 H), 2.75 (m, 1 H), 2.95-3.15 (m, 2H), 3.25 (m, 1 H), 3.5 (m, 2H), 7.3 -7.45 (m, 2H), 7.5 (d, 1 H), 7.7 (s, 1 H). MS (APCI): M / Z (MH +) 261.5; C16H24N2O + H requires 261.2.

PREPARATION 4 1-Hexyl-3,4-dimethyl-4-f3-r2- (trimethylsilyl) ethynyl-phenyl piperidine To a solution of 1-hexyl-3,4-dimethyl-4- (3-trifluoromethanesulfonyloxy-phenyl) piperidine (Preparation 1, 350 mg, 0.83 mmol) in tetrahydrofuran (12 mL) was added diisopropylamine (4 mL). ) and trimethylsilyletino (4, 5 g, 46 mmol) and the mixture was deoxygenated by evacuation and flushing with nitrogen five times. Copper iodide (1) (6.2 mg 0.033 mmol) and then catalytic amounts of palladium acetate (11) and 1,1'-bis (diphenylphosphino) ferrocene were added. The reaction mixture was heated to reflux under a nitrogen atmosphere for 8 hours, before being allowed to cool to room temperature. Water (10 mL) and dichloromethane (10 mL) were added, the phases were separated and the aqueous layer was further extracted with dichloromethane (2 x 10 mL). The combined organic extracts were then dried (Na 2 SO 4) and the solvent was removed in vacuo. The residual brown oil was purified by column chromatography on silica gel (25 g), eluting with a gradient of ethyl acetate: hexane: 0.880 ammonia (20: 79: 1 to 50: 49: 1), giving the title in the form of an oil (150 mg). NMR (CDCb): 0.25 (s, 9H), 0.75 (d, 3H), 0.9 (m, 3H), 1, 2-1, 4 (m, 9H), 1, 4-1 , 55 (m, 2H), 1, 6 (m, 1 H), 2.0 (m, 1 H), 2.2-2.4 (m, 4H), 2.4-2.6 (m , 2H), 2.8 (m, 1 H), 7.2-7.35 (m, 3H), 7.4 (s, 1 H). MS (thermospray): M / Z (MH +) 370.4; C24H39NS¡ + H requires 370.3.

PREPARATION 5 1-Hexanoyl-3,4-dmethyl-4- (3-hydroxyphenyl) -piperidine To a stirred solution of 3,4-dimethyl-4- (3-hydroxyphenyl) piperidine (3.8 g, 18.6 mmol, J. Org. Chem., 1991, 56, 1660) in dichloromethane (30 ml) a 0 ° C triethylamine (3.9 mL, 27.8 mmol) was added followed by the dropwise addition of hexanoic anhydride (4.7 mL, 20.4 mmol) for 5 minutes. The reaction was stirred under a nitrogen atmosphere for 3 hours at room temperature and then quenched by the addition of saturated aqueous sodium hydrogen carbonate (50 ml). The two layers were separated and the aqueous layer was extracted with dichloromethane (3 x 50 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate: hexane (1: 1). The title compound was obtained as a clear oil (4.5 g). NMR (CDCb, data selected from a 13: 9 mixture of rotamers): 0.65 (d, 3H), 0.9 (m, 3H), 1.25-1, 45 (m, 7H), 1 , 55-1, 75 (m, 3H), 2.05 (m, 1 H), 2.15 (m, 1 H), 2.25-2.55 (m, 2H), 2.95 (m, 0.59H), 3.15 (m, 0.41) H), 3.35 (m, 0.41 H), 3.5-3.7 (m, 1, 18H), 3.85 (m, 0.41 H), 4.4 (m, 0.41 H), 4, 75 (m, 0.59H), 6.7 (d, 1 H), 6.75-6.85 (m, 2H), 7.15 (t, 1 H). MS (thermospray): M / Z (MH +) 304.1; C19H29NO2 + H requires 304.2.

