MXPA00005291A - New 4-arylpiperidine derivatives for the treatment of pruritus - Google Patents

Abstract

There is provided a compound of formula I, wherein Het<1>, T, X, R<1>, R<2>and R<3>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 DERIVATIVES OF 4-ARILPIPERIDINE FOR THE TREATMENT OF PRURITE This invention relates to pharmaceutically useful compounds, in particular 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 irritable bowel syndrome, diarrhea, nausea, vomiting and pruritic dermatosis, such as allergic dermatitis and atopy in animals and humans. Compounds that bind opioid receptors are also indicated in the treatment of eating disorders, opioid overdose, depression, addition to tobacco and alcohol, sexual dysfunction, shock, stroke, spinal cord injury and brain trauma. There is a particular need for an improved treatment of the itch. Itching, or pruritus, is a common dermatological symptom that can lead to considerable discomfort in both animals and humans. Pruritus is often associated with inflammatory dermal disorders that may be caused by hypersensitivity reactions, including reactions to insect bites, such as mosquito bites, and environmental allergens, such as house dust mites or pollen, bacterial or fungal skin infections, or for ectoparasitic infections. Existing treatments that have been used in the treatment of pruritus include the use of corticosteroids and antihistamines. However, it is known that both treatments have deleterious side effects. Other therapies that have been used include the use of dietary supplements of essential fatty acids, although these have the disadvantage of their slowness in acting, and offer only limited efficacy against allergic dermatitis. A series of emollients such as soft paraffin, glycerin and lanolin have also been used, with limited success. Therefore, there is a continuing need for prior and / or improved pruritus treatments. Certain compounds based on 4-arylpiperidine are described in, among others, European patent applications EP 287339, EP 506468, EP 506478 and J. Med. Chem., 1993, 36, 2833-2850 as opiate antagonists. In addition, the international patent application WO 95/15327 describes azabicycloalkane derivatives useful as neuroleptic agents. According to the invention, compounds of formula I are provided: wherein Het1 is 5-, 6- or 7-links containing at least one nitrogen atom, and optionally one or more heteroatoms selected from oxygen and sulfur, and said heterocyclic ring is fully saturated, partially saturated or is aromatic in nature. T represents one or more optional substituents selected from H, halogen, OH, = 0, Ci-β alkyl, d-β alkoxy, C 3-6 cycloalkyl (the latter three groups are optionally substituted by one or more halogen atoms), arylalkyl (Ci-β) (the aryl portion of which is optionally substituted by one or more substituents selected from halogen, C? -4 alquiloalkyl and C alco-alkoxy (the latter two groups are optionally substituted by one or more halogen atoms)), -N (R4a) (R5), -N (R4b) S (O) mR6, -N (R4c) C (O) R7a and -N (R4d) C (O) OR7b, provided that when Het1 contains less than three carbon atoms (ie when the only two carbon atoms are those provided by the condensed benzene ring) and at least one heteroatom selected from oxygen and sulfur, T does not represent halogen or C? -6 alkoxy (the latter group is optionally substituted by one or more halogen atoms), 4a 4d 5 R a R and R independently represent H, alkyl C -i-β (said latter group is optionally substituted by one or more 4α-5 halogen atoms), or R and R, together with the nitrogen atom to which they are attached, form a 4 to 6-membered heterocyclic ring (said ring is optionally substituted by one or more substituents selected from C-- 4 alkyl, C 1-4 alkoxy, OH, 0 0, nitro, amino or halogen), R 6 represents Ci-β alkyl or aryl, said two groups being optionally substituted by one or more substituents selected from halogen, C? -4 alkyl or nitro, R7a and R7b independently represent C? -6 alkyl, C? -6 alkoxy, C3-6 cycloalkyl, aryl (said four groups are optionally substituted by one or more substituents selected from halogen, C-O alkyl nitro), or R73 represents H, m is 0, 1 or 2, R1 and R2 are each independently H or C1-4 alkyl, R3 represents aryl (optionally substituted by one or more substituents selected from OH, nitro, halogen, CN, CH2CN, CONH2 , CM alkyl, C1.4 alkoxy, C1..5 alkanoyl (the latter three groups are optionally substituted by one or more halogen atoms) and -N (R8a) (R8b)), C1-10 alkyl, C3-10 alkenyl or C3-10 alkynyl, wherein said alkyl, alkenyl or alkynyl group is optionally substituted and / or terminated by one or more substituents selected from 0R8c, S (0) nR8d, CN, halogen, C6-6 alkoxycarbonyl, alkanoyl C2-6, C2-6 alkanoyloxy, C3-β cycloalkyl, C9 cyanoalkanoyl, N (R9a) S (O) 2R10, Het2, aryl, adamantyl (the latter two groups are optionally substituted by one or more substituents selected from OH , nitro, amino, halogen, CN, CH2CN, CONH2, alkyl C -? - 4, C? -4 alkoxy and C? -5 alkanoyl (the latter three groups are optionally substituted by one or more halogen atoms)), or -W-A1-N (R9) (R9c), n is 0, 1 or 2, W represents a single bond, C (O) or S (0) p, A1 represents a single bond or alkylene C-MO, provided that when W and A1 represent single bonds, the group -N ( R9b) (R9c) is not directly attached to a saturated carbon atom, p is 0, 1 or 2, R8a to pβd represent one independently, H, C? -? Alkyl, C3-? Alkenyl, C3-alkynyl -?, C3-8 cycloalkyl, alkylphenyl CM, aryl (the latter six groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halogen, CN, CH2CN, CONH2, CM alkyl, C? -4 alkoxy and alkanoyl C? -5 (the latter three groups are optionally substituted by one or more halogen atoms)) or Het3, provided that R8d does not represent H when n represents 1 or 2, 9a Qc R a R represent each independently H, Ci-10 alkyl, C 3-10 alkenyl, C 3-10 alkynyl, C 3-8 cycloalkyl, C 4 -4 alkylphenyl, aryl (the latter six groups are optionally substituted by one or more substituents selected from OH, nitro, halogen , CN, CH2CN, CONH2, C? -4 alkyl, C? -4 alkoxy and C? -5 alkanoyl (the latter three groups are optionally substituted by one or more halogen atoms)), Het4, or R9b and R represent together a C2-6 alkylene without branches, said alkylene group is optionally interrupted by O, S, and / or a group N (R11) and is optionally substituted by one or more alkyl groups CM, R10 represents Ci-β alkyl, C3-cycloalkyl 8, alkylphenyl CO aryl, said last four groups being optionally substituted by one or more substituents selected from C1 alkyl. , alkoxy CM, OH, nitro, amino or halogen, R11 represents H, C? -6 alkyl, C3-8 cycloalkyl, A2- (Near or A2-aryl cycloalkyl, A2 represents Ci-? alkylene, Het2, Het3, Het4 represent independently heterocyclic groups of 3 to 8 links, said groups contain at least one heleroatome selected from oxygen, sulfur and / or nitrogen, said groups are optionally condensed to a benzene ring, and said groups are optionally substituted on the part of the heterocyclic ring and / o of the benzene condensed by one or more substituents selected from OH, = O, nitro, amino, halogen, CN, aryl, CM alkyl, CM alkoxy and C 1-5 alkanoyl (the latter three groups are optionally substituted by one or more atoms of halogen), X represents one or two optional substituents on the benzene ring, said substituents are selected from halogen, C 1 -C 4 alkyl, or C 4 -4 alkoxy (said last two groups are optionally substituted by one or more halogen atoms), or pharmaceutically or veterinarily acceptable derivatives thereof, said compounds collectively referred to hereafter as "the compounds of the invention". In the definitions used herein, alkyl, alkylene, alkoxy, alkoxycarbonyl, alkanoyl, alkanoyloxy, alkenyl, alkynyl and the alkyl portions of the alkylphenyl and arylalkoxy groups may, when there is a sufficient number of carbon atoms, be linear or branched chain and / or optionally be interrupted by one or more oxygen and / or sulfur atoms. The term halogen includes fluoro, chloro, bromo or iodo. The term "aryl" includes optionally substituted phenyl, naphthyl and the like, and "aryloxy" includes optionally substituted phenoxy and naphthyloxy and the like. Unless otherwise indicated, the aryl and aryloxy groups are optionally substituted by one or more (for example one to three) substituents selected from OH, nitro, amino, halogen, CN, CH2CN, CONH2, CM alkyl, CM alkoxy, C 1-4 alkoxycarbonyl and C? -5 alkanoyl (the latter four groups are optionally substituted by one or more halogen atoms). The heterocyclic rings representing Het2, Het3 and Het4 and which may represent N (R4a) (R5), may be fully saturated, partially unsaturated and / or of a total or partially aromatic character. Specific rings that may be mentioned include: for Het, dioxane, dioxolane, morpholino, piperidine, perhydroazepine, tetrahydrofuran, tetrahydropyran or tetrazole. To avoid doubt, when the heterocyclic groups (i.e. Het2, Het3, Het4 and some definitions of N (R4a) (R5)) are at least partially saturated, the possible substitution points include the atom (e.g. carbon) at the point of attachment of the heterocyclic group to the rest of the molecule. The Het groups (Het2, Het3 and Het4) can also be linked to the rest of the molecule through a heteroatom. The piperidine moiety of the compounds of formula I may be in the oxidized N form. Sulfur atoms which can interrupt the substituents (for example alkyl) in compounds of formula I, may be present in oxidized form (for example as sulfoxides or sulfones). All heterocyclic groups (ie Het1, Het2, Het3, Het4 and some definitions of N (R4a) (R5)) can 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.), maleic, malic, succinic, tartaric, cinnamic, ascorbic and related, base addition salts, salts formed with bases, for example sodium, potassium and alkylammonium salts CM. The compounds of the invention can also be in the form of quaternary ammonium salts, for example in the piperidine moiety, said salts can be formed by reaction with a series of alkylating agents, such as alkyl halide or sulfuric acid ester or a sulfonic acid aromatic. The compounds of the invention may exhibit tautomerism. All tautomeric forms of the compounds of formula I are included within the scope of the invention. The compounds of the invention contain one or more asymmetric centers and therefore can exist as enantiomers and diastereoisomers. The diastereoisomers can be separated using conventional techniques, for example by fractional crystallization or chromatography. The various stereoisomers can be isolated by separation of a racemic 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 produce racemization or epimerization. Alternatively, the desired optical isomers can be prepared by resolution, either by HPLC of the racemate using a suitable chiral support, or when appropriate, by fractional crystallization of the diastereomeric salts formed by reaction of the racemate with a suitable optically active acid or base. The invention includes the use of both individual isomers separately as well as mixtures of isomers. Radioisotope-tagged derivatives of compounds of formula I which are suitable for biological studies are also included within the scope of the invention. Preferred compounds of the invention include those in which: Het1 is condensed in the 3-position, 4 on the benzene ring relative to the piperidine ring, R1 represents C? -2 alkyl, R2 represents H or C? -2 alkyl, R3 represents saturated CMO alkyl (for example Cis), optionally interrupted by oxygen and / or substituted optionally by one or more substituents selected from OR8c, CN, halogen, C, alkoxycarbonyl, C2-6 alkanoyl, C2-6 alkanoyloxy, C3-cycloalkyl, C4-9 cycloalkanoyl, N (R) S (0) 2R, Het , phenyl (said last group is optionally substituted by one or more substituents selected from OH, C 1 -C 4 alkyl, C 2 -4 alkoxy, C 2-5 alkanoyl, halogen, nitro, amino, CN, CH 2 CN, CONH 2 and CF 3), and / or -W-A1-N (R9b) (R9c), R8c represents H, C1-6 alkyl, C3-8 cycloalkyl, phenyl or alkylphenyl CM (the latter two groups are optionally substituted by one or more substituents selected from OH, alkyl CM , alkoxy CM, C2-5 alkanoyl, halogen, nitro, amino, CN, CH2CN, CONH2 and CF3), 9a 9c R a R represent each independently H, C 1 -C 4 alkyl, C 2 -2 alkylphenyl or aryl (the latter two groups are optionally substituted by one or more substituents selected from C? -2 alquilo alkyl, C-2-2 alco alkoxy, OH or halogen), R represents alkyl or aryl CM, said two groups are optionally substituted by one or more substituents selected from C? -2 alquilo alkyl, C? -2 alco alkoxy, nitro or halogen, W represents C (O) or S (0) 2, A1 represents a bond single or alkylene CM, T represents H, OH, Ci-β alkyl (optionally substituted with one or more halogen atoms), CM alkoxy, C4-6 cycloalkyl, arylalkyl (C? -3), -NH (R5) or - N (H) S (0) 2R6, R represents H or C-γ-2 alkyl, R represents C -2 -2 alkyl.

