| Title of Invention | "4-(BENZIMIDAZOLY-AND IMIDAZOPYRIDINYL) PIPERIDINE DERIVATIVES AS SUBSTANCE PANTAGONIST |
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| Abstract | This invention concerns the compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein n is 0, 1 or 2; m is 1 or 2, provided that if m is 2, then n is 1; X is a covalent bond or a bivalent radical of formula -O-, -S-, -NR3-; =Q is =O or =NR3; R1 is Ar1, Ar1C1-6alkyl or di(Ar1)C1-6alkyl wherein the C1-6alkyl group is optionally substituted; R2 is Ar2, Ar2C1-6alkyl, Het or HetC1-6alkyl; L is a benzimidazole or imidazopyridine derivative of formula (A) or (B) Ar1 is optionally substituted phenyl Ar2 is naphtalenyl or optionally substituted phenyl; and Het is an optionally substituted monocyclic or bicyclic heterocycle; as substance P antagonists; their preparation, compositions containing them and their use as a medicine. |
| Full Text | This invention concerns l-(l,2-disubstituted piperidinyl)-4-(benzimidazolyl~ and imidazopyridinyl) piperidine derivatives having tachykinin antagonistic activity, in particular substance P antagonistic activity, and their preparation; it further relates to compositions comprising them, as well as their use as a medicine. Substance P is a naturally occurring neuropeptide of the tachykinin family. There are ample studies showing that substance P and other tachykinins are involved in a variety of biological actions, and therefore, play an essential role in various disorders (Regoli et al., Pharmacological Reviews 46(4), 1994, p. 551-599, "Receptors and Antagonists for Substance P and Related Peptides"). The development of tachykinin antagonists has led to date to a series of peptide compounds of which might be anticipated that they are metabolically too labile to be employed as pharmaceutically active substances (Longmore J. et al., DN&P 8(1), February 1995, p. 5-23, "Neurokinin Receptors"). The present invention concerns nonpeptide tachykinin antagonists, in particular nonpeptide substance-P antagonists, which in general are metabolically more stable, and hence, may be more appropriate as pharmaceutically active substances. Several nonpeptide tachykinin antagonists are disclosed in the art. For instance, EP-0,532,456-A, published on March 17, 1993, discloses 1-acylpiperidine compounds, in particular 2-arylalkyM-aryIcarbonyl-4-piperidinamme derivatives, and their use as substance P antagonists. EP-O,151,824-A and EP-0,151,826-A disclose structurally related AKbenzimidazolyl-and imidazopyridinyl)-l-(l-(carbonyl or imino)-4-piperidinyl)-4-piperidinamine derivatives as histamine- and serotonine antagonists. Also l-carbonyl-4-(benzimidazolyl- and imidazopyridinyl) piperidine derivatives all having anti-histaminic and anti-allergic activity are disclosed in EP-A-232,937, EP-A-282,133, EP-A-297,661, EP-A-539,421, EP-A-539,420, WO 92/06086 and WO 93/14083. The present compounds differ from the art compounds by their structure and by their favourable pharmacological properties. Hence, the present invention concerns novel compounds of formula -2- the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochernically isomeric forms thereof, wherein n is 0, 1 or 2; m is 1 or 2, provided that if m is 2, then n is 1; X is a covalent bond or a bivalent radical of formula -O~, -S-, -NR3-; =Q is=Oor=NR3; R1 is Ar1, A^Ci-ealkyl or dKAr^Ci.galkyl wherein the Chalky] group is optionally substituted with hydroxy, C^alkyloxy, oxo or a ketalized oxo substituent of formula -O-CH2-CH2-O- or -O-CH2-CH2-CH2-O-; R2 is Ar2, Ar2Ci.6alkyl, Het or HetCi.6alkyl; L is a radical of formula wherein p is 0, 1 or 2; -Y- is a bivalent radical of formula -CH2~, -CH(OH)-, -C(=O)-, -O-, -S-, -S(=O)-( -S(=O)2-, -NR3-, -CH2-NR3- or -C(=O)-NR3-; or a trivalent radical of formula =CH-; -A=B- is a bivalent radical of formula -CH=CH-, -N=CH- or -CH=N-; R3 independently is hydrogen or Ci.