PREPARATION 6 1-Hexanoyl-3,4-dimethyl-4- (trifluoromethanes? Lfonyl-oxyphenyl) pperidine To a stirred solution of 1-hexanoyl-3,4-dimethyl-4- (3-hydroxyphenyl) -piperidine (Preparation 5, 3.1 g, 10.1 mmol) in dichloromethane (30 mL) at room temperature was added by triethylamine portions (2.82 ml, 20.2 mmol) followed by? / - phenyltrifluoromethanesulfonimide (3.6 g, 15.1 mmol). The reaction was stirred under a nitrogen atmosphere at room temperature for 16 hours and then aqueous sodium hydroxide (30 ml of 2 N) was added. The biphasic mixture was stirred vigorously for 2 hours before the two layers separated and the aqueous layer was extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of ethyl acetate: hexane (1: 2 and then 2: 1). The title compound was obtained as a clear oil (3.6 g). NMR (CDCb, data selected from a 7: 5 mixture of rotamers): 0.55-0.65 (m, 3H), 0.85-0.95 (m, 3H), 1, 25-1, 4 (m, 4H), 1.45 (s, 3H), 1, 55-1, 75 (m, 3H), 2.0-2.5 (m, 4H), 2.9 (m, 0.58H ), 3.15 (m, 0.42H), 3.35 (m, 0.42H), 3.6 (m, 1.16H), 3.9 (m, 0.42H), 4.4 (m, 0.42H), 4.75 (m, 0.58H), 7.05-7.15 (m, 2H), 7.3 (m, 1 H), 7.4 (m, 1 H). MS (thermospray): M / Z (MH +) 436.4; C20H28F3NO4S + H requires 436.2.

PREPARATION 7 1-Hexanoyl-3,4-dimethyl-4- (3-methoxycarbonylphenyl) -pperidine To a solution of 1-hexanoyl-3,4-dimethyl-4- (trifluoromethanesulfonyloxyphenyl) piperidine (Preparation 6, 267 mg, 0.48 mmol) in anhydrous? /,? / -dimethylformamide (2 mL) was added triethylamine (0.degree. 18 ml) and methanol (0.4 ml). The mixture was deoxygenated by evacuation and washed with nitrogen five times. Palladium acetate (II) (4.4 mg) and 1,1'-bis (diphenylphosphino) ferrocene (8 mg) were added and the solution was purged with carbon monoxide. The reaction mixture was heated to 60 ° C in a carbon monoxide atmosphere for 7 hours and then cooled to room temperature and diluted with a saturated aqueous sodium chloride solution (10 ml). The phases were separated and the aqueous layer was extracted with dichloromethane (4 x 15 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (50 g), eluting with a mixture of hexane: ethyl acetate: 0.880 ammonia (66: 33: 1). The title compound was obtained as a pale yellow oil (110 mg). NMR (CDCb, data selected from a 9: 7 mixture of rotamers): 0.55-0.7 (m, 3H), 0.85-0.95 (m, 3H), 1.25-1, 4 (m, 4H), 1, 45 (s, 3H), 1, 6-1, 8 (m, 3H), 2.05-2.45 (m, 4H), 2.9 (m, 0.56H) ), 3.15 (m, 0.44H), 3.4 (m, 0.44H), 3.6 (m, 1.12H), 3.9 (m, 0.44H), 3.95 (s, 3H) , 4.4 (0.44H), 4.7 (m, 0.56H), 7.35-7.5 (m, 2H), 7.9 (m, 1 H), 7.95 (m, 1 H ).

MS (thermospray): M / Z (MH +) 346.3; C21H31NO3 + H requires 346.2.

PREPARATION 8 1-Hexane-1-3,4-dimethyl-4- (3-vinylphenyl) piperidine To a stirred solution of 1-hexanoyl-3,4-dimethyl-4- (trifluoromethanesulfonyloxyphenyl) piperidine (Preparation 6, 3.0 g, 6.90 mmol) in tetrahydrofuran (30 ml) at room temperature were sequentially added vinyl tributyl tin (2.12 ml, 7.24 mmol), lithium chloride (585 mg, 13.8 mmol) and tetrakis (triphenylphosphine) -palladium (0) (80 mg, 0.69 mmol). The mixture was heated to reflux under a nitrogen atmosphere for 1.5 hours, at which time a few crystals of 4-tert-butylcatechol were added. Then, heating was continued at reflux for an additional 16 hours. The mixture was cooled and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of ethyl acetate: hexane (1: 10 to 1: 3). The title compound was obtained as a clear oil (2.1 g). NMR (CDCb, data selected from a 5: 4 mixture of rotamers): 0.55-0.7 (m, 3H), 0.85-1, 0 (m, 3H), 1, 25-1, 4 (m, 4H), 1, 4 (s, 3H), 1, 6-1, 75 (m, 3H), 2.05-2.45 (m, 4H), 2.9 (m, 0.56H) ), 3.15 (m, 0.44H), 3.35 (m, 0.44H), 3.6 (m, 1, 12H), 3.9 (m, 0.44H), 4.4 (m, 0.44H), 4.7 (m, 0.56H), 5.25 (d, 1H), 5.75 (d, 1H), 6.7 (dd, 1H), 7.15 (m , 1 H), 7.2-7.35 (m, 3H). MS (APCI): M / Z (MH +) 314.5; C21H31NO + H requires 314.2.