More preferred compounds of the invention include those in which: Het1 represents a 5- or 6-membered heterocyclic ring, optionally containing an NH group, R1 represents methyl, R2 represents H or methyl, R3 represents C -? - saturated alkyl, substituted optionally by one or more substituents selected from OR8c, CN, halogen, and phenyl (said latter group is optionally substituted by one or more CM alkyl groups), R8C represents H, alkyl CM, phenyl or alkylphenyl CM (the latter two groups are optionally substituted by one or more alkyl groups CM), T represents H, NH2, C4-6 cycloalkyl or Ci-β alkyl (said latter group is optionally substituted by one or more halogen atoms), X represents halogen, particularly fluoro. Other more preferred compounds of the invention include those in which: Het1, together with the benzene ring to which it is condensed, represents an aromatic ring, particularly a benzimidazole group, benzotriazole, benzoxadiazole, benzoxazole, benzothiazole, cinnoline, indole, isoquinoline, phthalazine, quinazoline, quinoline or quinoxaline, T represents H, CH3, CHF2, CF3, ethyl, isopropyl, C4-5 cycloalkyl or NH2, R1 and R2 represent both methyl groups in mutually trans configuration, R3 represents C? -7 alkyl, optionally substituted by one or more substituents selected from OR8c and phenyl (said latter group is optionally substituted by one or more C? -2 alkyl groups), R8c represents C2-4 alkyl, phenyl or C-? - 2 alkylphenyl. Particularly preferred compounds of the invention include those in which: Het1, together with the benzene ring to which it is condensed, represents a benzimidazole group, T represents H, CHF2 or CF3, Preferred compounds of the invention include the compounds of the examples described below in the present. According to another aspect of the invention, methods are provided for the preparation of compounds of the invention, as illustrated below. The following procedures are illustrative of the general synthetic procedures that can be adopted to obtain the compounds of the invention. 1. The compounds of formula I, in which Het1 represents the 5-membered ring of a benzimidazole, optionally substituted at the 2-position by C6-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl (the last three groups are optionally substituted by one or more halogen atoms) or arylalkyl (C? -6) (the aryl portion of which is optionally substituted by one or more substituents selected from halogen, Ci-β alkyl and C? -6 alkoxy, the latter two groups are optionally substituted by one or more halogen atoms); they can be prepared by reacting a corresponding compound of formula II, wherein R1, R2, R3 and X are as defined hereinabove; with a compound of the formula IIIR'-CÍOR12 ^ III in which T3 represents H, C-? 6 alkyl, C-? 6 alkoxy, C3-6 cycloalkyl (the latter three groups are optionally substituted by one or more atoms) halogen) or arylalkyl (Ci-β) (the aryl group of which is optionally substituted by one or more substituents selected from halogen, Ci-6 alkyl and Ci-β alkoxy, the latter two groups are optionally substituted by one or more atoms of halogen) and R12 represents C? -2 alquilo alkyl, for example at a temperature between ambient and reflux temperature, in the presence of a suitable solvent and / or acid catalyst (for example acetic acid). The compounds of formula II can be prepared by reduction .NH, of a corresponding nitroaniline of formula IV, wherein R1, R2, R3 and X are as previously defined herein, for example by hydrogenation under standard catalytic conditions, or in the presence of a suitable reducing agent (eg finely divided metallic iron, combined with calcium chloride) and an appropriate solvent (e.g. water or a water / alcohol mixture). The compounds of formula IV can be prepared by nitration of a corresponding aniline of formula V, wherein R1, R2, R3 and X are as defined hereinbefore, under conditions known to those skilled in the art, for example by reaction with a suitable nitronium salt (for example nitronium tetrafluoroborate) in the presence of a suitable solvent (for example acetonitrile). Compounds of formula V can be prepared by hydrolysis of a corresponding HR minute formula VI wherein R1, R, R3 and X are as previously defined herein, under conditions known to those skilled in the art, for example by reaction at a temperature between ambient and reflux temperature with a suitable strong acid (e.g. HCl) and (optionally) an appropriate cosolvent (for example dioxane). The compounds of formula VI can be prepared by rearrangement of a corresponding compound of formula VII, wherein R1, R2, R3 and X are as defined hereinabove, for example at a temperature between 25 and 200 ° C in the presence of a suitable strong base (for example sodium hydride) and an appropriate solvent (per example 1-methyl-2-pyrrolidinone or N, N-dimethylformamide). The compounds of formula VII can be prepared by reaction of a corresponding compound of formula Vlll, wherein R1, R2, R3 and X are as defined hereinabove, with a compound of formula IX, L1-C (CH3) 2C (0) NH2 IX wherein L is a suitable leaving group (e.g. halogen, arenesulfonate, alkanesulfonate or perfluoroalkanesulfonate), for example at a temperature between room temperature and reflux temperature in the presence of a suitable base (for example, cesium carbonate in combination with sodium hydride) and an appropriate solvent (for example dioxane) . The compounds of formula Vlll can be prepared by reaction of a corresponding compound of formula X. wherein R1, R2, and X are as defined hereinabove, with a compound of formula XI, R3L1 XI wherein R3 and L1 are as defined hereinabove, for example under conditions known to those skilled in the art in the art, including, for example, alkylation at ambient temperature and reflux temperature in the presence of an organic solvent inert to the reaction (for example, N, N-dimethylformamide) and a suitable base (for example NaHCOs), and the arylation at ambient temperature and reflux temperature in the presence of a suitable catalyst system (for example tris (benzylidenacetopa) palladium (0) combined with tri-ortho-tolylphosphine), an appropriate strong base (for example tert-butoxide) of sodium) and a solvent inert to the reaction (for example toluene). 2. The compounds of formula I, in which Het1 represents the 5-membered ring of a benzimidazole, optionally substituted in the 2-position by T3, in which T3 is as defined hereinabove, provided that it does not represent C-? -6 or Ci-β haloalkoxy; they can be prepared by reacting a corresponding compound of formula II, as defined hereinbefore, with a compound of formula XII, or a derivative thereof (for example an acid halide or an anhydride) thereof (for example carboxylic acid) , wherein Ta is as defined hereinabove, provided that it does not represent C6-6 alkoxy or C6-6 haloalkoxy, for example at ambient temperature and 250 ° C. 3. The compounds of formula I in which Het1 represents the 5-membered ring of a benzimidazole, optionally substituted in the 2-position by a hydroxy group; they can be prepared by reacting a corresponding compound of formula II, as defined hereinabove, with a suitable carbonic acid derivative (for example urea), for example at room temperature and reflux temperature in the presence of a suitable solvent ( for example N, N-dimethylformamide). 4. The compounds of formula I in which Het1 represents the 5-membered ring of a benzimidazole, substituted in the 2-position by a fi-N (H) S (O) 2R group, in which R is as defined above at the moment; they can be prepared by reacting a corresponding compound of formula II, as defined above, with a compound of formula XIII, (L2) 2C = NS (0) 2R6 XIII wherein L2 represents a leaving group (as halogen) and R6 is as defined above, for example at ambient temperature and reflux temperature in the presence of a solvent inert to the reaction (for example toluene). 5. The compounds of formula I, in which Het1 represents the 5-membered ring of a benzimidazole, substituted in the 2-position by an amino group; can be prepared by hydrolysis of the corresponding compound of formula I, wherein Het1 represents the 5-membered ring of benzimidazole fi fi substituted at position 2 by a group N (H) S (0) 2R, wherein R is as previously defined herein, for example under conditions known to those skilled in the art. 6. The compounds of formula I, in which Het1 represents the 5-membered ring of a benzotriazole, can be prepared by reacting a corresponding compound of formula II, as defined hereinabove, with a suitable source of nitrosonium cation ( for example sodium nitrite combined with concentrated HCl), for example at a temperature between -10 ° C and room temperature in the presence of a reaction-inert solvent (for example a lower alkyl alcohol such as ethanol). 7. The compounds of formula I, in which Het1 represents the 5-membered ring of an idol, can be prepared by cyclization of a corresponding compound of formula XIV, wherein R1, R2, R3 and X are as defined hereinabove, for example at ambient temperature and reflux temperature in the presence of a suitable activator (for example copper iodide (I)) and an inert solvent the reaction (for example NN-dimethylformamide). The compounds of formula XIV can be prepared by reaction of a corresponding compound of formula XV, wherein R1, R2, R3, L1 and X are as hereinbefore defined, with acetylene, for example at ambient temperature and reflux temperature in the presence of a suitable catalyst system (for example b1s chloride ( triphenylphosphine) palladium (11) combined with copper iodide (1)) and an appropriate organic base (for example triethylamine). The compounds of formula XV, wherein L 1 represents chlorine, bromine or iodine, can be prepared by reaction of a corresponding compound of formula V, as defined above, with a halogen, under conditions known to those skilled in the art (e.g. by reaction with a solution of the halogen in acetic acid). 8. The compounds of formula I, wherein Het represents the 5-membered ring of a benzoxazole or benzothiazole, optionally substituted at the 2-position by Ta, wherein T3 is as defined hereinabove; they can be prepared by reaction of a corresponding compound of formula XVI, wherein E represents OH or SH, and R, R2, R3 and X are as defined hereinabove, with a compound of formula III or a compound of formula XII, as defined hereinabove, for example a ambient temperature and reflux temperature in the presence of a solvent inert to the reaction (for example xylene) and (if appropriate) a suitable catalyst (for example pyrimidinium para-toluene sulfonate) or a suitable base (for example triethylamine). The compounds of formula XVI can be prepared by reduction of a corresponding compound of formula XVII, XVIII wherein R1, R2, R3, E and X are as defined above, under conditions known to those skilled in the art (e.g. under conditions such as those described herein above for the production of compounds of formula II). The compounds of formula XVII can be prepared by nitration of a corresponding compound of formula XVIII, XVIII wherein R1, R2, R3, E and X are as defined above, for example under nitration conditions known to those skilled in the art (e.g. under conditions such as those described hereinabove for the production of compounds of formula IV). 9. The compounds of formula I, in which Het1 represents the 5-membered ring of a benzoxazole or a benzothiazole, optionally substituted in the 2-position by an OH group; they can be prepared by reaction of a corresponding compound of formula XVI, as defined hereinbefore, with a suitable carbonic acid derivative (for example 1,1'-carbonyldiimidazole), for example at a temperature between 0 ° C and reflux temperature in the presence of a solvent inert to the reaction (for example N, N-dimethylformamide). 10. The compounds of formula I, wherein R3 represents Ci-alkyl optionally substituted by C3-Cs cycloalkyl, Het, aryl, adamantyl, (said last two groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halogen, CN, CH2CN, CONH2, CM alkyl, CM alkoxy and C1-5 alkanoyl (said last three groups are optionally substituted by one or more halogen atoms)), or R3 represents C2-10 alkyl, C3-10 alkenyl or alkynyl C3-10 (said last three groups are all optionally substituted by one or more of the relevant substituents identified hereinabove with respect to R3), said alkyl, alkenyl or alkynyl groups being attached to the nitrogen of the piperidine through a CH2 group , in which Het2 is as defined above in this; can be prepared by reduction of a corresponding compound of formula XIX, wherein R31 represents H, C3-8 cycloalkyl, Het2, aryl, adamantyl (said last two groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halogen, CN, CH2CN, CONH2, CM alkyl, C-alkoxy and C? -5 alkanoyl (said last three groups are optionally substituted by one or more halogen atoms)), C1-9alkyl, C2-9alkenyl or C2alkynyl -9, said alkyl, alkenyl or alkynyl group is optionally substituted and / or terminated by one or more substituents selected from OR8c, CN, halogen, Ci-β alkoxycarbon, C2-6 alkanoyl, C2-6 alkanoyloxy, C3-8 cycloalkyl, C4-9 cycloalkanoyl, N (R9a) S (0) 2R10, Het2, aryl, adamantyl (said last two groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halogen, CN, CH2CN, CONH2, alkyl CM, alkoxy CM and C1..5 alkanoyl (di three last groups are optionally substituted by one or more halogen atoms), or -W-A1-N (R9b) (R9c), and R1, R2, R8c, R8d, R9a to R9c, R10, Het1, Het2, n, W, A1, T and X are as previously defined herein, using a suitable reducing agent (e.g., lithium aluminum hydride or a borane derivative), for example as described hereinabove. The compounds of formula XIX can be prepared by reaction of a corresponding compound of formula XX, wherein Het1, R1, R2, T and X are as defined hereinbefore, with a compound of formula XXI, R31C02H XXI or a suitable derivative (e.g. carboxylic acid) thereof (e.g., a halide or anhydride) of acid), wherein R31 is as defined hereinabove, 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 herein which describe the formation of a Het1 group. 11. The compounds of formula I can be prepared by reaction of a corresponding compound of formula XX, as defined hereinbefore, with a compound of formula XI, as defined above 2 ß in the present, under conditions which are known to those skilled in the art, for example as described hereinabove with respect to the production of compounds of formula Vlll. 12. The compounds of formula I, wherein R3 represents Ci-alkyl which, instead of being optionally substituted by the substituents defined hereinbefore, is optionally substituted by R, wherein R31 is as defined hereinabove; they can be prepared by reacting a corresponding compound of formula XX, as defined hereinbefore, with a compound of formula XXII, R31CHO XXII wherein R31 is as defined above, for example in the presence of a suitable reducing agent (by for example sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride) and an appropriate solvent (for example methanol). 13. The compounds of formula I, wherein R3 is a C? -? Or C, C4-10 alkenyl or C4-10 alkynyl group which is fully saturated from 1-C to 3-C (relative to the N atom of the piperidine), and said group R3 is substituted at 2-C (relative to the N atom of the piperidine) by S (0) R8d, S (0) 2R8d, alkanoyl, cycloalkanoyl, alkoxycarbonyl, CN, -C (O) -A1-N (R9b) (R9c), -S (O) -A1-N (R9b) (R9c), or -S (O) 2-A1-N (R9b) (R9c), wherein R8d, R9b, R9c and A1 are as defined hereinabove; can be prepared by reacting a corresponding compound of formula XX, as defined hereinbefore, with a compound of formula XXIII R3a-Z XXIII wherein R3a represents R3 as defined hereinbefore, except that it does not represent aryl, and that the chain R3a contains an additional carbon-carbon double bond, to the substituent Z, and Z represents S (0) R8d, S (0) 2R8d, alkanoyl, cycloalkanoyl, alkoxycarbonyl, CN, -C (0) -A1-N (R9b) (R9c), -S (0) -A1-N (R9b) (R9c), or -S (0) 2-A1-N (R9b) (R9c), wherein R8d, R9b, R9c and A1 are as defined above in the present; for example at ambient temperature and reflux temperature in the presence of a solvent inert to the reaction (for example THF). The compounds of formulas II, IX, X, XI, XII, XIII, XV (in which L1 does not represent chlorine, bromine or iodine), XVIII, XXI, XXII, XXIII and derivatives thereof, when they are not commercially available or not they are described below, can be obtained or analogously to the processes described herein or by conventional synthetic procedures, according to standard techniques, from readily available starting materials using appropriate reactants and reaction conditions. The compounds of formulas I, XIX and XX which contain other Het1 rings (in particular 6 and 7-membered rings) can be obtained by analogy with the processes described herein. For example, the 7-link Hetl rings containing 2 nitrogen atoms can be prepared by analogy with the process 2 described hereinabove. Other Het1 rings, for example, 7-membered Het1 rings containing 4 nitrogen atoms, can be obtained by methods known in the art, such as those described in Comprehensive Heterocyclic Chemistry II, edited by A.R. Katritstky, C.W. Rees and E.F.V. Scriven, 1st edition, Elsevier Science Ltd., (1996) or by the procedures described in The Chemistry of Heterocyclic Compounds, by A. Weissberger (John Wiley and Sons), volumes 5 (1953), 33 (1978) and 50 (1991 ), the descriptions of said documents are incorporated herein by reference. Those skilled in the art will appreciate that the compounds obtained by the above-mentioned processes can be further modified by interconversion of the substituents on the aromatic moieties to other desired substituents (see for example, Comprehensive Heterocyclic Chemistry II, edited by AR Katritstky, CW Rees and EFV Scriven, 1st edition, Elsevier Science Ltd., (1996)). 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, halogen can be hydrogenated to H, etc. Substituents on the alkyl groups in the aforementioned compounds can also be introduced, removed and interconverted using techniques that are well known to those skilled in the art. In some cases it is possible to introduce additional substituents directly into the compounds of formula I. For example, the chlorination of the phenyl group of compounds of formula I can be carried out by reaction with a solution of chlorine in acetic acid. Those skilled in the art will appreciate that these, and others, interconversions and transformations of various substituents or standard functional groups in 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, while carrying out the procedures described above, the functional groups of the intermediates may need to be protected by protecting groups. The functional groups that it is desirable to protect include oxo, hydroxy, amino and carboxylic acid. Suitable protecting groups for oxo include acetals, ketals (for example ethylene ketals) and dithynes. Suitable protecting groups for hydroxy include trialkylsilyl and diarylalkysilyl groups (for example tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) and tetrahydropyranyl. Suitable protecting groups for amino include tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl or ethanoyl. Suitable protecting groups for carboxylic acid include C 1-6 alkyl or benzyl esters. Suitable protecting groups for terminal alkynes include trialkylsilyl and diarylalkysilyl groups (for example tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl). The protection and deprotection of the functional groups can take place 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 extensively in "Protective Groups in Organic Chemistry", edited by J.W.F. McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis., 2nd edition, TW Greene &PGM Wutz, Wiley-lnterscience (1991). Those skilled in the art will appreciate that, to obtain compounds of formula I in a manner alternative and, on some occasions, more conveniently, the individual steps of the procedure mentioned hereinabove can be carried out in different order, and / or the individual reactions can be carried out at a different stage of the general route (i.e. substituents may be added and / or chemical transformations carried out, on different intermediates to those mentioned hereinabove in respect of a particular reaction.) This will depend, among other things, on factors such as the nature of the other functional groups present in a particular substrate, the availability of key intermediates and the strategy to be adopted by the protective group (if any). The implication will influence the choice of reagent used in the aforementioned synthetic steps, the need and type of protective groups used and the sequence to perform the synthesis. The methods can be adapted as appropriate to the reactants, reagents and other parameters of the reaction so that it will be apparent to the skilled person with reference to the standard textbooks and the examples provided hereunder. Those skilled in the art will appreciate that certain protected derivatives of compounds of formula I, which may be obtained prior to the final deprotection step, may not possess pharmacological activity as such, but may, in certain cases, be administered orally or parenterally and metabolized to then in the body forming compounds of the invention that are pharmacologically active. Said derivatives can therefore be described as "promedications". In addition, certain compounds of formula I can act as prodrugs of other compounds of formula I. Those skilled in the art will further appreciate that certain moieties, known to those skilled in the art as "pro-moieties", for example as described in " Design of Prodrugs "by H. Bundgaard, Elsevier, 1985 (the description of said document is incorporated herein by reference), can be located in appropriate functionalities, when said functionalities are present in compounds of formula i. For example, biologically inactive groups can be located in functional groups of compounds of formula I (for example an NH functionality in a Het1 group), and in the case of 5 or 6 link Het1 rings containing NH functionalities, said biolabile derivatives can be preferred. All protected derivatives, biolabel derivatives and prodrugs of 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 conventional manner. For example, a solution of free base can be treated with the appropriate acid, either neat or in a suitable solvent, and the resulting salt can then be isolated either by filtration or by vacuum evaporation of the reaction solvent. The pharmaceutically acceptable base addition salts can be obtained analogously by treating a solution of a compound of formula I with the appropriate base. Both types of salt can be formed or reversed using ion exchange resin techniques. The above procedures can be adapted as appropriate to the particular reactants and groups involved and other variants will be apparent to the skilled chemist by reference to standard textbooks and the examples provided hereunder to enable the preparation of all compounds of 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 products and, in particular, for use as medicines for animals. According to another aspect of the invention, the compounds of the invention are provided for use as medicaments, such as pharmaceuticals 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 through an opiate receptor, said diseases include irritable bowel syndrome, diarrhea, nausea, vomiting, pruritus or a medical condition characterized by the Itching as a symptom Therefore, according to another aspect of the invention, there is provided the use of compounds of the invention in the preparation of a medicament for the treatment of a disease mediated by an opioid receptor. The use of compounds of the invention is further provided in the preparation of a medicament for the treatment of irritable bowel syndrome, diarrhea, nausea, vomiting, pruritus 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 humans. Other diseases and conditions that may be mentioned include contact dermatitis, psoriasis, eczema and insect bites. Therefore, the invention provides a method of treatment or prevention of a disease mediated by an opioid receptor. In addition there is provided a method of treating irritable bowel syndrome, diarrhea, nausea, vomiting, pruritus or a medical condition characterized by pruritus as a symptom in an animal (for example a mammal), comprising the administration of a therapeutically effective amount of a compound of the invention to an animal in need of said 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 a non-toxic organic or inorganic acid or base addition salt, in a pharmaceutically acceptable dosage form. Depending on the disease and the patient to be treated, as well as the route of administration, the compositions may be administered at various doses (see below). Although it is possible to administer a compound of the invention directly without a formulation, preferably the compounds are employed in the form of a pharmaceutical, or veterinary, formulation comprising a pharmaceutically or veterinarily acceptable carrier, diluent or excipient and a compound of the invention. The vehicle, diluent or excipient can be selected with due consideration for the intended route of administration and standard pharmaceutical and / or veterinary practice. The pharmaceutical formulations containing the compositions of the invention may contain from 0.1% by weight to 90.0% by weight of the active ingredient. The methods by which compounds can be administered for veterinary administration include oral administration in capsules, boluses, tablets or purgatives, topical administration as ointment, pouring, spreading, bathing, spraying, creaming, shampooing, of collar or powder or, alternatively, can be administered by injection (for example subcutaneous, intramuscular or intravenous), or in the form of an implant. Said formulations can be prepared in a conventional manner according to standard veterinary practice. The formulations will vary with respect to the weight of active component contained therein depending on the species of animal being treated, the severity and type of infection and the animal's body weight. For parenteral administration, topical and oral, the typical dose ranges of the active ingredient are from 0.01 to 100 mg per kg of body weight of the animal. Preferably the range is from 0.1 to 10 mg per kg. The compositions are preferably formulated in a unit dosage form, each dose containing from about 1 to about 500 mg, more usually from about 5 to about 300 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, together with a pharmaceutically suitable carrier. In any case, the veterinary practitioner, or the expert, will be able to determine the actual dosage that will be most suitable for an individual patient, which may vary with the species, age, weight and response of the particular patient. The above dosages are examples of the average case; there may, of course, be individual cases where larger or smaller dosage intervals are necessary, and these 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 treatment in animals, the compounds can be administered with the animal feed, and for this purpose a food additive or premix can be prepared to mix it with the normal animal feed. For human use, the compounds are administered as a pharmaceutical formulation containing the active ingredient together with a pharmaceutically acceptable carrier or diluent. Said compositions include tablets, capsules and conventional ointment preparations which are formulated according to standard pharmaceutical practice. The compounds of the invention can be administered either separately or in combination with one or more agents used in the treatment or prophylaxis of the disease or in the reduction or suppression of the 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, itraconazole, griseofulvin, amphotericin B, antibacterials, for example enroflaxacin, marboflaxacin, ampicillin, amoxicillin, anti- inflammatories, for example prednisolone, betamethasone, dexamethasone , carprofen, ketoprofen, dietary supplements, for example gamma-linoleic acid, and emollients. 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 through opioid receptors. The skilled person will also appreciate that the compounds of the invention can be taken as a single dose based on "as needed" (ie, as needed or desired). Thus, according to another aspect of the invention, a pharmaceutical or veterinary formulation is provided which includes a compound of the invention mixed with a pharmaceutically or veterinarily acceptable adjuvant, diluent or vehicle. The compounds of the invention can also have the advantage that, in the treatment of human and / or animal patients, they can be more effective, less toxic, have a wider range of activity, be more potent, produce fewer side effects, be more easily absorbed or have other useful pharmacological properties more than 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 receptor in dog brain. The tests were carried out by the following procedure. Beagles bred in the laboratory were used as a source of dog brain tissue. The animals were sacrificed, their brains were removed and the cerebellum was discarded. The remaining brain tissue was sectioned into small pieces of approximately 3 g in weight 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 precipitate was resuspended in Tris buffer and stored at -80 ° C. The membrane material prepared in this way can be stored up to four weeks before use. For the mu assays increasing concentrations of the experimental compound were combined (5 x 10"12 to 10" 5 M), Tris buffer and 3H ligand ([D-Ala2, N-Me-Phe4, Gly-ol ^ -enkephalin, 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 Betaplate ™ GF / A glass fiber filters pre-soaked in 50 mM Tris buffer, pH 7.4, 0.1% polyethylenimine. The filters were then washed three times with 0.5 ml of ice-cold Tris pH 7.4 buffer. The washed filters were placed in bags and the Starscint ™ scintillation agent was added. The bags containing the filters and scintillation agent were heat sealed and counted with a beta Betaplate ™ 1204 counter. Duplicate samples were used for each experimental compound and the generated data were analyzed using IC50 analysis software with Graphpad Prism. The Ki values were calculated using Graphpad Prism according to the following formula: Ki = IC50 / 1 + [3H ligand] / KD where IC50 is the concentration at which 50% of the 3H ligand is displaced by the test compound 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 br (in relation to NMR) = width Cl = chemical ionization DMF = N, N-dimethylformamide DMSO = Dimethylsulfoxide d (in relation to time) = day d (relative to NMR) = doubled dd (relative to NMR) = double double EtOAc = ethyl acetate EtOH = ethanol h = hour (s) m (relative to NMR) = multiplet MeOH = methanol min (s) = minutes (s) q (in relation to NMR) = quartet q '(in relation to NMR) = quintet s (in relation to NMR) = singlet t (in relation to NMR) = triplet THF = tetrahydrofuran For HPLC purifications, the combination and evaporation of the appropriate fractions, determined by analytical HPLC, provided the desired compounds in the form of acetate salts. The HPLC analytical conditions used to highlight the appropriate fractions were: Phenomenex Magellan ™ column, 4.6 x 150 mm, packaged with silica Cis of 5, eluted with a gradient of acetonitrile: 0.1 M aqueous heptane sulfonic acid (10:90 at 90:10 in 30 minutes, followed by another 10 minutes at 90:10) at 1 ml per minute. The oven temperature of the column was 40 ° C and the ultraviolet detection of the components was carried out at 220 nm. When column chromatography is indicated, it usually refers to glass column packed with silica gel (40-63 m). Generally a pressure of about 165 kPa is applied, and the proportion of crude product: silica gel required for purification, is typically 50: 1. Alternatively, an Isolute ™ SPE column (solid phase extraction) or a Water Sep-Pak ™ cartridge packaged with silica gel at atmospheric pressure can be used. The proportion of crude product to silica gel required for purification is typically 100: 1. The hydrochloride salt can be obtained by methods normally known to those skilled in the synthetic chemistry art. Typically, to a solution of free base in dichloromethane (1 g: 100 ml), ethereal hydrochloric acid (1, CM, 1.2 equivalents), the excess solvent was decanted and the remaining precipitate was washed three times with ether and then dried under vacuum. Nuclear magnetic resonance imaging (NMR) spectral data were obtained using a Brucker AC3000, Brucker AM300, Varian Unity 300 or Varian Unity 40C spectrometer, with observed chemical shifts () being consistent with the proposed structures. The mass spectroscopy (MS) data were obtained in a Finnigan Masslab Navigator or a Fisons Instruments Trio 1000 spectrometer or a Fisons Instruments Trio 1000 APCI or a Micromass Platform LC spectrometer. The calculated and observed ions indicated refer to the lower mass isotopic composition. HPLC means high performance liquid chromatography. Ambient temperature means 20 to 25 ° C.