^alkyl; R4 is hydrogen, Ci-ealkyl, C3_7cycloalkyl or a radical of formula -Alk-R7 (c-l)or -Alk-Z-R8 (c-2); wherein Alk is Ci-galkanediyl; Z is a bivalent radical of formula -O-, -S- or -NR3-; R7 is phenyl; phenyl substituted with 1 or 2 substituents selected from halo, Ci_6alkyl or Ci-ealkyloxy; furanyl; furanyl substituted with 1 or 2 substituents selected from Cj.galkyl or hydroxyCi-galkyl; thienyl; thienyl substituted with 1 or 2 substituents selected from halo or Ci_galkyl; oxazolyl; oxazolyl substituted with 1 or 2 Ci^alkyl substituents; thiazolyl; thiazolyl substituted with 1 or 2 Ci-ealkyl substituents; pyridinyl or pyridinyl substituted with 1 or 2 Ci.galkyl substituents; -3- R8 is Ci.galkyl or Q-ealkyl substituted with hydroxy, carboxyl or C i .galky loxycarbony I; R5 is hydrogen, halo, hydroxy or Ci-ealkyloxy; R6 is hydrogen, Ci^alkyl or A^Ci-ealkyl; Ar1 is phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, Ci-4alkyl, haloCi.4alkyI, cyano, aminocarbonyl, Ci_4alkyloxy or haloC 1.4alkyloxy; Ar2 is naphtalenyl; phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from hydroxy, halo, cyano, nitro, amino, mono- or di(Ci_4alkyI)amino, Ci^alkyl, haloCi_4alkyI, Ci.4alkyloxy, haloCi.4aIkyloxy, carboxyl, Ci-4alkyloxycarbonyl, aminocarbonyl and mono- or di(Ci-4alkyl)aminocarbonyl; and Het is a monocyclic heterocycle selected from pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocycle selected from quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl and benzothienyl; each monocyclic and bicyclic heterocycle may optionally be substituted on a carbon atom by 1 or 2 substituents selected from halo, Ci_4alkyl or mono-, di- or tri(halo)methyl. The heterocycles in the definition of Het are preferably connected to the rest of the molecule, i.e. X, -C(=Q)- or Ci_6alkyl, by a carbon atom. As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; Ci^alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl and the like; Ci-ealkyl is meant to include Ci-4alkyl and the higher homologues thereof having 5 to 6 carbon atoms such as, for example, pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like; Ci_4alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propane-diyl, 1,4-butanediyl, and the like; Ci-ealkanediyl is meant to include Ci^alkanediyl and the higher homologues thereof having form 5 to 6 carbon atoms such as, for example, 1,5-pentanediyl, 1,6-hexanediyl and the like. As used in the foregoing definitions and hereinafter, haloCi_4alkyl is defined as mono- -4- or polyhalosubstituted C^alkyl, in particular Ci_4alkyl substituted with 1 to 6 halogen atoms, more in particular dlfluoro- or trifluoromethyl. The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. Said salts can conveniently be obtained by treating the base form of the compounds of formula (I) with appropriate acids such as, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydro-bromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzene-sulfonic, /Koluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids. The pharmaceutically acceptable addition salts as mentioned hereinabove are also meant to comprise the therapeutically active non-toxic base, in particular, a metal or amine addition salt forms which the compounds of formula (I) are able to form. Said salts can conveniently be obtained by treating the compounds of formula (I) containing acidic hydrogen atoms with appropriate organic and inorganic bases such as, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, 7v"-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely said salt forms can be converted by treatment with an appropriate base or acid into the free acid or base form. The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like. For isolation and purification purposes, it is also possible to use pharmaceutically unacceptable salts. Only the pharmaceutically acceptable, non-toxic salts are used therapeutically and those salts are therefore preferred. The term "stereochemically isomeric forms" as used hereinbefore defines all the possible isomeric as well as conformational forms which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture, more in particular the racemic mixture, of all possible stereochemically and conformationally isomeric forms, said mixtures containing all diastereomers, enantiomers and/or conformers of the basic molecular structure. More in particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic saturated radicals may have either the cis- or frawj-configuration; >C=NR3 and C3_6alkenyl radicals may have the E- or Z-configuration. For the compounds having two stereogenic centers, the relative stereodescriptors R* and S* are used in accordance with the Chemical Abstracts rules (Chemical Substance Name Selection Manual (CA), 1982 Edition, Vol. HI, Chapter 20). All stereochemically isomeric forms of the compounds of formula (I) both in pure form or mixtures thereof are intended to be embraced within the scope of the present invention. Some of the compounds of formula (I) may also exist in their tautomeric form. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention. For instance, compounds of formula (I) wherein X is -NH- and =Q is =O and compounds of formula (I) wherein ^^Y- is -C(=O)-NH- may exist in their corresponding tautomeric form. The TV-oxide forms of the compounds of formula (I) are meant to comprise those compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called TV-oxide, particularly those TV-oxides wherein one or more of the piperazine-nitrogens are TV-oxidized. Whenever used hereinafter, the term "compounds of formula (I)" is meant to also include their TV-oxide forms, their pharmaceutically acceptable addition salts, and their stereochemically isomeric forms. An important group of compounds are those compounds of formula (I) wherein L is a radical of formula (A) and Het is a monocyclic heterocycle selected from pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocycle selected from quinolinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benziso-thiazolyl, benzofuranyl and benzothienyl; each monocyclic and bicyclic heterocycle may optionally be substituted on a carbon atom by 1 or 2 substituents selected from halo, Ci_4alkyl or mono-, di- or tri(halo)methyl. Another important group of compounds are those compounds of formula (I) wherein L is a radical of formula (B) and Het is a monocyclic heterocycle selected from pyrrolyl, -6- pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocycle selected from quinolinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl and benzothienyl; each monocyclic and bicyclic heterocycle may optionally be substituted on a carbon atom by 1 or 2 substituents selected from halo, C]_4alkyl or mono-, di- or tri(halo)methyl. A first group of interesting compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply : a) R1 is Ar1 or A^Cj-ealkyl; or b) R2 is phenylCi-eaJkyl; quinolinyl; quinoxalinyl; optionally substituted isoxazolyl; optionally substituted pyridinyl; optionally substituted thiazolyl; optionally substituted pyrazinyl; optionally substituted benzofuranyl; benzothiazolyl; optionally substituted indolyl; optionally substituted pyrrolyl; thienyl; furanyl; naphtalenyl; phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from amino, halo, cyano, Q^alkyl, Ci_4alkyloxy and haloCi_4alkyI, in particular, selected from methyl and trifluoromethyl; or c) n is 1 or 2; or d) m is 1 or 2; or e) =Q is =O; or f) X is a covalent bond, -S-, -NH- or -O-. A second group of interesting compounds consists of those compounds of formula (I) wherein r^Y- is -NR3-, -CH2-, -CH(OH)-, -S-, -S(=O)- or -O-; -A=B- is -CH=CH- or -N=CH-; R4 is C,.6alkyl; or R4 is a radical of formula (c-1) wherein R7 is phenyl substituted with halo or C^alkoxy; thienyl; thiazolyl optionally substituted with Ci-ealkyl; oxazolyl optionally substituted with 1 or 2 Cj-ealkyl substituents; furanyl optionally substituted with Ci-ealkyl or hydroxyC,,6alkyl; or R4 is a radical of formula (c-2) wherein Z is a bivalent radical of formula -O-, and R8 is Ci-ealkyl; R5 is hydrogen; and R6 is hydrogen or A^Ci-ealkyl. Of special interest are those compounds of formula (I) wherein R1 is Ar^i.^alkyl, R2 is phenyl substituted with 2 substituents selected from methyl or trifluoromethyl, X is a covalent bond and =Q is =O. Further of special interest are those compounds of formula (I) wherein L is a radical of formula (A) and p is 0 or 1. -7- Also of special interest are those compounds of formula (I) wherein Lisa radical of formula (B)r n is 1 or 2, and m is 1 or 2, provided that if m is 2, then n is 1. A particular group of compounds consists of those compounds of formula (I) wherein R1 is phenylmethyl; R2 is phenyl substituted with 2 substituents selected from methyl or trifluoromethyl; n, m are 1; X is a covalent bond; and =Q is =O. Another particular group of compounds consists of those compounds of formula (I) wherein r^Y- is -NH- or -O-; - A=B- is -CH=CH- or -N^CH-; R4 is a radical of formula (c-1) wherein R7 is oxazolyl substituted with 1 or 2 Chalky I substituents, furanyl substituted with C^alkyl or hydroxyC,.6aIkyl; or R4 is a radical of formula (c-2) wherein Z is a bivalent radical of formula -O-, and R8 is Ci.galkyl; R5 is hydrogen; and R6 is hydrogen. Preferred compounds are those compounds of formula (I) wherein R1 is phenylmethyl; R2 is phenyl substituted with 2 substituents selected from methyl or trifluoromethyl; nt m are 1; X is a covalent bond; and =Q is =O; =SK*Y- is -NH-; -A=B- is -CH=CH- or -N=CH-; R4 is a radical of formula (c-1) wherein Alk is methyiene; and R7 is oxaxolyl substituted with 1 or 2 methyl substituents, furanyl