PREPARATION 9 1-Hexane-1-3,4-dimethyl-4- (3-formylphenyl) piperidine To a solution of 1-hexanoyl-3,4-dimethyl-4- (3-vinylphenyl) pperidine (Preparation 8, 2.4 g, 7.67 mmol) in acetone (20 mL) at room temperature was added water (5 ml),? / - 4-methylmorpholine oxide (1.1 g, 9.20 mmol) and finally osmium tetroxide (3.83 ml, 2.5% by weight solution in tert-butanol) . The yellow solution was stirred at room temperature for 1 hour and then sodium periodate (4.92 g, 23.9 mmol) was added in one portion. After stirring the reaction for 3 hours, a large precipitate appeared and the reaction mixture was filtered through Celite®, washing with acetone. The filtrate was concentrated in vacuo, the crude oil was dissolved in dichloromethane, dried (MgSO 4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate: hexane (1: 1). The title compound was isolated as a clear oil (2.0 g). NMR (CDCb, data selected from a 1: 1 mixture of rotamers): 0.55-0.7 (m, 3H), 0.85-0.95 (m, 3H), 1.25-1, 4 (m, 4H), 1, 45 (s, 3H), 1, 55-1, 8 (m, 3H), 2.1-2.5 (m, 4H), 2.95 (m, 0, 5H), 3.15 (m, 0.5H), 3.4 (m, 0.5H), 3.6 (m, 1 H), 3.9 (m, 0.5H), 4.4 ( m, 0.5H), 4.75 (m, 0.5H), 7.45-7.6 (m, 2H), 7.7 (m, 1 H), 7.75 (m, 1 H) 10.0 (s, 1 H). MS (thermospray): M / Z (MH +) 316.3; C20H29NO2 + H requires 316.2.

PREPARATION 10 1-Hexanoyl-3,4-dimethyl-4-. { 3-f4- (4-M-thylphenyl) -sulfonyl-4,5-dihydro-1,3-oxazol-5-illphenyl} piperidine To a solution of 1-hexanoyl-3,4-dimethyl-4- (3-formylphenyl) piperidine (Preparation 9, 758 mg, 2.40 mmol) in ethanol (20 mL) was added [(4-methylphenyl) sulfonyl] methyl isocyanide (460 mg, 2.34 mmol) followed by sodium cyanide (12 mg, 0, 24 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for five hours and then concentrated in vacuo. The residue was purified by column chromatography on silica gel using a gradient elution of hexane: ethyl acetate (67:33 to 0: 100). The title compound was isolated as a clear oil (909 mg). NMR (CDCb) (data selected from a 1: 1 mixture of rotamers): 0.55-065 (m, 3H), 0.85-0.95 (m, 3H), 1, 25-1, 45 (m, 7H), 1, 55-1, 75 (m, 3H), 2.05-2.45 (m, 4H), 2.45 (s, 3H), 2.9 (m, 0.5H ), 3.15 (m, 0.5H), 3.35 (m, 0.5H), 3.6 (m, 1 H), 3.9 (m, 0.5H), 4.4 (m, 0.5H), 4.7 (m, 0.5H), 5, 0 (d, 1 H), 6.05 (d, 1 H), 7.1-7.3 (m, 4H), 7.3-7.45 (m, 3H), 7.85 (d, 2H). MS (thermospray): M / Z (MH +) 511, 1; C 29 H 38 N 2 O 4 S + H requires 511, 3.

Biological Activity The Ki values of certain compounds of the present invention were determined in the opiate receptor binding assays and it was found that the compounds of Examples 4, 8, 18 and 20 had Ki values of 4,000 nM or less for the receptor μ. The compounds of the invention also possess affinity for the opiate receptors d and K.

Claims (19)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula I, wherein A represents a single bond, C? -4 alkylene, C2-4 alkenylene or C2-4 alkynylene, the alkylene, alkenylene or alkynylene groups being optionally substituted with one or more substituents selected from C? - alkyl, C1-6 alkoxy 4, halo or OH; D represents H, OH, CN, N (R4) (R5), N (H) R6, C (0) N (R4) (R5), C (0) OR7, C (0) R8, C (= NR9a ) R8 or C (= NOR9b) R8; with the proviso that when A represents C2-4 alkenylene or C2-4 alkynylene, and D represents OH, N (R4) (R5) or N (H) R6, then D is not directly attached to an unsaturated carbon atom; and with the proviso that when A represents a single bond, then D does not represent H, OH, N (R4) (R5) or N (H) R6; R 4 and R 5 independently represent H, C 1-6 alkyl, C 3-8 cycloalkyl, aryl, C 1-4 alkyl-phenyl, the last four groups being optionally substituted with one or more substituents selected from nitro, halo, C 1-4 alkyl or alkoxy C1-4 (the last two groups being optionally substituted with one or more halo atoms), or R4 and R5, together with the N atom to which they are attached, form a 4 to 7 membered heterocyclic ring, the ring optionally containing one or more additional heteroatoms selected from oxygen, nitrogen and sulfur and the ring being optionally substituted with one or more substituents selected from alkyl d-4, C1-4 alkoxy, OH, = 0, nitro, amino or halo; R6 represents C (O) R10a, C (O) OR10b OR S (O) 2R10c; R10a to R10c represent independently C 1-4 alkyl, C 3-8 cycloalkyl, aryl, alkyl d-4-phenyl (the four groups being optionally substituted with one or more substituents selected from nitro, halo, d-4 alkyl or C 1-4 alkoxy (both being last groups optionally substituted with one or more atoms of 1fia 7 ft halo)), or R represents H; R and R independently represent H, alkyl