EXAMPLES EXAMPLE 1 Trans- (±) -5- (1-hexyl-3,4-dimethyl-4-piperidinyl) -1 H-1, 2,3-benzotriazole It was added to a solution of trans- (±) -N- [2-amino-5- (1-hexyl-3,4-d-methyl-4-piperidinyl) phenyl] acetamide (preparation 3.53 mg, 0.153 mmol) in ethanol (1 ml); concentrated hydrochloric acid (0.2 ml) and the mixture was cooled in an ice bath. A solution of sodium nitrite (21 mg, 0.31 mmol) in water (0.1 ml) was added dropwise and stirred continuously for 3 hours at this temperature. An additional portion of hydrochloric acid (0.1 ml) was added and the reaction was allowed to reflux for 3 hours. The reaction mixture was cooled and diluted with ethyl acetate (100 ml) and water (50 ml), and then washed with a saturated sodium bicarbonate solution (50 ml). The separated organic phase was washed with brine (25 ml) and both aqueous phases were extracted with ethyl acetate (25 ml). The combined organic phases were dried (MgSO 4) and concentrated in vacuo. The residue was triturated with hexane twice and then dried with a vacuum pump to give the benzotriazole (44 mg) as a light yellow solid.

H-NMR (300 MHz, CDCl 3) (data selected): 0.70 (3 H, d), 0.85 (3 H, m), 1, 40 (3 H, s), 7.40 (1 H, d), 7.70 (1 H, s) and 7.85 (1 H, d). MS (Thermospray): M / Z (MH +) 315.3, C19H30N4 + H requires 315.5.

EXAMPLE 2 Trans- (±) -5-f1-hexyl-3,4-dimethyl-4-piperidinyl) -1H-benzimidazole A solution of trans- (±) -4- (1-hexyl-3,4-dimethyl-4-piperidinyl) -1,2-benzenediamine was heated at 100 ° C for 2 hours (preparation 5, 150 mg, 0.494 mmol) in 90% formic acid (1.0 ml). The reaction was diluted with water (50 ml) and poured into ethyl acetate (50 ml) and 2N sodium hydroxide (25 ml). The organic layer was washed with brine (25 ml) and both aqueous layers were extracted with ethyl acetate (50 ml). The combined organic phases were dried (MgSO4) and concentrated in vacuo to give the benzimidazole (130 mg) in the form of a light brown oil. This was dissolved in diethyl ether (1.0 ml) and treated with 1 N HCl in diethyl ether (0.46 ml, 0.46 mmol), which was added dropwise. The solvent was removed in vacuo affording the hydrochloride as a light brown solid. 6H NMR (300 MHz, CDCI3) (data selected from the free base): 0.80 (3H, d), 0.90 (3H, m), 1, 35 (3H, s), 7.25 (1H, d), 7.50 (1H, s), 7.60 (1 H, d) and 8.00 (1 H, s). MS (Thermospray): M / Z (MH +) 313.8, C2oH3oN3 + H requires 313.5.

EXAMPLE 3 Trans- (±) -2-methyl-5- (1-hexyl-3,4-dimethyl-4-piperidinyl) -1H-benzimidazole A solution of trans- (±) -N- [2-amino-5- (1-hexyl-3,4-dimethyl-4-piperidinyl) pheny] acetamide was heated (preparation 3, 150 mg, 0.434). mmol) in acetic acid (2.0 ml) at reflux for 2 hours. The reaction was diluted with water (25 ml) and ethyl acetate (50 ml) and then washed with 2N sodium hydroxide solution (50 ml). The separated organic phase was washed with brine (50 ml). Both aqueous layers were extracted with ethyl acetate (50 ml) and the combined organic phases were dried (MgSO 4) and concentrated in vacuo. The crude residue was chromatographed on Merck silica gel 230-400 mesh (10 g) using ethyl acetate: 2 N ammonium in methanol (95: 5) as eluent to give the benzimidazole (71 mg) as a pale yellow oil. . This was dissolved in diethyl ether (1 ml) and treated with 1 N HCl in diethyl ether (0.2 ml, 0.2 mmol). The solvent was removed in vacuo affording the hydrochloride as a pale brown solid. 5 H NMR (300 MHZ, CDCl 3) (data from the free base): 0.75 (3H, d), 0.85 (3H, m), 1.35 (3H, s), 2.60 (3H, s), 7.20 (1 H, d) and 7.40-7.50 (2H, as). MS (Cl): M / Z (MH +) 328.5, C2? H33N3 + H requires 328.5.

EXAMPLE 4 Trans- (±) -2- (trifluoromethyl-5- (1-hexyl-3,4-dimethyl-4-piperidinyl) -1H-benzimidazole A solution of trans- (±) -4- (hexyl-3,4-dimethyl-4-piperidinyl) -1,2-benzenediamine (preparation 5.25 mg, 82 mol) was heated at reflux for 2 hours in trifluoroacetic acid (1 ml). The cooled reaction was diluted with water (25 ml) and ethyl acetate (50 ml) and then washed with 2 N sodium hydroxide solution (25 ml). The organic layer was washed with brine (25 ml) and both aqueous layers were back-extracted with ethyl acetate (25 ml). The combined organic phases were dried (MgSO 4) and concentrated in vacuo. The residue was chromatographed on 230-400 Merck silica gel (10 g) using ethyl acetate: methanol (90:10) as the eluent to give the benzimidazole (29 mg) as a pale yellow oil. This was dissolved in diethyl ether (1 ml) and treated with 1 N HCl in diethyl ether (84 μl, 84 μmol). The solvent was removed in vacuo affording the hydrochloride as a pale brown solid. 5 H NMR (300 MHZ, CDCl 3) (data from the free base): 0.75 (3H, d), 0.85 (3H, m), 1.40 (3H, s), 7.35 (1H , d), 7.55 (1 H, s) and 7.65 (1H, d). MS (Cl): M / Z (MH +) 382.4, C21H30F3N3 + H requires 382.5.

EXAMPLE 5 Trans- (±) -6- (1-hexyl-3,4-dimethyl-4-piperidir? IQ-1 H-indole It was added to a solution of trans- (±) -2- [2- (trimethylsilyl) ethynyl] -5- (1-hexyl-3,4-dimethyl-4-piperidinyl) aniline (preparation 7, 211 mg, 0.55 mmol) in N, N-dimethylformamide (2 ml) under nitrogen; copper iodide (I) (208 mg, 1.09 mmol) and the reaction mixture was heated at 100 ° C for 1.5 hours. The cooled reaction was diluted with diethyl ether and filtered through Celite (R). The filtrate was washed with brine and the separated aqueous layer was extracted with diethyl ether (3 x 50 ml). The combined organic phases were dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on a 230-400 Merck silica gel (10 g) using a gradient of dichloromethane: ethanol: ammonium hydroxide (300: 8: 1 to 200: 8: 1) to afford the indole (51 mg) in shape of an oil. This was dissolved in dichloromethane (2 ml) and treated with 1 N HCl in diethyl ether (2 ml). The solvent was removed in vacuo to give the hydrochloride as a light yellow solid. 5 H NMR (300 MHz, CDCl 3, data from the free base): 0.80 (3H, s), 0.90 (3H, m), 1.35 (3H, s), 6.50 (1H, s), 7.10 (1 H, d), 7.15 (1 H, m), 7.25 (1 H, m), 7.60 (1 H, d) and 8.05 (1 H, ace). MS (Cl): M / Z (MH +) 313.4, C2-? H32N2 + H requires 313.5.

EXAMPLE 6 T rans- (±) -2-isopropyl-5- (1-hexy-3,4-dimethyl-4-piperidinyl) -1H-benzimidazole A solution of trans- (±) -4- (1-hexyl-3,4-dimethyl-4-p-peridinyl) -1,2-benzenediamine (preparation 5.36 mg, 0.119 mmol) in acid was heated to reflux. isobutyric acid (1 ml) for 4 hours. The cooled reaction was diluted with water (25 ml) and ethyl acetate (50 ml), then washed with a saturated solution of 2 N sodium bicarbonate (25 ml). The organic layer was washed with brine (25 ml) and both aqueous layers were back-extracted with ethyl acetate (25 ml). The combined organic phases were dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on 230-400 Merck silica gel (10 g) using ethyl acetate: 2 N ammonium in methanol (97: 3) as eluent to give the benzimidazole (3 mg) as a colorless oil. This was dissolved in diethyl ether (0.5 ml) and treated with 1 N HCl in diethyl ether (9 μl, 9 μmol). The solvent was removed in vacuo to provide the hydrochloride as a reddish solid. 5 H NMR (300 MHZ, CDCl 3, data from the free base): 0.80 (3H, d), 0.90 (3H, m), 1.30 (3H, s), 1.45 (6H, d) ) and 6.70-7.20 (3H, m). MS (Thermopuiverization): M / Z (MH +) 356.2, C23H37N3 + H requires 356.5.

EXAMPLE 7 Trans- (±) -2-methoxy-5- (1-hexyl-3,4-dimethyl-4-piperidinip-1H-benzimidazole A mixture containing trans- (±) -4- (1-hexyl-3,4-dimethyl-4-piperidinyl) -1,2-benzenediamine (preparation 5.33 mg, 0.109 mmol) was stirred. tetramethoxymethane (1 ml) and glacial acetic acid (7 ml) at room temperature for 2 hours and then heated to reflux for another 2 hours. The reaction mixture was concentrated in vacuo, dissolved in ethyl acetate (50 ml), then washed with a saturated solution of potassium carbonate (25 ml) and brine (25 ml). Each aqueous phase was extracted with ethyl acetate (25 ml), the combined organic phases were dried (MgSO 4) and concentrated in vacuo.

The residue was chromatographed on 230-400 Merck silica gel (10 g) using ethyl acetate: 2 N ammonium in methanol (97: 3) as eluent to give the benzimidazole (5 mg) as a colorless oil. 5H NMR (300 MHZ, CDCI3, data selected): 0.80 (3H, d), 0.90 (3H, s), 1, 35 (3H, s), 4.15 (3H, s) and 6.85-7.10 (3H, m). MS (Cl): M / Z (MH +) 344.4, C2? H33N30 + H requires 344.5.

EXAMPLE 8 Trans- (±) -2-cyclobutyl-5- (1-hexyl-3,4-d-methyl-4-p -peridinyl-1H-benzimidazole A stirred solution of trans- (±) -4- (1-hexyl-3,4-dimethyl-4-piperidinyl) -1,2-benzenediamine was heated to 145 ° C (preparation 5.58 mg, 0.19 mmol ) in cyclobutanecarboxylic acid (1 ml, 10 mmol) for 2 hours. The cooled reaction was treated with a 2 N sodium hydroxide solution (20 ml) and back-extracted with dichloromethane. The combined organic phases were dried (MgSO4) and concentrated in vacuo to give a black oil. The crude residue was chromatographed on 230-400 Merck silica gel (10 g) using ethyl acetate: 2 N ammonium in methanol (99: 1) as eluent to give the benzimidazole (47 mg) as a pale yellow oil. . The oil was dissolved in dry diethyl ether (1 ml) and treated with a solution of 1 N HCi in diethyl ether (128 μl, 128 μmol). The solvent was removed in vacuo to provide the hydrochloride as a purple solid. 5 H NMR (300 MHZ, CDCl 3, data from the free base): 0.75 (d, 3 H), 0.85 (m, 3 H), 1, 30 (s, 3 H), 3.75 (q ', 1H), 7.18 (m, 2H), 7.25 (s, 1 H) and 7.50 (as, 1 H). MS (Thermospray): M / Z (MH +) 368.3, C24H37N3 + H requires 368.3.