substituted with methyl or hydroxymethyl; or R4 is a radical of formula (c~2) wherein Alk is ethanediyl; Z is a bivalent radical of formula -O, and R8 is ethyl; R5 is hydrogen; and R6 is hydrogen-Most preferred are 14^3-bis(trifluoromethyl)benzayl]-4-[4~[[l-(2-ethoxyethy3)-lJ^-benzimidazol-2^ yl]aminoj-l"piperidinyl]"2-(phenylme%l)piperidme; 143,5"bis(trmuoromethyl)benzoyl3-4-[44tI--[(2-methyl-5-oxazolyI)rnethylJ-J^ bendrai4azol~2-yl]amino3-l--piperidmyl3-2--(phenylinethyl)piperidine; l-P.S-bisCtrifiuororaethy^benzoylJ^-^-CfS-CS-methyl^-furanyO-Sif-imidazo^.S-b]- pyridin-2-yl]amino3-l-piperidinyl]-2-(phenylmethyl)piperidine; l^S^-bisCtrifluoromethyObenzoylJ^^S^CS-KS-methyl^-ftiranyOmethyO-SH-im^ [4,5-b3pyridm-2-yl]amino3-l-pyrtoHdinyl3-2-(phenylmethyl)piperidine; l-(3,5"bis(trifluoromemyl)benzoylH-[4-{[I"C benzimidazol-2-yl]amino]-l-piperidinyl]piperiditie; l-lSVS-bisCtrifludromethyObenzoylJ^-IIl-^-ethoxyeOiy^-l^-beiizimJdazol^-ylj- ammo]-2-(phenylmethyl)piperidine; I - [S^-bisCtrifluoromethy l)bsnzoyI]-4-{[i-[{2-methyl-4-oxazolyl)methy 1}-1 H-benz- irnidazol-2-yl]amino]-2-(phenyimethyl}piperidme; l-f3,5-bis(trifluoromethyl)benzoyI}-4-[[l-{(5-methyl-2-furanyl)methyl]-lH-benz -8- imidazoI-2-yl]amino]-2-(phenyjlmethyI)piperidine; the stereoisomeric forms and the pharmaceutically acceptable acid addition salts thereof. The compounds of formula (I) can generally be prepared by reacting an intermediate of formula (II) wherein W1 is an appropriate leaving group such as, for example, a halogen, e.g. chloro or bromo, or a sulfonyloxy leaving group, e.g. methanesulfonyloxy or benzenesuifonyloxy, with an intermediate of formula (III). The reaction can be performed in a reaction-inert solvent such ass for example, a chlorinated hydrocarbon, e.g. dichloromethane, an alcohol, e.g. ethanol, or a ketone, e.g. methyl isobutylketone, and in the presence of a suitable base such as, for example, sodium carbonate, sodium hydrogen carbonate or triethylamine. Stirring may enhance the rate of the reaction. The reaction may conveniently be carried at a temperature ranging between room temperature and reflux temperature. Alternatively and under similar reaction conditions, intermediates of formula (II) wherein =Q is =O may be replaced by functional derivatives thereof such as, for example, anhydrides, e.g. isatoic anhydride, thus forming compounds of formula (I) wherein Q is oxygen, said compounds being represented by formula (1-1). In this and the following preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, trituration and chromatography. The compounds of formula (I) wherein L is a radical of formula (A), said compounds being referred to as (I-A), can be prepared by reductively TV-alkylating an intermediate of formula (V) with an intermediate of formula (IV). Said reductive Af-alkylation may be performed in a reaction-inert solvent such as, for example, dichloromethane, ethanol, toluene or a mixture thereof, and in the presence of a reducing agent such as, for example, a borohydride, e.g. sodium borohydride, sodium cyanoborohydride or triacetoxy borohydride. In case a borohydride is used as a reducing agent, it may be convenient to use a catalyst such as, for example, titanium(IV) isopropylate as described in J. Org. Chem, 1990, 55, 2552-2554. Using said catalyst may also result in an improved cisltrans ratio in favour of the trans isomer. It may also be convenient to -9- use hydrogen as a reducing agent in combination with a suitable catalyst such as, for example, palladium-on-charcoal or platinum-on-charcoal. In case hydrogen is used as reducing agent, it may be advantageous to add a dehydrating agent to the reaction mixture such as, for example, aluminium rert-butoxide. In order to prevent the undesired further hydrogenation of certain functional groups in the reactants and the reaction products, it may also be advantageous to add an appropriate catalyst-poison to the reaction mixture, e.g., thiophene or quinoline-sulphur. Stirring and optionally elevated temperatures and/or pressure may enhance the rate of the reaction. The compounds of formula (I) wherein L is a radical of formula (B) and ^y- is -NR3-, said compounds being represented by formula (I-B-l), can be prepared by reductively N-alkylating an intermediate of formula (VI) with an intermediate of formula (IV). Said reductive AT-alkylation may be performed in a similar way to the reductive Af-alkylation procedure described hereinabove. Alternatively, compounds of formula (I-B-l) may also be prepared by reacting an intermediate of formula (VII) with an intermediate of formula (VTH) wherein W2 is an appropriate leaving group such as, for example, a halogen, e.g. chloro, in the presence of a suitable catalyst such as, for example, copper. The reaction may be performed in a reaction-inert solvent such as, for example, A^Af-dimethylformamide. However, it is convenient to perform said reaction without solvent at a temperature just above the melting point of the reagents. Stirring enhances the rate of the reaction. -10- The compounds of formula (I) wherein L is a radical of formula (B) and .