C1-6, C3-8 cycloalkyl, aryl or alkyl d-4-phenyl, the last four groups being optionally substituted with one or more substituents selected from nitro, halo, C- or C 1-4 alkoxy alkyl (the last two groups being 9a 9b optionally substituted with one or more halo atoms); R and R independently represent d-β alkyl, cycloalkyl OJ-S, aryl, C 1-4 alkyl-phenyl, the last four groups being optionally substituted with one or more substituents selected from nitro, halo, C 1-4 alkyl or d-4 alkoxy (the last two groups being optionally substituted with one or more 9b 1? halo atoms), or R represents H; each of R and R is independently H or C 1-4 alkyl; R3 represents aryl (optionally substituted with one or more substituents selected from OH, nitro, halo, CN, CH2CN, CONH2, C1-4 alkyl, CM alkoxy, C1-5 alkanoyl (the last three groups being optionally substituted with one or more atoms halo) and -11a 11b N (R) (R)), C-MO alkyl, C3-10 alkenyl or C3-10 alkynyl, said alkyl, alkenyl and alkynyl groups being optionally substituted and / or terminated 11c 11d with one or more substituents selected from OR, S (0) pR, CN, halo, d-6-alkoxycarbonyl, C2-6 alkanoyl, C2-6 alkanoyl-oxy, C3-8 cycloalkyl, C4-9 cycloalkanoyl, N (R12a) S (0) 2R13, Het1, aryl, adamantyl (the last two groups being optionally substituted with one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, CM alkyl, CM alkoxy and C1-5 alkanoyl ( the last three groups being optionally 1 12b 12c substituted with one or more halo atoms)), or -WA -N (R) (R); p is 0, 1 or 2; W represents a single bond, C (O) or S (0) q; A1 represents a single bond or alkylene d.io; with the proviso that when W and A1 represent 1 b 1 c single bonds, then the group -N (R) R) is not directly attached to an unsaturated carbon atom; q is 0, 1 or 2; each of R11a to R11d independently represents H, d-alkyl, C3-10 alkenyl, C3-10 alkynyl, C3-8 cycloalkyl, alkyl d-4-phenyl, aryl (the last six groups being optionally substituted with one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, alkyl CM, alkoxy CM and alkanoyl C -? - 5 (the last three groups being optionally substituted with one or more halo atoms)) or Het2; with the proviso that when R11d does not represent H 12a 12c then p represents 1 or 2; each of R to R independently represents H, C?-C o alkyl, C 3-10 alkenyl, C 3-10 alkynyl, C 3-8 cycloalkyl, C C-phenyl alkyl, aryl (the last six groups being optionally substituted with one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, alkyl CM, alkoxy CM and alkanoyl C? -5 (the last three groups being optionally substituted with one or more halo atoms)), or * h 12c Het, or R and R together represent unbranched C 2-6 alkylene, the alkylene group being optionally interrupted with O, S and / or a group N (R 14) and being optionally substituted with one or more C 1 -C alkyl groups; R 13 represents C 1-6 alkyl, C 3-8 cycloalkyl, alkyl CM-phenyl or aryl, the four groups being optionally substituted with one or more substituents selected from CM alkyl, alkoxy CM, OH, nitro, amino or halo; R 14 represents H, C 1-6 alkyl, C 3-8 cycloalkyl, A2- (C 3-8 cycloalkyl) or A2-aryl; A2 represents alkylene C-i-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 being optionally fused to a benzene ring and said groups being optionally substituted in the part of the heterocyclic ring and / or of benzene condensed with one or more substituents selected from OH, = 0, nitro, amino, halo, CN, aryl, alkyl CM, alkoxy CM and alkanoyl d-5 (the last three groups being optionally substituted with one or more halo atoms); X is H, halo, C 1 O alkoxy CM alkyl (the last two groups being optionally substituted with one or more halo atoms); n is O, 1 or 2; or pharmaceutically or veterinarily acceptable derivatives thereof. 2. A compound according to claim 1, wherein the group A-D is attached in the meta position with respect to the piperidine ring.