EXAMPLE 9 Trans- (±) -2-benzyl-5- (1-hexyl-3,4-dimethyl-4-piperidinyl) -1H-benzimidazole A stirred solution of trans- (±) -4- (1-hexyl-3,4-dimethyl-4-piperidinyl) -1,2-benzenediamine was heated to 190 ° C (preparation 5, 48 mg, 0, 16 mmol) in phenylacetic acid (1 ml, 8 mmol) for 2 hours. The cooled reaction mixture was treated with a 2N sodium hydroxide solution (20 ml) and back-extracted with dichloromethane. The combined organic phases were dried (MgSO4) and concentrated in vacuo to give a black oil. The oil was chromatographed on Merck silica gel 230-400 mesh (10 g) using ethyl acetate: 2 N ammonium in methanol (99: 1) as eluent to give the benzimidazole (31 mg) as a pale yellow oil. The oil was dissolved in dry diethyl ether (1 ml) and treated with a solution of 1 N HCl in diethyl ether (77 μl, 77 μmol). The solvent was removed in vacuo to provide the hydrochloride as a white solid. 5 H NMR (300 MHz, CDCl 3, data from the free base): 0.75 (d, 3 H), 0.90 (m, 3 H), 1, 30 (s, 3 H), 4.25 (m, 2 H) ), 7.10-7.40 (m, 8H) and 7.60 (ace, 1 H). MS (Thermospray): M / Z (MH +) 404.2, C27H37N3 + H requires 404.3.

EXAMPLE 10 Trans- (±) -2-cyclopentyl-5- (1-hexyl-3,4-dimethyl-4-piperidinyl-1H-benzimidazole A stirred solution of trans- (±) -4- (1-hexyl-3,4-d.methyl-4-piperidinyl) -1,2-benzenediamine (preparation 5.49 mg, 0.161 mmol) was heated to reflux in reflux. Cyclopentanecarboxylic acid (1 ml) for 2 hours. The cooled reaction mixture was treated with ethyl acetate (25 ml) and washed with a 2 N sodium hydroxide solution (25 ml). The separated organic phase was washed with brine (25 ml) and each of the separated aqueous phases was extracted with ethyl acetate (25 ml). The combined organic phases were dried (MgSO 4) and concentrated in vacuo. The crude residue was chromatographed on a 230-400 Merck silica gel (10 g) using ethyl acetate: 2 N ammonium in methanol (99: 1) as eluent to give the benzimidazole (19 mg) as a pale yellow oil. . The oil was dissolved in diethyl ether (1 ml) and treated with a solution of 1 N HCl in diethyl ether (55 μl, 55 μmol). The solvent was removed in vacuo to provide the hydrochloride as a purple solid. 6H-NMR (300 MHZ, CDCI3, data from the free base): 0.75 (3H, d), 0.85 (3H, m), 1.30 (3H, s), 3.30 (1H, q '), 7.20 (1 H, d) and 7.60 (2H, m). MS (Thermospray): M / Z (MH +) 382.3, C25H39N3 + H requires 382.6.

EXAMPLE 11 Trans- (±) -2- (difluoromethyl) -5- (1-hexyl-3,4-dimethyl-4-piperidinyl) -1H-benzimidazole A solution of trans- (±) -4- (1-hexyl-3,4-d-methyl-4-pperidinyl) -1,2-benzenediamine was heated to reflux (preparation 5, 55 mg, 0.181 mmol) in difiuoroacetic acid (1 ml) for 4 hours. The cooled reaction mixture was diluted with water (25 ml) and ethyl acetate (50 ml) and washed with a 2 N sodium hydroxide solution (25 ml). The organic phase was washed with brine (25 ml) and both aqueous layers were back-extracted with ethyl acetate (25 ml). The combined organic phases were dried (MgSO 4) and concentrated in vacuo. The residue was chromatographed on a 230-400 Merck silica gel (10 g) using ethyl acetate: 2 N ammonium in methanol (97: 3) as eluent to give the benzimidazole (47 mg) as a pale yellow oil. This was dissolved in diethyl ether (1 ml) and treated with a solution of 1 N HCl in diethyl ether (142 μl, 142 μmol). The solvent was removed in vacuo affording the hydrochloride as a pale yellow solid. 5 H NMR (300 MHZ, CDCl 3, data from the free base): 0.70 (3H, d), 0.85 (3H, m), 1.40 (3H, s), 6.85 (1H, t), 7.30 (1 H, d) and 7.60 (2H, m). MS (Thermospray): M / Z (MH +) 364.2, C2? H3? F2N3 + H requires 364.5.

EXAMPLE 12 Trans- (±) -2-etl-5- (1-hexyl-3,4-dimethyl-4-p-peridin-p-1H-benzimidazole A solution of trans- (±) -4- (1-hexyl-3,4-dimethyl-4-piperidinyl) -1,2-benzenediamine (preparation 5.55 mg, 0.181 mmol) in acid was heated to reflux. propionic (1 ml) for 4 hours. The cooled reaction mixture was diluted with water (25 ml) and ethyl acetate (50 ml) and washed with a 2 N sodium hydroxide solution (25 ml). The organic phase was washed with brine (25 ml) and both aqueous layers were back-extracted with ethyl acetate (25 ml). The combined organic phases were dried (MgSO 4) and concentrated in vacuo.

The residue was chromatographed on 230-400 Merck silica gel (10 g) using ethyl acetate: 2 N ammonium in methanol (99: 1) as eluent to give the benzimidazole (30 mg) as a pale yellow oil. This was dissolved in diethyl ether (1 ml) and treated with a solution of 1 N HCl in diethyl ether (100 μl, 100 μmol). The solvent was removed in vacuo affording the hydrochloride as a pale yellow solid. 6H-NMR (300 MHZ, CDC, data selected from the free base): 0.75 (3H, d), 0.85 (3H, m), 1.35 (3H, s), 1.40 (3H, t ), 2.90 (2H, q), 7.20 (1 H, d) and 7.50 (2H, m). MS (Thermospray): M / Z (MH +) 342.1, C22H.34N3 + H requires 342.5.

EXAMPLE 13 Trans- (±) -5- (1-hexyl-3,4-dimethyl-4-p-peridinyl) -1,3-dihydro-2H-benzimidazol-2-one A mixture of trans- (±) -4- (1-hexyl-3,4-dimethyl-4-piperidinyl) -1,2-benzenediamine (preparation 5, 195 mg, 0.643 mmol), urea (244) was refluxed. mg, 4.07 mmol) and N, N-dimethylformamide (2.1 ml) for 5 hours. The cooled mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (25 ml) and water (25 ml). The organic phase was extracted with brine (25 ml) and each separated aqueous phase was extracted with ethyl acetate (25 ml). The combined organic phases were dried (MgSO4) and concentrated in vacuo.

The crude product was chromatographed on Merck silica gel 230-400 mesh (10 g) using ethyl acetate: 2 N ammonium in methanol (97: 3) as eluent to give the benzimidazolone (30 mg) as a pale brown solid. . 5 H NMR (300 MHZ, CDCl 3, data from the free base): 0.75 (3H, d), 0.90 (3H, m), 3.30 (1H, as) and 7.00 (3H, m). MS (Thermospray): M / Z (MH +) 330.1, C20H30N3O + H requires 330.5.

EXAMPLE 14 Trans- (±) -N-r5- (1-hexyl-3,4-dimethyl-4-piperidinyl) -1H-benzimidazole-2-illmethanesulfonamide It was added to a solution of trans- (±) -4- (1-hexyl-3,4-dimethyl-4-piperidinyl) -1,2-benzenediamine (preparation 5, 1, 05 g, 3.46 mmol) in toluene (30 ml) under a nitrogen atmosphere; a solution of N-methanesulfonylcarbonimidic acid dichloride ([Neidlein and Hausmann, Tetrahedron Lett., 1965, 1753], 0.61 g, 3.46 mmol) in toluene (5 ml). The reaction was heated at 85 ° C for 5 hours, then cooled to room temperature and allowed to stand under nitrogen overnight. The reaction mixture was concentrated in vacuo and the residue was partitioned between dichloromethane (50 ml) and a saturated solution of sodium bicarbonate (50 ml), stirring said mixture for 1 hour. The organic layer was separated and the aqueous washings were extracted with dichloromethane (2 x 50 ml). The combined organic phases were dried (Na 2 S 4) and concentrated in vacuo to give a dark green-black solid. The residue was chromatographed on 230-400 Merck silica gel (50 g), eluted with hexane: ethyl acetate (40:60 to 20:80) and basified with three drops of concentrated ammonium hydroxide to provide the sulfonamide. in the form of a yellow solid (495 mg). 5 H NMR (300 MHZ, CD3OD) (data from the free base): 0.75 (3H, d), 0.90 (3H, t), 1, 30-1, 40 (9H, m), 1, 45-1, 6 (2H, m), 1, 70 (1 H, m), 2.10 (1 H, m), 2.25-2.50 (4H, m), 2.55-2, 70 (2H, m), 2.85 (1H, m), 3.00 (3H, s) and 7.15-7.25 (3H, m). MS (Electrospray): M / Z (MH +) 407.2, C21H34N4O2S + H requires 407.3.

EXAMPLE 15 Trans- (±) -5- (1-hexyl-3,4-dimethyl-4-piperidinyl-MH-benzyl-2-ylamine) A solution of trans- (±) -N- [5- (1-hexyl-3,4-dimethyl-4-piperidinyl) -1H-benzimidazole-2-yl] was heated to reflux. methanesulfonamide (example 14, 150 mg, 3.22 mmol) in 48% hydrobromic acid (5 ml) and glacial acetic acid (5 ml) for 48 hours. The reaction mixture was cooled and basified to pH 10 with a 2 N sodium hydroxide solution. The product was extracted with dichloromethane (3 x 25 ml) and the solvent was dried (Na 2 SO 4). The crude product was chromatographed on Merck silica gel 230-400 mesh (8 g) eluting with ethyl acetate: dichloromethane (20:80). The starting material was collected from the column before washing with methanokydloromethane (40:60). The residue was concentrated in vacuo and then redissolved in dichloromethane (30 ml). The solvent was dried (Na 2 S 4), filtered and concentrated in vacuo to give the benzimidazolamine (15 mg) as a light brown solid. 5 H NMR (300 MHz, CD 3 OD, data selected from the free base): 0.80 (3 H, d), 0.90 (3 H, t), 1.80 (1 H, m), 2.20 (1 H , m), 2.40 (1 H, m), 2.90 (1 H, m), 6.95 (1 H, d) and 7.10-7.20 (2H, m) ..}. MS (Electrospray): M / Z (MH +) 329.2, C20H32N4 + H requires 329.3.

EXAMPLE 16 Trans- (±) -2- (trifluoromethyl) -5-ri- (3-phenylpropyl) -3,4-d-methyl-4-piperidn-n-n- 1H-benzimidazole A solution of trans- (±) -2- (trifluoromethyl) -5- (3,4-dimethyl-4-piperidinyl) -1H-benzimidazole (preparation 11, 100 mg, 0.34 mmol) in N was treated, N-dimethylformamide (3 ml) with sodium bicarbonate (45 mg, 0.54 mmol) and then 1-bromo-3-phenylpropane (82 μl, 108 mg, 0.54 mmol). The reaction was heated at 80 ° C for 6 hours and the solvent was removed in vacuo. The residue was partitioned between dichloromethane and water. It was dried (Na 2 S 4) and the organic solvent was removed by evaporation in vacuo. The residue was chromatographed on a 230-400 Merck silica gel (5 g) using a gradient of ethyl acetate: hexane: ammonium hydroxide (39: 60: 1 to 49: 50: 1) to provide the benzimidazole in the form of an oil. 5 H NMR (300 MHZ, CDCl 3, data from the free base): 0.70 (d, 3H), 1, 40 (s, 3H) and 7.10-7.30 (m, 8H). MS (Thermospray): M / Z (MH +) 416.2, C24H28F3N3 + H requires 416.5.

EXAMPLE 17 T? Ans- (±) -2- (trifluoromethyl) -5-p- (2-phenoxyethyl) -3,4-d, methyl-4-piperidinip-1H-benzimidazole A solution of trans- (±) -2- (trifluoromethyl) -5- (3,4-dimethyl-4-piperidinyl) -1H-benzimidazole (preparation 11, 50 mg, 0.17 mmol) was treated in N, N-dimethylformamide (2 ml) with sodium bicarbonate (23 mg, 0.27 mmol) and then -bromofenetol (38 mg, 0.19 mmol). The reaction was heated at 60 ° C for 6 hours and stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue was partitioned between dichloromethane and water. It was dried (Na 2 S 4) and the organic solvent was removed by evaporation in vacuo. The residue was chromatographed on 230-400 Merck silica gel (5 g) using a gradient of ethyl acetate: hexane: ammonium hydroxide (0: 99: 1 to 49: 50: 1) to provide benzimidazole (20 mg ) in the form of an oil. 6 H NMR (300 MHZ, CDCl 3, selected data from the free base): 0.70 (d, 3 H), 1, 30 (s, 3 H), 3.50 (m, 1 H), 4.10 (m, 2H), 4.20 (m, 1 H), 6.60 (m, 2H), 6.90 (m, 4H) and 7.30 (m, 2H). MS (Thermospray): M / Z (MH +) 418.4, C23H26F3N3O + H requires 418.5.

EXAMPLE 18 Trans- (±) -2- (trifiuoromethyl) -5-ri- (3-methylphenethyl) -3,4-dimethyl-4-piperidin-1H-benzimidazole A solution of trans- (±) -2- (trifluoromethyl) -5- (3,4-dimethyl-4-piperidinyl) -1H-benzimidazole (preparation 11.51 mg, 0.17 mmol) in N, N was treated. dimethylformamide (2 ml) with sodium bicarbonate (28 mg, 0.33 mmol) and then 1- (2-bromoetyl) -3-methylene benzene (37 mg, 0.19 mmol). The reaction was heated at 60 ° C for 24 hours. The reaction mixture was cooled to room temperature and partitioned between dichloromethane (10 ml) and water (10 ml). The organic layer was dried (Na 2 SO 4) and filtered and the solvent was removed in vacuo. The residue was chromatographed on a 230-400 Merck silica gel (5 g) using a gradient of ethyl acetate: hexane: ammonium hydroxide (10: 89: 1 to 50:49: 1) to provide the benzimidazole (5 mg ) in the form of an oil. 6H NMR (300 MHz, CDCI3, selected data from the free base): 0.80 (m, 3H), 1, 30 (s, 3H), 2.30 (s, 3H), 3.40 (t, 1 H), 6.60 (m, 2H), 7.00 ( m, 3H) and 7.10-7.20 (m, 2H). MS (Thermospray): M / Z (MH +) 416.4, C24H28F3N3 + H requires 416.5.

EXAMPLE 19 Trans-f ±) -5- (1-benzyl-3,4-dimethyl-4-piperidin-1H-benzimidazole A solution of trans- (±) -N- [2-amino-5- (1-benzyl-3,4-dimethyl-4-piperidinyl) phenyl] formamide was heated to reflux (preparation 14, 98 mg , 0.29 mmol) in formic acid (11 ml) for 6 hours, and made alkaline by the addition of a 2 N sodium hydroxide solution. The aqueous layer was washed with ethyl acetate (30 ml) and the layer was dried organic (Na2S? 4) and concentrated in vacuo. The residue was chromatographed on Merck silica gel 230-400 mesh (10 g) using methanol: dichloromethane: ammonium hydroxide (10: 89: 1) as eluent to give the benzimidazole (72 mg) as an oil. 5 H NMR (300 MHz, CDCl 3, data from the free base): 0.70 (d, 3H), 1, 40 (s, 3H), 2.40 (d, 2H), 2.50 (s, 2H) ), 2.90 (m, 1 H), 3.50 (d, 1 H), 3.60 (d, 1 H), 7.20-7.40 (m, 7H) and 7.50-7 60 (m, 2H). MS (Thermospray): M / Z (MH +) 320.8, C2? H25N3 + H requires 320.5.

EXAMPLE 20 Trans-f ±) -5-ri- (2-propoxyethyl) -3,4-dimethyl-4-piperidinin-1H-benzimidazoi A solution of trans- (±) -5- (3,4-dimethyl-4-piperidinyl) -1 H -benzimidazoi (preparation 15, 30 mg, 0.13 mmol) in N, N-dimethylformamide (2 ml) was treated. ); with 2-chloro-ethi-propyl ether (17 mg, 0.14 mmol) and then 25 mg sodium bicarbonate, 0.3 mmol) and a catalytic amount of sodium iodide. The mixture was heated at 60 ° C for 6 hours. The reaction mixture was partitioned between a solution of sodium bicarbonate (10 ml) and diethyl ether (10 ml). The separated organic phase was dried (Na 2 S 4) and concentrated in vacuo. The title compound was purified by preparative HPLC on a Phenomenex Magellen ™ column, 150 mm x 21 mm, flow 20 ml.min -1, using UV detection at 220 nm, eluent acetonitrile: 0.1 M aqueous ammonium acetate (30 mL). : 70 to 95: 5, over 10 minutes) MS (Thermospray): M / Z (MH +) 316.3, C19H29N3O + H requires 316.5.

EXAMPLE 21 Trans- (± -5-p- (5-methyl-hexyl) -3,4-dimethyl-4-piperidinin-1H-benzimidazole A solution of trans- (±) -5- (3,4-dimethyl-4-piperidinyl) -1H-benzimidazole (preparation 15, 30 mg, 0.13 mmol) in N, N-dimethylformamide was treated. (2 ml); with 1-bromo-5-methylhexane (25 mg, 0.14 mmol), followed by sodium bicarbonate (25 mg, 0.3 mmol). The mixture was heated at 60 ° C for 6 hours. The reaction mixture was partitioned between a saturated solution of sodium bicarbonate (10 ml) and diethyl ether (10 ml). The separated organic phase was dried (Na2S?) And the solvent was removed by evaporation in vacuo. The title compound was purified by preparative HPLC on a Phenomenex Magellen ™ column, 150 mm x 21 mm, flow 20 ml.min -1, using UV detection at 220 nm, eluent acetonitrile: 0.1 M aqueous ammonium acetate (30 mL). : 70 to 95: 5, over 10 minutes) MS (Thermospray): M / Z (MH +) 328.3, C2? H33N3 + H requires 328.5.