-^Y is -S- , said compounds being represented by formula (I-B-2), can be prepared by reacting an intermediate of formula (IX) wherein W3 is a suitable leaving group such as, for example, a sulfonyloxy leaving group, e.g. methanesulfonyloxy or benzenesulfonyloxy, with an intermediate of formula (X). Said reaction may be performed using a similar reaction procedure as for the preparation of compounds of formula (I) form intermediates (II) and (HI). The compounds of formula (I) wherein Lisa radical of formula (B) and ^Y- is-O-, said compounds being represented by formula (I-B-3), can be prepared by reacting an intermediate of formula (XI) with an intermediate of formula (VHI).The reaction may be performed in a reaction-inert solvent such as, for example, A^Ar-dimethylformamide and in the presence of a suitable base such as, for example, sodium hydride. Stirring and temperatures up to reflux temperature may enhance the rate of the reaction. The compounds of formula (I) may be converted into each other following art-known transformations. For instance, compounds of formula (I-B-l) wherein R3 is hydrogen may be converted into their corresponding M-alkyl derivatives using a suitable alkylating agent such as, for example, an alkyliodide, e.g. methyl iodide, in the presence of a suitable base such as, for example, sodium hydride. Also, compounds of formula (I-B-2) may be converted to their corresponding sulfoxides using a suitable oxidizing agent such as, for example, 3-chlorobenzene-carboperoxoic acid. -11 The compounds of formula (I) may be converted into each other following art-known transformations. The compounds of formula (I) may also be converted to the corresponding i^-oxide forms following art-known procedures for converting a trivalent nitrogen into its Af-oxide form. Said JV-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. t.butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents. The starting materials and some of the intermediates are known compounds and are commercially available or may be prepared according to conventional reaction procedures generally known in the art. For example, intermediates of formula (HI) wherein L is a radical of formula (B) and intermediates of formula (V) may be prepared as described in EP~0,378,254-A, WO 92/06086, WO93/14083, EP-*0,539,421-A and EP-0,539,420-A In particular, intermediates of formula (HI) wherein L is a radical of formula (B) and s^Y- is -NR3-, said intermediates being represented by formula (DI-B-1), may be prepared by first reacting an intermediate of formula (XII) wherein P1 is a suitable protecting group such as for example, phenylmethyl or a Ci^alkyloxycarfeonyl group, with an intermediate of formula (VIII) using the same reaction procedure as for the preparation of compounds of formula (I-a) from intermediates (VH) and (VHI); and subsequently deprotecting the thus formed intermediate using art-known deprotection techniques. -12- Alternatively, intermediates of formula (III-B-1) may also be prepared by reductively 7V-alkylating an intermediate of formula (VI) with an intermediate of formula (XIII) wherein P1 is a suitable protecting group such as for example, phenylmethyl or a Ci-ealkyloxycarbonyl group, using the same reaction procedure as for the preparation of compounds of formula (I-B-l) from intermediates (IV) and (VI); and subsequently deprotecting the thus formed intermediate using art-known deprotection techniques. Intermediates of formula (HI) wherein L is a radical of formula (B) and r^y- is -O-, said intermediates being represented by formula (HI-B-3), may be prepared by first reacting an intermediate of formula (XIV) wherein P1 is a suitable protecting group such as for example, phenylmethyl or a Ci-galkyloxycarbonyl group, with an intermediate of formula (VIE) using the same reaction procedure as for the preparation of compounds of formula (I-B-3) from intermediates (XI) and (VDI); and subsequently deprotecting