3. - a compound according to claim 1 or claim 2, wherein R1 represents C? -2 alkyl.

4. A compound according to any one of Claims 1 to 3, wherein R2 represents H or C1-2 alkyl.

5. A compound according to any one of the Claims 1 to 4, wherein R3 represents saturated C1-10 alkyl, optionally substituted with one or more substituents selected from OR11c, CN, halo, C2 ^ alkanoyl, d-4-carbonyl alkoxy, N (R12a) S02R13, Het1, aryl (the latter group being optionally substituted with one or more substituents selected from OH, alkyl CM, alkoxy CM, C2-5 alkanoyl, halo, nitro, amino, CN and CONH2), or -W-A1-N (R12b) ( R12c).

6. A compound according to any one of Claims 1 to 5, wherein R c represents H, Ci-β alkyl or aryl (the last groups being optionally substituted with one or more substituents selected from OH, alkyl CM, CM alkoxy, C2-5 alkanoyl, halo, nitro, amino, CN and CONH2); R12a to R12c independently represent H, alkyl CM, alkyl d-2-phenyl or aryl (the last three groups being optionally substituted with one or more substituents selected from halo, alkyl CM O alkoxy CM); W represents C (O); and / or A represents a single link.

7. A compound according to any one of the Claims 1 to 6, wherein R 13 represents C 1 -C 2 alkyl, phenyl or aryl alkyl (the last three groups being optionally substituted with one or more substituents selected from halo, C 1 O alkoxy CM alkyl).

8. - A compound according to any one of the

Claims 1 to 7, wherein A represents a single bond, d-4 alkylene, C 2-4 alkenylene or C 2-4 alkynylene, said alkylene, alkenylene or alkynylene groups being optionally substituted with one or more OH and / or methyl groups. 9. A compound according to any one of Claims 1 to 8, wherein D represents H, OH, CN, N (H) R4, N (H) C (O) R10a, N (H) C ( O) OR10b, N (H) S (O) 2R10c, C (0) N (R4) (R5), C (0) OR7, C (0) R8 or C (= NOH) R8; R 4 and R 5 independently represent H, C 1 -C 4 alkyl or C 3 -phenyl alkyl, the last two groups being optionally substituted with alkoxy CM; R7 and R8 independently represent H or alkyl CM; I 1 O 1 O or R R a independently represent CM alkyl, said group being optionally substituted with one or more halo atoms.

10. A compound according to any one of Claims 1 to 9, wherein R3 represents saturated C? -7 alkyl, optionally substituted with one or more substituents selected from CN, 0- (CIT alkyl), phenyl or O -(phenyl).

11. A compound according to any one of Claims 1 to 10, wherein X represents halo.

12. A compound according to any one of the Claims 1 to 11, wherein n represents 0 or 1.

13. A compound as defined in any one of Claims 1 to 12, for use as a medicament.

14. - A compound as defined in any one of Claims 1 to 12, for use as an animal medicament.

15. A formulation comprising a compound as defined in any one of Claims 1 to 12, in admixture with a pharmaceutically or veterinarily acceptable adjuvant, diluent or vehicle.

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

17. The use of a compound as defined in any one of Claims 1 to 12, in the manufacture of a medicament for the curative or prophylactic treatment of a disease mediated by an opioid receptor.