EXAMPLE 22 Trans- (±) -2- (difluoromethyl) -5- (1-benzyl-3,4-dimethyl-4-piperidinyl) -1H-benzimidazole A mixture of trans- (±) -4- (1-benzyl-3,4-dimethyl-4-piperidinyl) -1,2-benzenediamine (preparation 16, 2.00 g, 6.46 mmol) was heated to reflux. in difluoroacetic acid for 4 hours. The reaction mixture was cooled and diluted with water (50 ml) and ethyl acetate (50 ml). The mixture was treated with a 2N sodium hydroxide solution and stirred until the aqueous layer became alkaline. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 x 75 ml). The combined organic phases were washed once with saturated brine (100 ml) and dried (Na 2 S 4). The solvent was concentrated in vacuo to give a brown gum (2.8 g). The residue was chromatographed on Merck silica gel 230-400 mesh (75 g) eluting with ethyl acetate: hexane (50:50). The product was collected as a yellow syrup which solidified in vacuo (2.3 g). 5 H NMR (300 MHz, CDCl 3, data from the free base): 0.75 (3H, d), 1.35 (3H, s), 3.45 (1H, d), 3.65 (1H, d), 6.85 (1 H, t), 7.20-7.40 (7H, m), 7.75 (1 H, m) and 9.85-10.05 (1 H, as). MS (Electrospray): M / Z (MH +) 370.0, C22H25F2N3 + H requires 370.2.

EXAMPLE 23 Trans- (±) -2- (difluoromethyl) -5- (1-pentyl-3,4-dimethyl-4-pyridinyl) -1H-benzimidazole A solution of trans- (±) -2- (difluoromethyl) -5- (3,4-dimethyl-4-p-peridinyl) -1H-benzimidazole was cooled to 0 ° C (preparation 17, 50 mg, 0.18 mmol) in methanol (4 ml) and treated with valeraldehyde (16 mg, 20 μl, 0.18 mmol) and sodium triacetoxyborohydride (53 mg, 0.25 mmol). The solution was allowed to warm to room temperature and was stirred for 16 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (75 ml) and a saturated solution of sodium bicarbonate (75 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 x 50 ml). The combined organic phases were dried (Na 2 S 4) and concentrated in vacuo.TM giving a clear gum. The residue was purified on silica Sep-Pak (5 g) eluting with ethyl acetate: hexane (20:80) to afford the title compound as a clear crystal (29 mg). 5H-NMR (300 MHZ, CDCI3, data from the free base): 0.70 (3H, d), 0.90 (3H, t), 1.35 (3H, s), 2.55-2.70 (2H, m), 2.95 (1 H, m), 6.85 (1 H, t), 7.35 (1 H, d) and 7.45-7.65 (2H, m). MS (Electrospray): M / Z (MH +) 350.1, C20H29F2N3 + H requires 350.2.

EXAMPLE 24 Trans- ±) -2- (difluoromethyl) -5-ri- (2-benzyloxyethyl-3,4-d »methyl-4-piperidinin-1H-benzimidazole A solution of trans- (±) -2- (difluoromethyl) -5- (3,4-dimethyl-4-piperidinyl) -1H-benzimidazole was cooled to 0 ° C (preparation 17, 50 mg, 0, 18 mmol) in methanol (4 ml) and treated with benzyloxyacetaldehyde (27 mg, 0.18 mmol) and sodium triacetoxyborohydride (53 mg, 0.25 mmol). The solution was allowed to warm to room temperature and was stirred for 16 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (75 ml) and a saturated solution of sodium bicarbonate (75 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 x 50 ml). The combined organic phases were dried (Na 2 S 4) and concentrated in vacuo to give a clear gum. The residue was purified on silica Sep-Pak ™ (5 g) eluting with ethyl acetate: hexane (20:80) to give an off white solid (32 mg). 5 H NMR (300 MHz, CDCl 3, data from the free base): 0.70 (3H, d), 1.35 (3H, s), 3.65 (2H, t), 4.55 (2H, s) ), 6.90 (1H, t), 7.20-7.35 (5H, m) and 7.40-7.75 (3H, m). MS (Electrospray): M / Z (MH +) 414.1, C24H29F2N3O + H requires 414.2.

EXAMPLE 25 Trans- (±) -2- (difluoromethyl) -5-ri- (2-phenoxyethyl) -3,4-dimethyl-4-p8peridin-1H-benzimidazole A solution of trans- (±) -2- (difluoromethyl) -5- (3,4-dimethyI-4-pyridinyl) -1H-benzimidazole was prepared at 0 ° C (preparation 17, 50 mg, 0.18 mmol) in methanol (4 ml) and treated with 2-phenoxyacetaldehyde (25 mg, 0.18 mmol) and sodium triacetoxyborohydride (53 mg, 0.25 mmol). The solution was allowed to warm to room temperature and was stirred for 16 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (75 ml) and a saturated solution of sodium bicarbonate (75 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 x 50 ml). The combined organic phases were dried (Na 2 S 4) and concentrated in vacuo to give a clear gum. The residue was purified on silica Sep-Pak ™ (5 g) eluting with ethyl acetate: hexane (20:80) to give the title compound as a white solid (19 mg). 5 H NMR (300 MHZ, CDCl 3, data from the free base): 0.75 (3H, d), 1.35 (3H, s), 4.10 (2H, t), 6.85 (1H, t), 6.80-6.95 (2H, m), 7.25-7.55 (5H, m) and 7.75 (1H, m). MS (Thermospray): M / Z (MH +) 400.1, C23H27F2N3O + H requires 400.2.

EXAMPLE 26 Trans-fD ^^ difluoromethyl-d-ri-O-phenoxypropyl-S ^ -dBmetiM-piperidinip-I H-benzimidazole A solution of trans- (±) -2- (difluoromethyl) -5- (3,4-dimethyl-4-piperidinyl) -1 H -benzimidazole was cooled to 0 ° C (preparation 17, 50 mg, 0.18 mmol) in methanol (4 ml) and treated with 3-phenoxypropanal (27 mg0.18 mmol) and sodium triacetoxyborohydride (53 mg, 0.25 mmol). The solution was allowed to warm to room temperature and was stirred for 16 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (75 ml) and a saturated solution of sodium bicarbonate (75 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 x 50 ml). The combined organic phases were dried (Na 2 SO 4) and concentrated in vacuo to give a clear gum. The residue was purified on silica Sep-Pak ™ (5 g) eluting with ethyl acetate: hexane (20:80) to give the title compound as an off-white gum (20 mg).

H NMR (300 MHZ, CDCl 3, data from the free base): 0.75 (3H, d), 1.35 (3H, s), 4.05 (2H, t), 6.90 (1H, t ), 6.85-6.95 (3H, m) and 7.20-7.40 (4H, m). MS (Electrospray): M / Z (MH +) 414.1, C24H29F2N30 + H requires 414.2.

EXAMPLE 27 Trans- (±) -2- (difluoromethyl) -5-n- (4-methylphenethyl) -3,4-dimethyl-4-piperidinip-1H-benzimidazole A solution of trans- (±) -2- (difluoromethyl) -5- (3,4-dimethyl-4-p-peridinyl) -1H-benzimidazole was cooled to 0 ° C (preparation 17, 50 mg, 0, 18 mmol) in methanol (4 ml) and treated with 2- (4-methylphenyl) acetaldehyde (24 mg, 0.18 mmol) and sodium triacetoxyborohydride (53 mg, 0.25 mmol). The solution was allowed to warm to room temperature and was stirred for 16 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (75 ml) and a saturated solution of sodium bicarbonate (75 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 x 50 ml). The combined organic phases were dried (Na2SO4) and concentrated in vacuo to give a clear gum. The residue was purified on silica Sep-Pak ™ (5 g) eluting with ethyl acetate: hexane (20:80) to afford the title compound as a light brown gum (16 mg). 5 H NMR (300 MHz, CDCl 3, selected data from the free base): 0.75 (3H, d), 1.35 (3H, s), 2.35 (3H, s), 2.95 (1H, m ), 6.90 (1 H, t), 6.95-7.05 (3H, m), 7.35 (1 H, m) and 7.75 (1 H, m). MS (Electrospray): M / Z (MH +) 398.1, C24H29F2N3 + H requires 398.2.

EXAMPLE 28 Trans- (±) -2-methyl-6- (1-hexyl-3,4-dimethyl-4-pyridinyl) -1,3-benzoxazole To a stirred solution of trans- (±) -2-amino-5- (1-hexyl-3,4-dimethyl-4-piperidinyl) phenol (preparation 19, 194 mg, 0.637 mmol), triethylamine (98 μl) was added. 0.701 mmol) and acetyl chloride (50 μl, 0.701 mmol) in xylenes (10 ml); pyridinium para-toluenesulfonate (80 mg, 0.319 mmol) and the reaction mixture was heated to reflux overnight. After cooling, the reaction mixture was diluted with water 100 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic phases were dried (Na 2 S 4), filtered and concentrated in vacuo to give the crude product which was filtered and purified by chromatography on silica gel eluting with a gradient of ethyl acetate: dichloromethane: ammonium hydroxide ( 150: 349: 1 to 200: 299: 1) to provide the title compound (117 mg) as a pale yellow oil. 5 H NMR (400 MHz, CßDβ), (data from the free base): 0.86 (m, 6H), 1.19 (s, 3H), 1, 21-1, 34 (m, 7H), 1 , 43 (m, 2H), 1.78 (m, 1 H), 2.08 (s, 3H), 2.09-2.35 (m, 4H), 2.45 (m, 2H), 2 , 68 (m, 1 H), 7.06 (dd, 1 H), 7.28 (d, 1 H) and 7.61 (d, 1 H). MS (APCI +): M / Z (MH +) 329.3, C2? H32N2Q + H requires 329.3.

EXAMPLE 29 Trans- (±) -6- (1-hexyl-3,4-dimethyl-4-piperidinyl) -1,3-benzoxazole It was added to a stirred solution of trans- (±) -2-amino-5- (1-hexyl-3,4-d-methyi-4-p-piperidin) phenol (preparation 19, 109 mg, 0.358 mmol), triethylamine (55 μL, 0.394 mmol) and triethyl orthoformate (66 μL, 0.394 mmoi) in xylenes (10 mL); pyridinium para-toluenesulfonate (5 mg, 2 mol) and the reaction mixture was heated to reflux overnight. After cooling, the reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic phases were dried (Na 2 S 4), filtered and concentrated in vacuo to give the crude product which was filtered and purified by chromatography on silica gel eluting with ammonium hydroxide: methanol: dichloromethane (1: 10: 489 ) providing the title compound (76 mg) as a pale yellow oil. 6 H NMR (400 MHZ, CßDβ), (data from the free base): 0.79 (d, 3 H), 0.86 (t, 3 H), 1, 15 (s, 3 H), 1, 23-1 , 33 (m, 7H), 1, 46 (m, 2H), 1.75 (m, 1 H), 2.06-2.31 (m, 4H), 2.39 (m, 2H), 2 , 66 (m, 1 H), 7.02 (dd, 1 H), 7.29 (m, 2H) and 7.66 (d, 1 H). MS (APCI +): M / Z (MH +) 315.3, C20H30N2O + H requires 315.2.

EXAMPLE 30 Trans- (±) -2-ethyl-6- (1-hexyl-3,4-dimethyl-4-piperidinyl) -1,3-benzoxazole To a stirred solution of trans- (±) -2-amino-5- (1-hexyl-3,4-dimethyI-4-piperidinyl) phenol (preparation 19, 145 mg, 0.476 mmol), triethylamine (73 μl) was added. , 0.524 mmol) and propionyl chloride (46 μl, 0.524 mmol) in xylenes (10 ml); pyridinium para-toluenesulfonate (4 mg, 2 mol) and the reaction mixture was heated to reflux for 120 hours. After cooling, the reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic phases were dried (Na 2 S 4), filtered and concentrated in vacuo to give the crude product which was filtered and purified by chromatography on silica gel eluting with ammonium hydroxide: methanoi: dichloromethane (1: 10: 489 ) providing the title compound (89 mg) as a pale yellow oil. NMR dp (400 MHz, CßDβ), (data selected from the free base): 0.85 (m, 6H), 1.12 (t, 3H), 1, 20 (s, 3H), 1, 22-1, 36 (m, 7H), 1.44 (m, 2H), 1 , 79 (m, 1H), 2.09-2.36 (m, 4H), 2.45 (m, 2H), 2.52 (q, 2H), 2.69 (m, 1 H), 7 , 04 (dd, 1 H), 7.30 (d, 1 H) and 7.64 (d, 1 H). MS (APCI +): M / Z (MH +) 343.3, C2? H34N2O + H requires 343.3.

EXAMPLE 31 Trans- (±) -6- (1-hexyl-3,4-dimethyl-4-piperidinyl) -1,3-benzoxazole-2 (3H) -one It was added to a stirred solution of trans- (±) -2-amino-5- (1-hexyl-3,4-dimethyl-4-piperidinyl) phenol (preparation 19, 183 mg, 0.601 mmol) in N, N-dimethylformamide (3 ml); 1,1 '-carbonyldiimidazole (107 mg, 0.661 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with a saturated aqueous sodium bicarbonate solution (100 ml) and extracted with dichloromethane (3 x 100 ml). The combined extracts were washed with brine (100 ml), dried (Na 2 SO 4), filtered and concentrated in vacuo to give the crude product which was purified by chromatography on silica gel eluting with a gradient of methanol: dichloromethane: Ammonium hydroxide (10: 489: 1 to 15: 484: 1) to provide the title compound (82 mg) as a pale yellow oil. 6H-NMR (400 MHZ, CßDβ), (data from the free base): 0.81 (d, 3H), 0.85 (t, 3H), 1, 10 (s, 3H), 1, 23-1 , 30 (m, 7H), 1.44 (m, 2H), 1.67 (m, 1H), 2.07-2.45 (m, 6H), 2.72 (m, 1H), 6, 62 (d, 1 H), 6.76 (dd, 1 H), 6.90 (d, 1 H) and 8.15 (as, 1H). MS (APCf): M / Z (MH +) 331, 3, C2? H30N2O + H requires 331, 2.

Preparation of starting materials PREPARATION 1 Trans- (±) -N-r3- (1-hexyl-3,4-dimethyl-4-p-peridinyl) phenynacetamide It was added dropwise to a stirred solution of trans- (±) -3- (1-hexyl-3,4-dimethyl-4-piperidinyl) aniline (preparation 23, 2.0 g, 6.93 mmoi) in dichloromethane (56 ml) and triethylamine (14 ml); Acetyl chloride (0.988 ml, 1.09 g, 13.9 mmol). The cloudy orange mixture was stirred for 60 hours at room temperature and the reaction was partitioned between a saturated solution of sodium bicarbonate (50 ml) and dichloromethane (100 ml). The organic phase was washed with brine (50 ml) and both aqueous phases were extracted with dichloromethane. The combined extracts were dried (MgSO 4) and concentrated in vacuo. The crude residue was chromatographed on a Merck 230-400 silica gel (25 g) using ethyl acetate: 0.5 N ammonium in dioxane (98: 2) as eluent to give the amide (2.30 g) as a an orange oil NMR dH (300 MHz, CDCl 3) (data selected): 0.80 (3H, d), 0.90 (3H, t), 2.15 (3H, s) and 7.0-7.4 (4H, m). MS (Thermospray): M / Z (MH +) 331, 6, C21H34N2O + H requires 331, 3.

PREPARATION 2 Trans- (±) -N-r2-nitro-5- (1-hexyl-3,4-dimethyl-4-piperidinyl) phenynacetamide It was added in portions to a solution of trans- (±) - N- [3- (1-hexyl-3,4-dimethyl-4-piperidinyl) phenyl] acetamide (preparation 1, 2.29 g, 6.93 mmol) in dry acetonitrile (45 ml), cooled in an ice bath; nitronium tetrafluoroborate (1.1 g, 7.62 mmol). The reaction was stirred for 45 minutes and TLC (silica plate eluted with ethyl acetate) showed that starting material remained. An additional portion of nitronium tetrafluoroborate (0, 55 g, 3.81 mmol) and the reaction was stirred for another 30 minutes, this procedure was repeated again (two equivalents in total). The mixture was then poured into a saturated aqueous solution of sodium bicarbonate (50 ml) and extracted with ethyl acetate (50 ml). The organic phase was washed with brine (50 ml) and both aqueous phases were extracted with ethyl acetate (50 ml). The combined extracts were dried (MgSO4) and concentrated in vacuo. The crude residue was chromatographed on a 230-400 Merck silica gel (25 g) using ethyl acetate as the eluent to give the nitrophenylacetamide (1.43 g) as an orange semisolid. 6 H NMR (300 MHz, CDCl 3) (data selected): 0.80 (3H, d), 0.90 (3H, t), 1.30 (3H, s), 2.30 (3H, s), 7 , 1 (1H, d), 8.15 (1H, d), 8.80 (1H, s) and 10.4 (1H, as). MS (Thermospray): M / Z (MH +) 376.9, C2? H33N3O3 + H requires 376.6.