the thus formed intermediate using art-known deprotection techniques. Intermediates of formula (IV) may be prepared by condensing an intermediate of formula (II) with an intermediate of formula (XV) in an analogous way as described in EP-0,532,456-A Ways to prepare intermediates of formula (XV) are also described in EP-0,532,456-A. However, intermediates of formula (XV) wherein R1 is optionally substituted A^Ci-ealkyl or di(Ar1)Ci_6alkyl, said R1 being represented by -CH(Rla)2 and said intermediates being represented by formula (XV-a), may also be prepared as depicted in scheme 1. -13-Scheme 1 In scheme 1, the intermediates of formula (XVI-b) may be prepared by reacting an intermediate of formula (XVI-a) with an aldehyde or a ketone of formula (XVII). The Ci_6alkylcarbamate moiety in the intermediates of formula (XVI-b) may be converted into a fused oxazolone which in turn may be reduced to an intermediate of formula (XVI-d). Said intermediate (XVI-d) may in turn be deprotected, thus forming an intermediate of formula (XV-a). Subsequently, intermediates of formula (XV-a) may be reacted with an intermediate of formula (II) to prepare intermediates of formula (IV) wherein R1 is defined as -CH(Rla)2, said intermediates being represented by formula (IV-a). The reactions performed in scheme 1 may all be conducted following conventional methods that are generally known in the art. Intermediates of formula (XV) wherein n and m are 1 and R1 is Ar1, said intermediates being represented by formula (XV-b), may be prepared by reacting a benzaldehyde of formula (XVIH) with an intermediate of formula (XIX) or a functional derivative thereof, and subsequently deprotecting the resulting ketalized 4-piperidinone derivative using art-known deprotection techniques. Said reaction may be performed in a reaction-inert solvent such as, for example, toluene, and in the presence of an acid such as, for example, p-toluenesulfonic acid. -14- Intermediates of formula (HI) wherein L is a radical of formula (A), said intermediates being represented by formula (III-A), may suitably be prepared by reacting an intermediate of formula (XIII) with an intermediate of formula (V) according to the previously described reductive W-alkylation procedure, and subsequently deprotecting the thus formed intermediate. In particular, intermediates of formula (III-A) wherein R1 is -CH(Rla)2, said intermediates being represented by formula (III-A-1), may be prepared as is depicted in scheme 2. The ketalized intermediate of formula (XVI-c) may be transformed to the corresponding ketone of formula (XVI-e) which subsequently may be reductively aminated with a pyrrolidine, piperidine- or homopiperidine derivative of formula (V). The thus obtained intermediate may then be reduced with a suitable reducing agent to an intermediate of formula (IH-A-1). Pure stereochemically isomeric forms of the compounds of formula (I) may be obtained by the application of art-known procedures. Diastereomers may be separated by physical methods such as selective crystallization and chromatographic techniques, e.g., counter-current distribution, liquid chromatography and the like. The compounds of formula (I) as prepared in the hereinabove described processes are generally racemic mixtures of enantiomers which can be separated from one another -15- following art-known resolution procedures. The racemic compounds of formula (I) which are sufficiently basic or acidic may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid, respectively chiral base. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali or acid. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereo-specifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials. The compounds of formula (I) have valuable pharmacological properties in that they interact with tachykinin receptors and they antagonize tachykinin-induced effects, especially substance P-induced effects, both in vivo and in vitro and are thus of use in the treatment of tachykinin-mediated diseases, and in particular in substance P-mediated diseases. Tachykinins, also referred to as neurokinins, are a family of peptides among which substance P (SP), neurokinin A (NKA), neurokinin B (NKB) and neuropeptide K (NPK) may be identified. They are naturally occurring in mammals, including human beings, and are distributed throughout the central and peripheral nervous system, where they act as neurotransmitters or neuromodulators. Their actions are mediated through several subtypes of receptors, such as, for