18. The use according to claim 17, wherein the disease is pruritus.

19. A process for the preparation of a compound as defined in claim 1, comprising: a) for compounds of formula I wherein A represents C2-4 alkynylene (group in which the carbon-carbon triple bond) that, β with respect to the benzene ring), said alkynylene group being optionally substituted in the 3- and / or 4-C position (with respect to the benzene ring) with one or more substituents defined in Claim 1 in relation to A, and / or one of the groups defined in Claim 1 in relation to D, or (when D is not attached to the 3- or 4-C position) said substituted alkynylene group being in the 2-C position (with respect to the ring) of benzene) with CN, C (0) N (R4) (R5), C (0) OR7, C (0) R8, C (= NR9a) R8 or C (= NOR9b) R8, the reaction of a corresponding compound of formula II, wherein L1 is a suitable leaving group and R1, R2, R3, X and n are as defined in Claim 1, with a compound of formula III, M = AD III wherein M represents (where appropriate) H , a tin-containing moiety, a boron derivative, a zinc halide, a magnesium halide or an alkali metal, A3 represents a single bond or C1-2 alkylene (optionally substituted with one or more substituents selected from CM alkyl, alkoxy CM, OH or halo), and D is as defined in Claim 1, with the proviso that when A3 represents a single bond, then D does not represent H, OH, N (R4) (R5) or N (H ) R6, where R4, R5 and R6 are as defined in Claim 1; b) for compounds of formula I wherein A represents C2-4 alkenylene (group in which the carbon-carbon double bond is, β with respect to the benzene ring), said alkenylene group being optionally substituted at C-2 (with with respect to the benzene ring) with CM alkyl and also optionally substituted with 3- and / or 4-C (with respect to the benzene ring) with one or more of the substituents defined in Claim 1 in relation to A and / or one of the groups defined in Claim 1 in relation to D, or said alkenylene group being substituted in the 2-C position (with respect to the benzene ring) with CN, C (0) N (R4) (R5), C ( 0) OR7, C (0) R8, C (= NR9a) R8 or -9b \ r-? 8 C (= NOR) R, the reaction of a corresponding compound of formula II, as defined above, with a compound of formula IV, wherein the dashed line represents the optional cis or trans geometry, R15 represents H or alkyl CM, and A3 and M are as defined above and D is as defined in Claim 1; c) for compounds of formula I in which A represents a single bond and D represents CN, the reaction of a compound of formula V, wherein R1, R2, R3 and X are as defined in Claim 1, with an alkali metal cyanide; d) for compounds of formula I wherein A represents alkylene CM, C2-4 alkenylene or C2-4 alkynylene, said alkylene, alkenylene or alkynylene groups being optionally substituted with one or more substituents selected from CM alkyl, CM alkoxy, halo or OH, and D represents NH2 (which is linked to a CH2 group), the reduction of a corresponding compound of formula I wherein A represents (where appropriate) a single bond, C1-3 alkylene, C2-3 alkenylene or alkynylene C2-3, said alkylene, alkenylene or alkynylene groups being optionally substituted with one or more substituents selected from CM alkyl, CM alkoxy, halo or OH, and D represents CN; e) for compounds of formula I in which D represents C (0) NH2, the controlled hydrolysis of a corresponding compound of formula I in which D represents CN; f) for compounds of formula I in which A represents a single bond and D represents C (0) - (alkyl d-β) or C (O) - (alkyl d-4-phenyl), the alkyl and alkylphenyl groups being optionally substituted with one or more of the substituents defined in Claim 1 with respect to R8, the hydrolysis of a corresponding compound of formula IX, wherein R 15 represents C 1-6 alkyl, R 16 represents H, C? -5 alkyl, phenyl or alkyl d-3-phenyl, the last three groups being optionally substituted with one or more substituents selected from nitro, halo, alkyl or C? CM alkoxy (the last two groups being optionally substituted with one or more halo atoms), the broken line indicates the optional cis or trans geometry, and R1, R2, R3, X and n are as defined in Claim 1; g) for compounds of formula I in which D represents C (0) R8, where R8 is as defined in claim 1, with the proviso that it does not represent H, the reaction of a corresponding compound of formula I in which D represents CN with an organometallic compound capable of releasing an anion containing R8a, wherein R8a is defined as defined R8 in Claim 1, with the proviso that it does not represent H; h) for compounds of formula I wherein A represents a single bond and D represents C (0) OR7, where R7 is as defined in Claim 1, with the proviso that it does not represent H; the reaction of a corresponding compound of formula V, as defined above, with carbon monoxide and an alcohol of formula R7aOH, wherein R7a is defined as R7 in Claim 1, with the proviso that it does not represent H; i) for compounds of formula I wherein A represents alkylene CM, C2-4 alkenylene or C2-4 alkynylene, said alkylene, alkenylene or alkynylene groups being optionally substituted with one or more substituents selected from CM