PREPARATION 3 Trans- (± -N-r2-amino-5-1-hexyl-3,4-dimethyl-4-piperidinyl) phenyl-1-acetamide A solution of trans- (±) - N- [2-nitiO-5- (1-hexyl-3,4-dimethyl-4-piperidinyl) phenyl] acetamide was subjected to hydrogenation (preparation 2, 1, 43 g, 3 , 81 mmol) and 10% palladium on carbon (175 mg) in methanol (34 ml) in a pump at a pressure of 415 kPa and room temperature for 48 hours. The mixture was filtered and the filtrate was concentrated in vacuo affording acetamide (1.4 g) as a yellow semi-solid. 5 H NMR (300 MHZ, CDCl 3) (data selected): 0.80 (3H, s), 0.90 (3H, t), 2.20 (3H, s) and 6.75-7.20 (4H, m). MS (Thermospray): M / Z (MH +) 345.3, C21H34N3O + H requires 346.5.

PREPARATION 4 Trans- (±) -2-ntr-5- (1-hexyl-3,4-dimethyl-4-piperidinyl) aniline A solution of trans- (±) -N- [2-nitro-5- (1-hexyl-3,4-dimethyl-4-piperidinyl) phenyl) was heated at 100 ° C for 15 minutes. acetamida (preparation 2, 1.81 g, 4.82 mmol) in Claisens base (5 ml) (17.6 g of KOH in 12.6 ml of water made up to 50 ml with methanol). Hot water (5 ml) was added and the mixture was heated for another 15 minutes. The reaction was cooled and the methanol was removed in vacuo. The reaction was partitioned between ethyl acetate (50 ml) and water (50 ml) and the separated aqueous layer was extracted with ethyl acetate (50 ml). The combined organic phases were washed with brine (50 ml), dried (MgSO 4) and concentrated in vacuo to give the crude nitroaniline (1.23 g) as an orange oil. 5 H NMR (300 MHZ, CDCl 3) (data selected): 0.80 (3H, s), 0.90 (3H, m), 6.10 (2H, as), 6.60 (1H, s), 6 , 65 (1H, d) and 8.05 (1 H, d). MS (Thermospray): M / Z (MH +) 334.3, C19H30N3O2 + H requires 334.5.

PREPARATION 5 Trans- (±) -4- (1-hexyl-3,4-dimethyl-4-piperidinyl M.2-benzenediamine A solution of trans- (±) -2-nitro-5- (1-hexyl-3,4-d.methyl-4-piperidinyl) aniline was subjected to hydrogenation (preparation 4, 1, 23 g, 3.69 mmol ) and 10% palladium on carbon (151 mg) in ethanol (20 ml), in a pump at a pressure of 415 kPa at room temperature for 48 hours. The mixture was filtered through Celite (R), washed with methanol and the filtrate was concentrated in vacuo to give the diamine as a dark brown oil. This compound was very sensitive to oxidation by air and was stored cold in an inert atmosphere. 6 H NMR (300 MHZ, CDCl 3) (data selected): 0.80 (3H, d), 0.90 (3H, m) and 6.65 (3H, a s). MS (Thermospray): M / Z (MH +) 304.6, C19H33N3 + H requires 304.5.

PREPARATION 6 Trans- (±) -2-vodo-5- (1-hexyl-3,4-dimethyl-4-piperidinyl) aniline It was added to a solution of trans- (±) -3- (1-hexyl-3,4-dimethyl-4-piperidinyl) aniline (preparation 23, 272 mg, 0.94 mmol) in glacial acetic acid (5 ml); iodine (478 mg, 1.89 mmol) and the reaction was stirred overnight. A saturated solution of potassium bicarbonate was added until the effervescence stopped and the mixture was diluted with dichloromethane: methanol (100 ml, 10: 1). The separated organic layer was washed with a saturated solution of sodium thiosulfate and then brine. The organic layer was dried (MgSO 4) and concentrated in vacuo. The residue was chromatographed on 230-400 Merck silica gel using dichloromethane: ethanol: ammonium hydroxide (200: 8: 1) as eluent to provide iodoaniline (88 mg) as a yellow oil. 5 H NMR (300 MHz, CDCl 3) (data selected): 0.80 (3H, s), 0.90 (3H, m), 4.00 (2H, as), 6.45 (1H, d), 6.70 (1 H, s) and 7.50 (1 H, d). MS (Thermospray): M / Z (MH +) 415.4, C? 9H3? IN2 + H requires 415.4. 7é PREPARATION 7 Trans- (±) -2-r2- (trimethylsilyl-ethynyn-5- (1-hexyl-3,4-dimethyl--piperidinyl) aniline It was added to a solution of trans- (±) -2-iodo-5- (1-hexyl-3,4-dimethyl-4-piperidinyl) aniline (preparation 6, 271 mg, 0.656 mmol) in triethylamine (10 ml) under a nitrogen atmosphere at room temperature; b1s (triphenylphosphine) palladium (II) chloride (23 mg, 33 μmol) and copper (I) iodide (6.2 mg, 33 μmol). Trimethylsilylacetylene (120 μl, 84 mg) was added0.84 mmol) and the mixture was heated at 60 ° C overnight. The cooled reaction was diluted with ethyl acetate (50 ml), filtered through a pad of Celite (R) and the filtrate was washed with brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on a 230-400 Merck silica gel using dic [oromethane: ethanol: ammonium hydroxide (300: 8: 1) as eluent to give trimethylisilylaniline (211 mg) as an oil. 5 H NMR (300 MHz, CDCl 3) (data selected): 0.10 (9H, s), 0.80 (3H, s), 0.90 (3H, m), 4.20 (2H, a s), 6.60 (2H, m) and 7.20 (1 H, d). MS (Cl): M / Z (MH +) 385.2, C24H40N2S + H requires 385.7.

PREPARATION 8 Trans- (±) -N-r3- (1-benzyl-3,4-dimethyl-4-piperidin5l) pheninacetamda It was added dropwise to a stirred solution of trans- (±) -3- (1-benzyl-3,4-dimethyl-4-piperidinyl) aniline (preparation 27, 37.4 g, 0.15 mol) and triethylamine (70 ml, 0.50 mol) under a nitrogen atmosphere; acetyl chloride (17.4 ml, 0.244 mol). The reaction mixture was stirred for 12 hours at room temperature and then washed with a saturated solution of sodium bicarbonate (200 ml), which was back extracted with dichloromethane. The combined organic phases were dried (MgSO 4) and concentrated in vacuo to give a black oil (43 g). The crude oil was chromatographed on Merck silica gel 230-400 mesh (1 kg) using a gradient of CH2Cl2: ethyl acetate: ammonium hydroxide (60: 38: 2 to 0: 98: 2) affording acetamide (22). g) in the form of a brown foam. 5 H NMR (300 MHz, CDCl 3, selected data): 0.80 (d, 3H), 1, 30 (s, 3H), 2.15 (s, 3H), 3.50 (m, 2H) and 7, 00-7.40 (m, 9H). MS (Thermospray): M / Z (MH +) 337.1, C22H28N2O + H requires 337.2.

PREPARATION 9 Trans- (±) -N-f2-nitro-5- (1-benzyl-3,4-dimethyl-4-piperidinyl) phenynacetamide A cooled (0 ° C) solution of trans- (±) -N- [3- (1-benzyl-3,4-dimethyl-4-piperidinyl) phenyl] acetamide was degassed five times (preparation 8, 3.7 g, 11 mmol) in acetonitrile (100 ml) was removed by evacuation and then stirred under a nitrogen atmosphere. Nitronium tetrafluoroborate (95%, 2.4 g, 16.6 mmol) was added in portions and the reaction was stirred under nitrogen for 2 hours. The reaction was poured into a saturated solution of sodium bicarbonate (100 ml) and extracted with ethyl acetate (150 ml). The separated organic phase was dried (MgSO 4) and concentrated in vacuo. The residue was chromatographed on a 230-400 Merck silica gel (150 g) using a gradient of hexane: ethyl acetate: ammonium hydroxide (50: 49: 1 to 0: 99: 1) to provide the product (2, 2 g) in the form of an oil. 5 H NMR (300 MHz, CDCl 3, data from the free base): 0.80 (d, 3H), 1, 30 (s, 3H), 2.30 (s, 3H), 3.40 (d, 1 H), 3.60 (d, 1 H), 7.10 (d, 1 H), 7.20-7.40 (m, 5H), 8.10 (m, 1H) and 8.80 (m) , 1 HOUR). MS (Thermospray): M / Z (MH +) 384.5, C22H27N303 + H requires 382.5.

PREPARATION 10 Trans- (±) -2-nitro-5- (1-benzyl-3,4-dimethyl-4-piperidinyl) aniline A mixture of Claisens base (5 ml) (prepared from KOH (17.6 g) dissolved in water (12.6 ml) and diluted to 50 ml with methanol) and trans is heated in a steam bath for 30 minutes. - (±) -N- [2-Nitro-5- (1-benzyl-3,4-dimethyl-4-piperidinyl) phenyl] acetamide (preparation 9, 2.20 g, 5.77 mmol). Water (5 ml) was added and the reaction mixture was heated for another 15 minutes. The reaction was cooled to room temperature and the methanol was removed by evaporation in vacuo. The residue was partitioned between water (15 ml) and dichloromethane (15 ml). The organic phase was then separated, dried (Na 2 SO 4) and the solvent was removed by evaporation in vacuo. The residue was chromatographed on 230-400 Merck silica gel (75 g) eluting with a gradient of hexane: ethyl acetate: ammonium hydroxide (49: 50: 1 to 0: 99: 1), followed by ethyl acetate. ethyl: ethanol: ammonium hydroxide (89: 10: 1) to give the product (1.2 g) as an oil. 5 H NMR (300 MHz, CDCl 3, data from the free base): 0.80 (d, 3H), 1.30 (s, 3H), 3.40 (d, 1 H), 3.60 (d, 1H), 6.00 (ss, 2H), 6.60 (m, 2H), 7.20-7.40 (m, 5H) and 8.00 (d, 1H). MS (Thermospray): M / Z (MH +) 340.3, C2oH25N3O2 + H requires 340.4.

PREPARATION 11 Trans- (±) -2- (trifluoromethyl) -5- (3,4-dimethyl-4-piperidinip-1H-benzimidazole A solution of trans- (±) -2-nitro-5- (1-benzyl-3,4-dimethyl-4-piperidinyl) aniline (preparation 10, 1, 1 g, 2.24 mmol) in diethyl ether was treated. (3 ml); with pyridine (0.18 ml, 2.24 mmol). The reaction was then cooled to 0 ° C and trifluoroacetic acid (0, 3 ml, 3.24 mmol). Stirring was continued under a nitrogen atmosphere for 18 hours (during which time the reaction had warmed to room temperature) and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (20 ml) and washed with water (3 x 20 ml). The organic layer was dried (Na 2 SO 4) and the solvent was removed in vacuo to give the crude product (1.3 g) as an orange oil. (MS (Thermospray): M / Z (MH +) 436.7, C22H24N3F3? 3 + H requires 435.5).

This was dissolved in methanol (14 ml) and 10% palladium on carbon was added (Degussa E101, 168 mg). The reaction mixture was hydrogenated at a temperature of 60 ° C, pressure 415 kPa, for 18 hours, after which it was filtered through a filtering agent to remove the catalyst and the solvent was removed by evaporation under vacuum to provide the product gross in the form of a reddish brown crystalline solid. This was used directly in the next step without further purification. 6H-NMR (300 MHZ, CDCI3, data from the free base): 0.90 (d, 3H), 1.40 (s, 3H), 1.80-2.40 (m, 5H), 3.10 (m, 2H) and 6.50-6.70 (m, 3H). MS (Thermospray): M / Z (MH +) 298.3, C15H18F3N3 + H requires 298.3.

PREPARATION 12 Trans- (±) -N-f3- (1-benzyl-3,4-dimethyl-4-piperidinyl) fenipformamide Oxalyl chloride (1.48 ml, 2.16 g, 17 mmol) in dichloromethane (9 ml) was added dropwise to an ice-cold solution of imidazole (1.16 g, 17 mmol), triethylamine (4, 71 ml, 3.43 g, 34 mmol) and formic acid (0.65 ml, 0.78 g, 17 mmol) in dichloromethane (27 ml). The reaction was stirred at room temperature for 15 minutes, at which time a white precipitate was observed, and a solution of trans- (±) -3- (1-benzyl-3,4-d) was added dropwise. methyl-4-p-peridinyl) aniline (5.0 g, 17.0 mmol) in dichloromethane (10 ml). The reaction was then stirred at room temperature overnight, filtered to remove the triethylamine hydrochloride and the filtrate was washed with a saturated solution of sodium bicarbonate (30 ml), water (20 ml) and brine (10 ml). The solvent was removed in vacuo and the crude residue (5 g) was chromatographed on Merck silica gel 230-400 mesh (150 g) using a gradient of hexane: ethyl acetate: ammonium hydroxide (50: 49: 1 a). 25: 74: 1) providing the formamide (2.4 g) in the form of an oil. 6 H NMR (300 MHz, CDC b, data selected from a mixture of diastereoisomers): 0.79 (3 H, d), 1.33 (3 H, s), 3.45 (1 H, d), 3.60 (1 H, d), 6.90-7.50 (9H, m), 8.40 (0.5H, s) and 8.64 (0.5H, d). MS (Cl): M / Z (MH +) 323.2, C2? H26N2O + H requires 323.4.

PREPARATION 13 Trans- (±) -N-r2-nitro-5- (1-benzyl-3,4-dimethyl-4-piperidinyl) pheninformamide It was added to a stirred solution of trans- (±) -N- [3- (1-benzyl-3,4-dimethyl-4-pyridinyl) phenyl] formamide (preparation 12, 2.35 g, 7.3 mmol) in dry acetonitrile (45 ml) at 0 ° C; nitronium tetrafluoroborate (1.07 g, 8.03 mmol) in portions for 5 minutes under nitrogen atmosphere. After 1 hour, TLC (silica plate eluted with hexane: ethyl acetate: ammonium hydroxide, 50: 49: 1) showed incomplete reaction, so that another part of nitronium tetrafluoroborate (503 mg, 4.01) was added. mmol). After another hour, the reaction was poured into a saturated solution of sodium bicarbonate and extracted with ethyl acetate (2 x 50 ml). The combined extracts were washed with saturated brine (30 ml), dried (MgSO 4) and evaporated in vacuo. The crude product (3 g) was chromatographed on Merck silica gel 230-400 mesh (90 g) using a gradient of hexane: ethyl acetate: ammonium hydroxide (50: 49: 1 to 0: 99: 1) to provide the nitrophenylformamide in the form of a brown gum (1.1 g). 5 H NMR (300 MHz, CDCl 3, data selected from a mixture of diastereomers): 0.80 (3H, d), 1.35 (3H, s), 3.45 (1H, d), 3.59 (1 H, d), 7.10-7.40 (7H, m), 8.20 (1H, d), 8.60 (0.5, as) and 8.80 (0.5H, as). MS (Cl): M / Z (MH +) 368.0, C2? H25N303 + H requires 367.5.

PREPARATION 14 Trans- (±) -N-r2-amino-5- (1-benzyl-3,4-dimethyl-4-piperidinyl) fenipformamide It was added to a solution of trans- (±) -N- [2-nitro-5- (1-benzyl-3,4-dimethyl-4-piperidinyl) phenyl] formamide (preparation 13, 164 mg, 0.42 mmol ) in water: ethanol (15:85, 25 ml); iron powder (213 mg, 3.8 mmol) together with calcium chloride (24 mg, 0.21 mmol). The reaction was refluxed for 2 hours and the solvent was removed by evaporation in vacuo. The residue was partitioned between dichloromethane (25 ml) and water (25 ml). The aqueous layer was extracted with dichloromethane (3 x 10 ml). The combined organic phases were dried (Na 2 SO 4) and the solvent was removed by evaporation in vacuo. The residue was chromatographed on 230-400 Merck silica gel (10 g) using methanol: dichloromethane: ammonium hydroxide (10: 89: 1) as eluent to give the aminophenylformamide as a pale yellow foam (98 mg). 6H NMR (300 MHz, CDCI3, data selected from the free base): 0.80 (d, 3H), 1, 30 (s, 3H), 3.40 (d, 1 H), 3.60 (d, 1 H), 6 , 70 (t, 1H), 6.90-7.0 (m, 2H), 7.10-7.30 (m, 3H) and 8.40 (m, 1 H). MS (Thermospray): M / Z (MH +) 338.6, C21H27N3O + H requires 338.5.

PREPARATION 15 Trans- (±) -5- (3,4-dimethyl-4-piperidinyl) -1H-benzimidazole It was added to a solution of trans- (±) -5- (1-benzyl-3,4-dimethyl-4-piperidinyl) -1H-benzimidazole (preparation 19, 644 mg, 2.02 mmol) in methanol (10 ml. ); 10% carbon palladium (Degussa E101, 113 mg) and the reaction mixture was hydrogenated at 60 ° C and a pressure of 415 kPa for 40 hours. The reaction mixture was filtered through a filter agent to remove the catalyst. The solvent was removed by evaporation in vacuo and the crude product (240 mg) was used directly in the next step without further purification. 6H NMR (300 MHZ, CDCI3, data selected from the free base): 0.70 (d, 3H), 1, 40 (s, 3H), 7.0-7.40 (m, 3H) and 8.00 (d, 1H). MS (Thermospray): M / Z (MH +) 230.1, C14H19N3 + H requires 230.3.

PREPARATION 16 Trans- (±) -4- (1-benzyl-3,4-dimethyl-4-piperidinylM, 2-benzenediamine A solution of trans- (±) -2-nitro-5- (1-benzyl-3,4-dimethyl-4-piperidinyl) -aniline (preparation 10, 5.8 g, 17.1 mmol) in ethanol was treated. (300 ml) with iron powder (8.6 g, 153.9 mmol), calcium chloride (950 mg, 8.55 mmol) and water (88 ml). The reaction was refluxed for 5 hours. Another part of iron (4.3 g) and calcium chloride (475 mg) were added, and the reaction was allowed to reflux for another 3 hours. The reaction was cooled and filtered through a pad of Celite ^. The reaction mixture was concentrated in vacuo and the residue was partitioned between dichloromethane (150 ml) and water (150 ml). The organic layer was separated and the aqueous layer was extracted with dichloromethane (3 x 75 ml). The combined organic phases were dried (Na 2 S 4) and concentrated in vacuo to give a dark foam (4.32 g). 5 H NMR (300 MHz, CDCb, data selected from the free base): 0.90 (3H, d), 1, 25 (3H, s), 3.45 (1H, d), 3.60 (1H, d), 6.55-6.70 (3H, m) and 7.15-7.25 (5H, m). MS (Thermospray): M / Z (MH +) 310.1, C20H27N3 + H requires 310.2.

PREPARATION 17 Trans- (±) -2- (difluoromethyl-5- (3,4-dimethyl-4-piperidin!) - 1H-benzimidazoi A solution of trans- (±) -2- (difluoromethyl) -5- (1-benzyl-3,4-dimethyl-4-piperidinyl) -1H-benzimidazole (Example 22.2) was treated. , 99 g, 5.41 mmol) in ethanol (80 ml) with palladium on 10% activated carbon (100 mg), and hydrogenated at 50 ° C for 72 hours. The reaction mixture was allowed to cool and the catalyst was removed by filtration through a pad of Celite (R), which was washed well with ethanol. The solution was concentrated in vacuo to give a yellow foam (1.36 g). 6H-NMR (300 MHZ, CDCb, data from the free base): 0.65 (3H, d), 1.45 (3H, s), 6.90 (1H, t), 7.35 (1H , d), 7.55 (1 H, s) and 7.65 (1 H, d). MS (Electrospray): M / Z (MH +) 280.1, C? 5H? 9F2N3 + H requires 280.2.

PREPARATION 18 Trans- (±) -2-nitro-5- (1-hexyl-3,4-dimethyl-4-piperidinyl) phenol It was added to a stirred solution of trans- (±) -3- (1-hexyl-3,4-d.methyl-4-p.peridinyl) -phenol (preparation 20, 2.88 g, 9.96 mmol) in acetonitrile (85 ml) at 0 ° C, a solution of nitronium tetrafluoroborate (1.59 g, 12.0 mmol) in acetonitrile (15 ml). After 2 hours the reaction mixture was diluted with aqueous sodium bicarbonate (100 ml) and extracted with ethyl acetate (3 x 100 ml). The combined extracts were washed with brine (100 ml), dried (Na S 4), filtered and concentrated in vacuo to give the crude product which was purified by chromatography on silica gel eluting with methanol: dichloromethane: ammonium (10: 489: 1) to provide the title compound (1.07 g) as a yellow oil. 6H-NMR (400 MHZ, CßDβ, selected data from the free base): 0.71 (d, 3H), 0.87 (t, 3H), 0.92 (s, 3H), 1, 02 (m, 1H ), 1, 23-1, 32 (m, 6H), 1, 42 (m, 2H), 1, 52 (m, 1H), 1, 93 (m, 2H), 2.18 (m, 3H) , 2.33 (m, 1H), 2.55 (m, 1H), 6.28 (dd, 1 H), 6.78 (d, 1 H) and 7.62 (d, 1 H). MS (APCI +): M / Z (MH +) 335.3, C19H30N2O3 + H requires 335.2.

PREPARATION 19 Trans- (±) -2-amino-5- (1-hexyl-3,4-dimethyl-4-p-peridinophenol) It was added to a solution of trans- (±) -2-nitro-5- (1-hexyl-3,4-dimethyl-4-piperidinyl) -phenol (preparation 18, 644 mg, 1.93 mmol) in tetrahydrofuran ( 15 ml); Platinum (IV) oxide (9 mg, 39 μmol) and the reaction mixture was stirred at a pressure of 345 kPa of hydrogen gas for 10 hours. The reaction mixture was purged with nitrogen, filtered under a nitrogen atmosphere and the crude product was (typically) used directly in the subsequent reaction. On occasion, the product was purified after concentration in vacuo by chromatography on silica gel eluting with methanol: dichloromethane: ammonium hydroxide (10: 989: 1) to afford the title compound as an oil sensitive to air. NMR dH (C6D6), (data selected): 0.86 (t, 3H), 0.97 (d, 3H), 1, 24-1.32 (m, 9H), 1.45 (m, 3H) , 1.81 (m, 1 H), 2.16-2.41 (m, 5H), 2.53 (m, 1H), 2.78 (m, 1 H), 6.42-6.46 (m, 2H) and 6.64 (dd, 1H). MS (APCI +): M / Z (MH +) 305.3, C19H32N2O + H requires 305.3.

PREPARATION 20 Trans- (±) -3- (1-hexyl-3,4-dimethyl-4-piperidini-phenol) It was added to a stirred solution of trans- (±) -3- (3,4-dimethyl-4-piperidinyl) phenol (JA Werner et al., J. Org. Chem., 1996, 61, 587 , 2.0 g, 9.8 mmol) in N, N-dimethylformamide (50 ml); sodium bicarbonate (1.76 g, 20.95 mmol) and bromohexane (1.64 g, 9.9 mmol). The reaction mixture was heated to reflux for 3 hours and then cooled to room temperature. The reaction mixture was diluted with water (100 ml) and extracted with dichloromethane (4 x 50 ml). The combined extracts were washed with brine (100 ml), dried (MgSO 4), filtered and concentrated in vacuo to give the crude product. This was purified by column chromatography on silica gel (50 g) eluting with ethyl acetate: hexane: 0.880 ammonium (30: 70: 1) to afford the title compound as a light brown oil (2.68 g) . 6 H NMR (300 MHZ, CDCl 3), (data from the free base): 0.75 (d, 3 H), 0.85 (t, 3 H), 1, 15-1, 25 (m, 6 H), 1 , 3 (s, 3H), 2.0 (m, 1H), 2.35 (m, 4H), 2.6 (m, 2H) and 6.55-7.2 (m, 4H).

MS (Thermospray): M / Z (MH +) 290.2, C19H31NO + H requires 290.3.

PREPARATION 21 Trans- (±) -2-methyl-2-y3- (1-hexyl-3,4-dimethyl-4-piperidinyl) phenoxypropionamide It was added to a solution of trans- (±) -3- (1-hexyl-3,4-dimethyl-4-piperidinyl) phenol (preparation 20, 20 g, 69.2 mmol) in 1,4-dioxane (250 ml) under a nitrogen atmosphere; cesium carbonate (32.5 g, 100 mmol), carefully followed by sodium hydride (60% dispersion in mineral oil, 4 g, 100 mmol) in four portions over 30 minutes. The resulting mixture was stirred for 30 minutes, 2-bromo-2-methylpropionamide (16.6 g, 100 mmol) was added and the mixture was heated under reflux overnight. The reaction mixture was cooled, filtered and concentrated in vacuo to give the crude product, which was purified by means of column chromatography on silica gel (600 g), eluting with a gradient of ethyl acetate: hexane: 0.880 ammonium ( 30: 70: 1 to 50: 50: 1) to provide the recovered starting phenol (5.9 g), followed by the title compound as a white solid (14.3 g). 6 H NMR (300 MHz, CDCl 3), (data from the free base): 0.75 (d, 3 H), 0.85 (m, 3 H), 2.0 (m, 1 H), 2.3 (m , 4H), 2.5 (m, 2H), 2.8 (m, 1H), 5.45 (ss, 1H), 6.65 (ss, 1H) and 6.75-7.2 (m, 4H). MS (Thermospray): M / Z (MH +) 375.4, C23H38N202 + H requires 375.3.

PREPARATION 22 Trans- (±) -N-r3- (1-hexyl-3,4-dimethyl-4-piperidinyl) fenip-2-hydroxy-2-methylpropionamide It was added to a solution of trans- (±) -2-methyl-2- [3- (1-hexyl-3,4-d.methyl-4-piperidinyl) phenoxy] propionamide (preparation 21, 13.13 g, 35 mmol) in N-methylpyrrolidinone (175 ml) under nitrogen; Sodium hydride (60% dispersion in mineral oil, 4 g, 100 mmol) in four parts for 30 minutes. The resulting mixture was stirred for 30 minutes, and heated at 170 ° C overnight. The reaction mixture was cooled and carefully poured into water (200 ml) and extracted with diethyl ether (3 x 150 ml). The combined extracts were washed with water (2 x 100 ml), dried (Na 2 S 4) and concentrated in vacuo to give the title compound as an orange oil (12.9 g), which was used without further purification. . 5 H NMR (300 MHz, CDCl 3), (data selected from the free base): 0.8 (d, 3H), 0.9 (m, 3H), 2.0 (m, 1 H), 2.3 (m, 4H), 2.5 (m, 2H), 2.8 ( m, 1 H), 7.05-7.55 (m, 4H) and 8.75 (ss, 1H). MS (Thermospray): M / Z (MH +) 375.4, C23H38N2O2 + H requires 375.3.

PREPARATION 23 Trans- (±) -3- (1-hexyl-3,4-dimethyl-4-piperidinyl) aniline A solution of trans- (±) -N- [3- (1-hexyl-3,4-dimethyl-4-piperidinyl) phenyl] -2-hydroxy-2-methylpropionamide was heated at reflux overnight (preparation 22, 12.9 g, 34.3 mmol) in 1,4-dioxane: 5 N HCl (1: 1, 150 mL). The reaction mixture was cooled, diluted with water (100 ml) and extracted with diethyl ether (3 x 200 ml). The pH of the aqueous layer was adjusted to 8-9 using 5 N NaOH and extracted with dichloromethane (5 x 200 ml). The combined extracts were washed with brine (100 ml), dried (Na2SO4) and concentrated in vacuo to give the crude product, which was purified by column chromatography on silica (200 g), eluting with ethyl acetate: hexane: ammonium 0.880 (40: 60: 1), affording the title compound as a clear oil (8.8 g). 6H NMR (300 MHz, CDCI3), (data from the free base): 0.8 (d, 3H), 0.9 (m, 3H), 1.95 (m, 1 H), 2.35 (m, 4H), 2.55 (m, 2H), 2.8 ( m, 1 H), 3.6 (s, 2H) and 6.5-7.1 (m, 4H). MS (Thermospray): M / Z (MH +) 289.5, C? 9H32N2 + H requires 289.3.

PREPARATION 24 Trans- (±) -3- (1-benzyl-3,4-d-methyl-4-p-peridinophenol) It was added to a stirred solution of trans- (±) -3- (3,4-dimethyl-4-piperidinyl) phenol (JA Werner et al., J. Org. Chem., 1996, 61, 587, 2.08 g, 10.15 mmol) in N, N-dimethylformamide (50 ml); sodium bicarbonate (1.70 g, 20.3 mmol) and benzyl bromide (1.35 ml, 11.2 mmol). The reaction mixture was heated to reflux for 90 minutes. The reaction mixture was diluted with water (75 ml) and extracted with dichloromethane (100, 50 and then 25 ml). The organic fractions were dried (Na2SO4), filtered and concentrated in vacuo to give the crude product. This was purified by column chromatography on silica (70 g) eluting with ethyl acetate: hexane: 0.880 ammonium (30: 70: 1) to afford the title compound as a pale pink oil. 5 H NMR (300 MHZ, CDCl 3), (data selected from the free base): 0.8 (d, 3H), 1, 2 (s, 3H), 2.9 (d, 1H), 3.5 (d, 1 H), 3.6 (d, 1 H), 6.6 -6.9 (m, 3H), 7.1-7.4 (m, 6H). MS (Thermospray): M / Z (MH +) 296.4, C20H25NO + H requires 296.2.

PREPARATION 25 Trans- (±) -2-methyl-2-r3- (1-benzyl-3,4-d? Methyl-4-piperidinium-phenoxypropionamide) It was added to a solution of trans- (±) ~ 3- (1-benzyl-3,4-dimethyl-4-piperidinyl) phenol (preparation 24, 12.57 g, 42.6 mmol) in 1. , 4-dioxane (250 ml) under a nitrogen atmosphere; cesium carbonate (49.5 g, 152 mmol), carefully followed by anhydrous sodium hydride (4 g, 168 mmol) in four portions over 30 minutes. The resulting mixture was stirred for 1 hour, 2-bromo-2-methylpropionamide (20.5 g, 124 mmol) was added and the mixture was heated under reflux overnight. The reaction mixture was cooled, filtered and concentrated in vacuo to give the crude product, which was purified by means of column chromatography on silica gel (600 g), eluting with a gradient of ethyl acetate: hexane: 0.880 ammonium ( 25: 75: 1 to 100: 0: 1) to provide the recovered starting phenol (1.44 g), followed by the title compound as a clear solid (12.8 g). 5 H NMR (300 MHZ, CDC b), (data from the free base): 0.8 (d, 3 H), 1, 35 (s, 3 H), 1, 95 (m, 1 H), 2.35 ( m, 2H), 2.55 (m, 2H), 2.8 (m, 1 H), 3.5 (m, 2H), 5.4 (ss, 1 H), 6.65 (ss, 1 H), 6.75-7.4 (m, 9H). MS (Thermospray): M / Z (MH +) 381, 2, C24H32N202 + H requires 381, 2.

PREPARATION 26 Trans- (±) -N-r3- (1-benzyl-3,4-dimethyl-4-piperidinyl) -phenn-2-hydroxy-2-methylpropionamide It was added to a solution of trans- (±) -2-methyl-2- [3- (1-benzyl-3,4-dimethyl-4-piperidinyl) phenoxy] proponamide (preparation 25, 12.77 g, 33.6 mmol) in N, N-dimethylformamide (330 ml) under nitrogen; Anhydrous sodium hydride (1.65 g, 69 mmol) in four portions for 30 minutes. The resulting mixture was stirred for 1 hour, and then heated to reflux overnight. The reaction mixture was cooled, treated carefully with water (200 ml) and stirred for 1 hour. It was then diluted again with water (300 ml) and extracted with diethyl ether (3 x 500 ml). The combined extracts were washed with water (300 ml) and brine (300 ml), dried (Na 2 SO 4) and concentrated in vacuo to give a yellow foam (14.25 g), which was purified by means of column chromatography on silica (500 g), eluting with a gradient of ethyl acetate: hexane: 0.880 ammonium (25: 75: 1 to 30: 70: 1 to 40: 60: 1) to provide the title compound as a creamy solid ( 10.16 g). 6 H NMR (300 MHZ, CDCl 3), (data from the free base): 0.8 (d, 3H), 1.35 (s, 3H), 1.55 (m, 6H), 2.0 (m , 1 H), 2.1-2.9 (m, 6H), 3.4-3.65 (m, 2H), 7.0-7.55 (m, 9H), 8.65 (ss, 1 HOUR). MS (Thermospray): M / Z (MH +) 381.2, C24H32N2O2 + H requires 381.2.

PREPARATION 27 Trans- (±) -3- (1-benzyl-3,4-dimethyl-4-piperidini-aniline) A solution of trans- (±) -N- [3- (1-benzyl-3) was refluxed overnight., 4-dimethyl-4-piperidinyl) phenyl] -2-hydroxy-2-methylenepropionamide (preparation 26, 10.1 g, 26.5 mmol) in 1,4-dioxane: 5 N HCl (1 : 1, 200 ml). The reaction mixture was cooled and basified to pH 13 with a 10 N sodium hydroxide solution. It was then diluted with water (300 ml) and extracted with diethyl ether (3 x 300 ml). The combined extracts were washed with water (300 ml) and brine (300 ml), dried (Na2SO4) and concentrated in vacuo to give a brown oil which was purified by chromatography on a silica column (400 g), eluting with ethyl acetate. ethyl: hexane: ammonium hydroxide (25: 75: 1), affording the title compound as a golden oil (7.6 g). 6 H NMR (300 MHz, CDCl 3), (data from the free base): 0.8 (d, 3 H), 1, 3 (s, 3 H), 1.55 (m, 1 H), 1.95 ( m, 1 H), 2.25-2.6 (m, 4H), 2.85 (m, 1H), 3.4-3.7 (m, 2H), 6.45-7.4 (m , 9H). MS (Thermospray): M / Z (MH +) 295.3, C20H26N2 + H requires 295.2.

Biological Activity The Ki values of certain compounds of the present invention were determined in the opiate receptor assays, and it was found that the compounds of Examples 3, 7, 12, 18, 21 and 28 all had Ki values of 4000 nM. or smaller for the μ receiver. The compounds of the invention also possess affinity for the opiate receptors d and kappa.