alkyl, CM alkoxy, halo or OH, and D represents OH (which is linked to a CH2 group), the reduction of a corresponding compound of formula I wherein A represents (where appropriate) a single bond, d-3 alkylene, C2-3 alkenylene or alkynylene C2-3, said alkylene, alkenylene or alkynylene groups being optionally substituted with one or more substituents selected from among CM alkyl, CM alkoxy, halo or OH, and D represents C (0) OR7a, where R7a is as defined above; j) for compounds of formula I wherein A represents alkylene CM, C2-4 alkenylene or C2-4 alkynylene, said alkylene, alkenylene or alkynylene groups being gem-disubstituted with two alkyl groups CM (at position a with respect to D) and optionally being substituted with one or more additional substituents selected from among CM alkyl, CM alkoxy, halo or OH, and D represents OH, the reaction of a corresponding compound of formula I wherein A represents (where appropriate) a single bond, C?-C3 alkylene, C2-3 alkenylene or C2-3 alkynylene, said alkylene, alkenylene or alkynylene groups being optionally substituted with one or more substituents selected from CM alkyl, CM alkoxy, halo or OH, and D represents C (0) OR7a, where R7a is as defined above, with an organometallic compound releasing CM alkyl; k) for compounds of formula I wherein D represents C (O) N (R4) (R5), where R4 and R5 are as defined in Claim 1: A) the reaction of a corresponding compound of formula I in the that D represents C (0) OR7a, and R7a is as defined above, with a compound of formula XI, HN (R4) (R5) XI or an acid addition salt thereof, wherein R4 and R5 are as defined in Claim 1; B) the reaction of a corresponding compound of formula I in which D represents C (O) OH with a compound of formula XI, as defined above. I) for compounds of formula I in which D represents C (O) OH, the hydrolysis of a corresponding compound of formula I in which D represents C (0) OR7a, where R7a is as defined above; m) for compounds of formula I in which D represents fi N (H) R, where R is as defined in claim 1, the reaction of a corresponding compound of formula I in which D represents NH2 with a compound of formula XII, R6-L1 XII wherein R6 is as defined in Claim 1 and L is as defined above; n) for compounds of formula I wherein A represents alkyl CM and D represents N (R4) (R5) or N (H) C (O) R10a attached at the 1, 2 or 3-C position (with respect to the ring of benzene), where R 4, R 5 and R 10a are as defined in claim 1, the reaction of a corresponding compound of formula I in which A represents alkenylene CM a, β-, β, β- or β, d-unsaturated ( respectively) with respect to the benzene ring and D represents H, with a compound of formula XI, as defined above, or a compound of formula XIII, NC-R10a XIII wherein R is as defined in Claim 1; o) for compounds of formula I wherein A represents C2-4 alkylene optionally substituted with one or more substituents selected from among CM alkyl, CM alkoxy, halo or OH, and D represents OH, the oxidation of a corresponding borane adduct of formula XIV, XIV wherein x is 1, 2 or 3, and is (where appropriate) (3-x) or 1, R17 is (where appropriate) H, halo, an alkyl, or a cycloalkyl group, providing one Or two bonds with boron, A represents (where appropriate) alkylene Cz-4 optionally substituted with one or more substituents selected from CM alkyl, d-4 alkoxy, halo or OH, and R, R2, R3, X and n are as are defined in Claim 1; p) for compounds of formula I in which A represents a C2-4 alkylene group substituted (in position a with respect to D) with an OH group and D represents OH, the reaction of a corresponding compound of formula I in which A represents a C2-4 alkylene group and D represents H, with a dihydroxylation reagent; q) for compounds of formula I wherein A represents a single bond or a C? -2 alkylene group (where appropriate) and D represents C (0) H, the reaction of a corresponding compound of formula 1 wherein A represents an alkylene group C2 ^? substituted (in position a with respect to D) with an OH group and D represents OH, with a reagent that performs the oxidative cleavage of 1,2-dol; r) for compounds of formula I in which D represents C (= NR9a) R8 or C (= NOR9b) R8, where R8, R9a and R9b are as defined in claim 1, the reaction of a corresponding compound of formula I in wherein D represents C (0) R8 with a compound of formula XV, 9a H2N-R XV or a compound of formula XVI, H2N-OR9b XVI 9a 9b wherein R and R are as defined in Claim 1; s) for compounds of formula I in which A represents substituted alkylene CM (in position a with respect to D) with an OH group and D represents N (H) CH3 (at the end of the alkylene chain), reducing a corresponding compound of formula XVII, wherein r is 0, 1 or 2, L2 represents H or a capable group, when attached to a C2 alkylene unit, of undergoing a 1, 2-elimination (with respect to the L2 group), and R1, R2, R3 , X and n are as defined in Claim 1; t) for compounds of formula I in which R3 represents Ci-alkyl optionally substituted with C3-8 cycloalkyl, Het, aryl, adamantyl (the last two groups being optionally substituted with one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, CM alkyl, CM alkoxy and C1-5 