Claims (28)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula I wherein Het1 represents a 5-, 6- or 7-membered heterocyclic ring containing at least one nitrogen atom, and optionally one or more heteroatoms selected from oxygen and sulfur, and said heterocyclic ring is fully saturated, partially saturated or is of a character aromatic; T represents one or more optional substituents selected from H, halogen, OH, = 0, C-? 6 alkyl, C-? 6 alkoxy, C3-6 cycloalkyl (the latter three groups are optionally substituted by one or more carbon atoms). halogen), arylalkyl (Ci-β) (the aryl portion of which is optionally substituted by one or more substituents selected from halogen, CM alkyl and alkoxy CM (the latter two groups are optionally substituted by one or more halogen atoms)), -N (R4a) (R5), -N (R4b) S (0) mR6, -N (R4c) C (0) R7a and - N (R4d) C (0) OR7b, provided that when Het1 contains less than three carbon atoms, ie when the only two carbon atoms are those provided by the condensed benzene ring) and at least one heteroatom selected from oxygen and sulfur, T does not represent halogen or Ci-β alkoxy (the latter group is optionally substituted by one or more atoms of 4a 4d 5 halogen), R a R and R independently represent H, C 1-6 alkyl (said last group is optionally substituted by one or more halogen atoms), or R 4a and R 5, together with the nitrogen atom to which they are attached , form a 4 to 6 membered heterocyclic ring (said ring is optionally substituted by one or more substituents selected from CM alkyl, alkoxy CM, OH, = 0, nitro, amino or halogen), R6 represents alkyl or aryl C -? - 6, said two groups are optionally substituted by one or more substituents selected from halogen, CM O nitro alkyl, R7a and R7b independently represent C? -6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, aryl (said four groups are optionally substituted by one or more substituents selected from halogen, CM alkyl or nitro), or R7a represents H, m is 0, 1 or 2, R1 and R2 are each independently H or C alkyl, R3 represents aryl (optionally substituted by one or more substituents selected from OH, nitro, halogen, CN, CH2CN, CONH2, alkyl CM, alkoxy CM, alkanoyl C1-5 (the latter three groups are optionally substituted by one or more halogen atoms) and -N (R8a) (R8b)) , C1-10 alkyl, C3-10 alkenyl or C3-10 alkynyl, wherein said alkyl, alkenyl or alkynyl group is optionally substituted and / or terminated by one or more substituents selected from OR8c, S (0) nR8d, CN , halogen, C6-6 alkoxycarbonyl, C2-6 alkanoyl, C2-6 alkanoyloxy, C3-8 cycloalkyl, C4-9alkanoyl, N (R9a) S (0) 2R10, Het2, aryl, adamantyl (the last two groups they are optionally substituted by one or more substituents selected from OH, nitro, amino, halogen, CN, CH2CN, CONH2, CM alkyl, CM alkoxy and C? -5 alkanoyl (the latter three groups are optionally 1 9b 9c substituted by one or more halogen atoms)), or -WA -N (R) (R), n is 0, 1 or 2, W represents a single bond, C (O) or S (0) p, A1 represents a bond encillo or alkylene d-10, provided that when W and A1 represent simple 9b 9c bonds, the group -N (R) (R) is not directly attached to an unsaturated carbon atom, p is 0, 1 or 2, R8a a R8d each independently represents, H, C? -α- alkyl, C3-10 alkenyl, C3-? Alkynyl, C3-8 cycloalkyl, alkylphenyl CM, aryl (the latter six groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halogen, CN, CH2CN, CONH2, CM alkyl, CM alkoxy and C-1-5 alkanoyl (the latter three groups are optionally substituted by one or more halogen atoms)) or Het3, provided that R8d does not represent H when n represents 1 or 2,

Qa Qc R a R each independently represents H, alkyl d-10, alkenyl C3-10, C3- [alpha] alkynyl, C3-8 cycloalkyl, alkylphenyl CM, aryl (the latter six groups are optionally substituted by one or more substituents selected from OH, nitro, halogen, CN, CH2CN, CONH2, CM alkyl, CM alkoxy and alkanoyl) C1-5 (said last three groups are optionally 4 9b 9c substituted by one or more halogen atoms)), Het, or R and R together represent a C2-6 alkylene without branches, said alkylene group being optionally interrupted by O, S , and / or a group N (R11) and is optionally substituted by one or more aiquilo groups CM, R represents C1-6 alkyl, C3-8 cycloalkyl, alkylphenyl CM or aryl, said four groups are optionally substituted by one or more substituents selected from CM alkyl, alkoxy CM, OH, nitro, amino or halogen, R11 represents H, C1-6 alkyl, C3-8 cycloalkyl, A2- (C3-8 cycloalkyl) or A2-aryl, A2 represents d6 alkylene , Het2, Het3, Het4 independently represent heterocyclic groups With 3 to 8 links, said groups contain at least one heteroatom selected from oxygen, sulfur and / or nitrogen, said groups are optionally fused to a benzene ring, and said groups are optionally substituted on the heterocyclic ring part and / or of the benzene condensed by one or more substituents selected from OH, = 0, nitro, amino, halogen, CN, aryl, alkylCM, alkoxyCM and alkanoylC? -5 (the latter three groups are optionally substituted by one or more carbon atoms) halogen), X represents one or two optional substituents on the benzene ring, said substituents are selected from halogen, alkylCM, or alkoxyCM (said last two groups are optionally substituted by one or more halogen atoms), or pharmaceutical derivatives or veterinarily acceptable of these. 2. A compound as claimed in claim 1, wherein Het1 is condensed in the 3,4 position in the benzene ring relative to the piperidine ring.

3. - A compound as claimed in claim 1 or 2, wherein R1 represents C? -2 alkyl.

4. A compound as claimed in any of claims 1 to 3, wherein R2 represents H or C? -2 alkyl.

5. A compound as claimed in any of claims 1 to 4, wherein R3 represents saturated C1-10 alkyl, optionally interrupted by oxygen and / or optionally substituted by one or more substituents selected from OR8c, CN, halogen, alkoxycarbonyl, C2-6 alkanoyl, C2-6 aanoyloxy, C3-8 cycloalkyl, C4-9 cycloalkanoyl, N (R9a) S (O) 2R10, Het2, phenyl (the latter group is optionally substituted by one or more substituents selected from OH, alkyl CM, alkoxy CM, alkanoyl C2-5, halogen, nitro, amino, CN, CH2CN, CONH2 and CF3), and / or -W-A1-N (R9b) (R9c).

6. A compound as claimed in any of claims 1 to 5, wherein R8c represents H, C1-6 alkyl, C3-cycloalkyl, phenyl or alkylphenyl CM (the latter two groups are optionally substituted by one or more substituents selected from OH, alkyl CM, alkoxy CM, C2-5 alkanoyl, halogen, nitro, amino, CN, CH2CN, CONH2 and CF3); R a R each independently represents H, C 1 -C 2 alkyl, C 2 -2 alkyl or aryl (the latter two groups are optionally substituted by one or more substituents selected from C alquilo -2 alquilo alkyl, C? -2 alco alkoxy, OH or halogen) , R10 represents alkyl or aryl CM, said two groups are optionally substituted by one or more substituents selected from C alquilo -2 alquilo alkyl, C? -2 alco alkoxy, nitro, or halogen), W represents C (O) or S (O) 2, and / or A1 represents a single bond or alkylene CM.

7. A compound as claimed in any of claims 1 to 6, wherein T represents H, OH, C1-6 alkyl (optionally substituted with one or more halogen atoms), CM alkoxy, cycloalkyl, arylalkyl ( C? -3), -NH (R5) or -N (H) S (0) 2R6, 8.- A compound as claimed in any of claims 1 to 7, wherein R5 represents H, or C-alkyl ? -2, and / or R6 represents C? -2 alkyl. 9. A compound as claimed in any of claims 1 to 8, wherein Het represents a 5- or 6-membered heterocyclic ring containing an NH group. 10. A compound as claimed in any of claims 1 to 9, wherein R1 and R2 represent both methyl groups in mutually trans configuration. 11. A compound as claimed in any of claims 1 to 10, wherein R3 represents saturated d-7 alkyl optionally substituted by one or more substituents selected from CN, halogen, 0- (CM alkyl), 0- (phenyl), 0- (alkylphenyl CM) and phenyl (the latter three groups are optionally substituted by one or more CM alkyl groups). 12. A compound as claimed in any of claims 1 to 11, wherein T represents H, NH2, cycloalkyl -6 or alkyl C-? -6 (said latter group is optionally substituted by one or more carbon atoms). halogen). 13. A compound as claimed in any of claims 1 to 8 or 10 to 12, wherein Het1, together with the benzene ring to which it is condensed, represents an aromatic heterocycle selected from benzimidazole, benzotriazole, benzoxadiazole, benzoxazole , benzothiazole, cinnoline, ndol, soquinoline, phthalazine, quinazoline, quinoline or quinoxaline. 14. A compound as claimed in any of claims 1 to 13, wherein T represents H, CH3, CHF2, CF3, ethyl, isopropyl, C4-5 cycloalkyl or NH2. 15. A compound as claimed in any of claims 1 to 14, wherein R3 represents saturated C1-10 alkyl optionally substituted by one or more substituents selected from O- (C2-4 alkyl), O- (phenyl) , O- (alkylphenyl d-2) and phenyl (said latter group is optionally substituted by one or more C 1 -2 alkyl groups. 16. A compound as claimed in any of claims 1 to 15., wherein Het1, together with the benzene ring to which it is condensed, represents a benzimidazole group. 17. A compound as defined in any of claims 1 to 16, for use as a medicament. 1

8. A compound as defined in any of claims 1 to 16, for use as an animal medicament. 1

9. A formulation comprising a compound as defined in any of claims 1 to 16, in a mixture with a pharmaceutically or veterinarily acceptable adjuvant, diluent or vehicle. 20. A formulation as claimed in claim 19, which is a veterinary formulation. 21. The use of a compound as defined in any of claims 1 to 16, in the preparation of a medicament for the curative or prophylactic treatment of a disease mediated by an opioid receptor. 22. The use as claimed in claim 21, wherein the disease is pruritus. 23. A process for the preparation of a compound as defined in claim 1, comprising: a) For compounds of formula I, in which Het1 represents the 5-membered ring of a benzimidazole, optionally substituted in the 2-position by alkyl Ci-β, alkoxy d-6, cycloalkyl C 3-6 (the latter three groups are optionally substituted by one or more halogen atoms) or arylalkyl (C 6 -6) (the aryl part of which is optionally substituted by one or more substituents selected from halogen, d-β alkyl and β-alkoxy, said last two groups being optionally substituted by one or more halogen atoms), can be prepared by reaction of a corresponding compound of formula II, wherein R, R, R "and X are as defined hereinabove, with a compound of formula III ^ -C OR 2 ^ III in which T3 represents H, C? -6 alkyl, C17-alkoxy e, C3-6 cycloalkyl (the latter three groups are optionally substituted by one or more halogen atoms) or arylalkyl (C1-6) (the aryl group of which is optionally substituted by one or more substituents selected from halogen, Ci- 6 and C6-C6 alkoxy, the latter two groups are optionally substituted by one or more halogen atoms) and R12 represents C2-2 alkyl, b) for compounds of formula I, in which Het1 represents the 5-membered ring of a benzimidazole, optionally substituted at the 2-position by Ta, where Ta is as defined hereinabove, provided that it does not represent C6-6 alkoxy or haloalkoxy d-β, a corresponding compound of formula can be prepared by reaction. II, as defined earlier herein, with a c Compound of formula XII, T ^ -C ^ OH XII or an appropriate derivative thereof, wherein Ta is as defined hereinabove, provided that it does not represent C1-6 alkoxy or C1-6 haloalkoxy, c) for compounds of formula I, in which Het1 represents the 5-membered ring of a benzimidazole, optionally substituted at the 2-position by a hydroxy group, can be prepared by reaction of a corresponding compound of formula II, as defined hereinabove, with a suitable carbonic acid derivative, d) for compounds of formula I, in which Het1 represents the 5-membered ring of a benzimidazole, substituted in the 2-position by a group N (H) S (O) 2R6, wherein R6 is as defined in claim 1, by reaction of a corresponding compound of formula II, as defined above, with a compound of formula XIII, (L2) 2C = NS (0) 2R6 XIII wherein L2 represents a group outgoing and R6 is as defined in claim 1, e) for compounds of formula I, in which Het represents the 5-membered ring of a benzimidazole, substituted in the 2-position by an amino group, can be prepared by hydrolysis of the corresponding compound of formula I in which Het1 represents the ring of 5 links of a fi-benzimidazole substituted in the 2-position by a group N (H) S (O) 2R, in which R is as defined in claim 1, f) for compounds of the formula I, in which Het1 represents the 5-membered ring of a benzotriazole, can be prepared by reaction of a corresponding compound of formula II, as defined above, with a suitable source of nitrosonium cation, g) for compounds of formula I, wherein Het1 represents the ring of 5 indole links, can be prepared by cyclization of a corresponding compound of formula XIV, wherein R1, R2, R3 and X are as defined in claim 1, h) for compounds of formula I, wherein Het1 represents the 5-membered ring of a benzoxazole or benzothiazole, optionally substituted at the 2-position by Ta, in which Ta is as defined above, can be prepared by reaction of a corresponding compound of formula XVI, wherein E represents OH or SH, and R1, R2, R3 and X are as defined in claim 1, with a compound of formula III or a compound of formula XII, as defined above, i) for compounds of formula I, in which Het1 represents the 5-membered ring of a benzoxazole or a benzothiazole, optionally substituted in the 2-position by an OH group, can be prepared by reaction of a corresponding compound of formula XVI, as defined above, with a derivative suitable carbonic acid, j) for compounds of formula I, wherein R3 represents Ci-alkyl optionally substituted by C3-C8 cycloalkyl, Het2, aryl, adamantyl, (said last two groups are optionally substituted by one or more substituents selected from OH , nitro, amino, halogen, CN, CH2CN, CONH2, alkyl CM, alkoxy CM and alkanoyl C? -5 (said last three groups are optionally substituted by one or more halogen atoms)), or R3 represents C2-? alkyl, C3-10 alkenyl or C3-20 alkynyl (said three last groups are all optionally substituted by one or more of the relevant substituents identified in claim 1 with respect to R3), said alkyl, alkenyl or alkynyl group being attached to the nitrogen of the piperidine through a CH2 group, in which Het2 it is as defined in claim 1; they can be prepared by reduction of a corresponding compound of formula XIX, wherein R31 represents H, C3-8 cycloalkyl, Het2, aryl, adamantyl (said last two groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halogen, CN, CH2CN, CONH2, C-alkyl, alkoxy CM and C 1-5 alkanoyl (said last three groups are optionally substituted by one or more halogen atoms), C 1-9 alkyl, C 2-9 alkenyl or C 2-9 alkynyl, said alkyl, alkenyl or alkynyl group is optionally substituted and / or terminated by one or more substituents selected from 0R8c, S (0) nR8d, CN, halogen, alkoxycarbonyl d-β, C2-6 alkanoyl, C2-6 alkanoyloxy, 9-10 2 C3-8 cycloalkyl, C4-9 cycloalkanoyl, N (R) S (0) 2R, Het, aryl, adamantyl (said last two groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halogen, CN, CH2CN, CONH2, CM alkyl, CM alkoxy and alkanoyl C? -5 (said last three groups are optionally substituted by one om s halogen atoms)), or -W-A1-N (R9b) (R9c), and R1, R2, R8c, R8d, R9a to R9c, R10, Het1, Het2, n, W, A1, T and X are as defined in claim 1, k) reaction a corresponding compound of formula XX, wherein Het1, R1, R2, T and X are as defined in claim 1, with a compound of formula XI, R3L1 XI wherein L1 is a leaving group and R3 is as defined in claim 1, I) for compounds of formula I, wherein R3 represents Ci-alkyl which, instead of being optionally substituted by the substituents defined in claim 1, is optionally substituted by R31, wherein R31 is as defined above; they can be prepared by reacting a corresponding compound of formula XX, as defined above, with a compound of formula XXII, R31CHO XXII wherein R31 is as defined above, m) for compounds of formula I, wherein R3 is a C?-βalkyl, alkenyl d-10 or C 4-10 alkynyl group which is fully saturated from 1-C to 3-C (relative to the N atom of piperidine), and said R 3 group is substituted at 2-C (relative to the N atom of piperidine) by S (0) R8d, S (0) 2R8d, alkanoyl, cycloalkanoyl, alkoxycarbonyl, CN, -C (0) -A1-N (R9b) (R9c), -S ( O) -A1-N (R9b) (R9c), or -S (O) 2-A1-N (R9b) (R9c), wherein R8d, R9b, R9c and A1 are as defined in claim 1; can be prepared by reaction of a corresponding compound of formula XX, as defined above, with a compound of formula XXIII R3a-Z XXIII wherein R3a represents R3 as defined in claim 1, except that 3a does not represent aryl, and the R chain contains a carbon-8d double bond additional 8d carbon a, β to the substituent Z, and Z represents S (0) R, S (0) 2R, alkanoyl, cycloalkanoyl, alkoxycarbonyl, CN, -C (0) -A1 -N (R9b) (R9c), -S (O) -A1-N (R9b) (R9c), or -S (0) 2-A1-N (R9b) (R9c), wherein R8d, R9b, R9c and A1 are as defined in claim 1, n) conversion of a functional group on an alkyl, heterocycle or aryl group in a compound of formula I to another. 24. A compound of formula II, as defined in claim 23, or a protected derivative thereof. 25. A compound of formula XIV, as defined in claim 23, or a protected derivative thereof. 26. A compound of formula XVI, as defined in claim 23, or a protected derivative thereof. 27. A compound of formula XIX, as defined in claim 23, or a protected derivative thereof. 28. A compound of formula XX, as defined in claim 23, or a protected derivative thereof.