alkanoyl (the last three groups being optionally substituted with one or more halo atoms), or R3 represents Cz-io alkyl, C3-10 alkenyl or C3 alkynyl 10 (the last three groups being optionally substituted with one or more of the relevant substituents identified in Claim 1 with respect to R3), said alkyl, alkenyl or alkynyl groups being attached to the piperidine nitrogen atom by a CH2 group, being Het1 as defined in Claim 1, the reduction of a corresponding compound of formula XIX, wherein R31 represents H, C3-8 cycloalkyl, Het1, aryl, adamantyl (the last two groups being optionally substituted with one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, CM alkyl, alkoxy CM and C 1-5 alkanoyl (the last three groups being optionally substituted with one or more halo atoms), C 1-9 alkyl, C 2-9 alkenyl or C 2-9 alkynyl, said alkyl, alkenyl or alkynyl groups being optionally substituted and / or terminated with one or more substituents selected from 11c 11d OR, S (0) pR, CN, halo, d-6-alkoxycarbonyl, C2-6 alkanoyl, C2-6-0XY alkanoyl, 12a 13 1 C3-8 cycloalkyl, C4-9 cycloalkanoyl, N (R) S (2 2) R, Het, aryl, adamantyl (the last two groups being optionally substituted with one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, CM alkyl, CM alkoxy and C1 alkanoyl) 5 (the last three groups optionally being substituted with one or more halo atoms)), or -W-A1-N (R12b) (R12c), where R1, R2, R11c, R11d, R12a to R12c, R13, Het1, n, p, W, X, A1, A and D as defined in Claim 1; u) the reaction of a corresponding compound of formula XX, wherein R1, R2, A, D, X and n are as defined in Claim 1, with a compound of formula Vlll, R3-L1 Vlll wherein R3 is as defined in Claim 1 and L1 is as defined previously; v) for compounds of formula I wherein R3 represents Ci-alkyl which, instead of being optionally substituted with the substituents defined in claim 1, is optionally substituted with R31, where R31 is as defined above, the reaction of a compound corresponding to formula XX, as defined above, with a compound of formula XXII, R31CHO XXII wherein R31 is as defined above, in the presence of a reducing agent; w) for compounds of formula I in which R3 is a d-? or alkyl group, C4-10 alkenyl or C4-10 alkynyl which is fully saturated in 1- to 3-C (with respect to the N-atom of piperidine) , and the group R 3 being substituted at 2-C 11d 11d (with respect to the N-atom of piperidine) with S (0) R, S (0) 2R, alkanoyl, cycloalkanoyl, alkoxycarbonyl, CN, -C (0) - A1-N (R12b) (R12c), -S (0) -A1-N (R12b) (R12c) or -S (0) 2-A1-N (R12b) (R 2c), where R11d, R12b, R12c and A1 as defined in Claim 1, the reaction of a corresponding compound of formula XX, as defined above, with a compound of formula XXIII, R3a-Z XXIII 3a 3 wherein R represents R as defined in Claim 1, with the exception that it does not represent aryl and that the R3a chain contains an additional carbon-carbon double bond a, β with respect to the substituent Z, and Z represents S (0) R11d, S (0) 2R11d, alkanoyl, cycloalkanoyl, alkoxycarbonyl, CN, -C (0) -A1-N (R12b) (R12c), -S (0) -A 1-N (R12b) (R12c) or -S (0) 2-A1-N (R12b) (R12c), being 11b 12b 12c 1 R, R, R and A as defined in Claim 1; x) for compounds of formula I in which A represents Cz ^ alkylene substituted (at position a with respect to D) with an OH group, D represents N (R4) (R5) (at the end of the alkylene chain), and R4 and R5 are as defined in Claim 1, the reaction of a compound of formula XXIV, wherein R1, R2, R3, X and n are as defined in Claim 1 and r is as defined above, with a compound of formula XI, as defined above; y) for compounds of formula I wherein D represents N (H) R4, where R is as defined in Claim 1, with the proviso that it does not represent aryl, the reduction of a corresponding compound of formula XXV, wherein R4b and R4c, together with the carbonyl group to which they are attached, form a C1-6 alkano group, C3-6 alkanone, C3-8 cycloalkanone, phenyl (CM) -alkanal or phenyl (C2-4) -alkanone , the five groups being optionally substituted with one or more substituents selected from nitro, halo, CM O alkoxy CM alkyl (the last two groups being optionally substituted with one or more halo atoms) and R1, R2, R, A, X and n they are as defined in Claim 1 (with the proviso that the group -N = C (R4b) (R4c) is not directly attached to an unsaturated carbon atom); z) for compounds of formula I wherein A represents alkylene CM, C2-4 alkenylene or C2-4 alkynylene, the alkylene, alkenylene or alkynylene groups being optionally substituted with one or more substituents selected from CM alkyl, CM alkoxy, halo or OH, and D represents N (R4) (R5) (attached to a CH2 group), where R4 and R5 are as defined in Claim 1, the reduction of a corresponding compound of formula I in which A represents (where appropriate) ) a single bond, C1-3 alkylene, C2-3 alkenylene or C2-3 alkynylene, said alkylene, alkenylene or alkynylene groups being optionally substituted with one or more substituents selected from CM alkyl, CM alkoxy, halo or OH, and D represents C (0) N (R4) (R5); aa) the conversion of a functional group present on an alkyl, heterocyclic or aryl group of a compound of formula I into another functional group.