example, NKi, NK2 and NK3 receptors. Substance P displays highest affinity for NKi receptors, whereas NKA preferentially binds to NK2 receptors and NKB preferentially binds to NK3 receptors. However, the selectivity of these tachykinins is relatively poor and under physiological conditions the action of any of these tachykinins might be mediated by activation of more than one receptor type. Substance P and other neurokinins are involved in a variety of biological actions such as pain transmission (nociception), neurogenic inflammation, smooth muscle contraction, plasma protein extravasation, vasodilation, secretion, mast cell degranulation, and also in activation of the immune system. A number of diseases are deemed to be engendered by activation of neurokinin receptors, in particular the NKi receptor, by excessive release of substance P and other neurokinins in particular cells -16- such as cells in the neuronal plexi of the gastrointestinal tract, unmyelinated primary sensory afferent neurons, sympathetic and parasympathetic neurons and nonneuronal cell types (DN&P 8(1), February 1995, p. 5-23, "Neurokinin Receptors" by Longmore J. et al.; Pharmacological Reviews 46(4), 1994, p. 551-599, "Receptors and Antagonists for Substance P and Related Peptides" by Regoli et al.). The compounds of the present invention are potent inhibitors of neurokinin-mediated effects, in particular those mediated via the NKi receptor, and may therefore be described as tachykinin antagonists, especially as substance P antagonists, as indicated in vitro by the antagonism of substance P-induced relaxation of pig coronary arteries which is described hereinafter. The binding affinity of the present compounds for the human, guinea-pig and gerbil neurokinin receptors may be determined in vitro in a receptor binding test using 3H-substance P as radioligand. The subject compounds also show substance-P antagonistic activity in vivo as may be evidenced by, for instance, the antagonism of substance P-induced plasma extravasation in guinea-pigs. In view of their capability to antagonize the actions of tachykinins by blocking the tachykinin receptors, and in particular antagonizing the actions of substance P by blocking the NKi receptor, the subject compounds are useful in the prophylactic and therapeutic treatment of tachykinin-mediated diseases such as, for example, - pain, in particular traumatic pain such as postoperative pain; traumatic avulsion pain such as brachial plexus; chronic pain such as arthritic pain such as occurring in osteo-, rheumatoid or psoriatic arthritis; neuropathic pain such as post-herpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia, fibromyalgia, causalgia, peripheral neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy, AIDS-related neuropathy, occipital neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, phantom limb pain; various forms of headache such as migraine, acute or chronic tension headache, temperomandibular pain, maxillary sinus pain, cluster headache; odontalgia; cancer pain; pain of visceral origin; gastrointestinal pain; nerve entrapment pain; sport's injury pain; dysmennorrhoea; menstrual pain; meningitis; arachnoiditis; musculoskeletal pain; low back pain e.g. spinal stenosis; prolapsed disc; sciatica; angina; ankylosing spondyolitis; gout; burns; scar pain; itch; and thalamic pain such as post stroke thalamic pain; - respiratory and inflammatory diseases, in particular inflammation in asthma, influenza, chronic bronchitis and rheumatoid arthritis; inflammatory diseases of the gastrointestinal tract such as Crohn's disease, ulcerative colitis, inflammatory bowel disease and non-steroidal anti-inflammatory drug induced damage; inflammatory -17- diseases of the skin such as herpes and eczema; inflammatory diseases of the bladder such as cystitis and urge incontinence; and eye and dental inflammation; emesis, i.e. nausea, retching and vomiting, including acute emesis, delayed emesis and anticipatory emesis, no matter how emesis is induced, for example, emesis may be induced by drugs such as cancer chemotherapeutic agents such as alkylating agents, e.g. cyclophosphamide, carmustine, lomustine and chlorambucil; cytotoxic antibiotics, e.g. dactinomycin, doxorubicin, mitomycin-C and bleomycin; anti-metabolites, e.g. cytarabine, methotrexate and 5-fluorouracil; vinca alkaloids, e.g. etoposide, vinblastine and vincristine; and others such as cisplatin, dacarbazine, procarbazine and hydroxyurea; and combinations thereof; radiation sickness; radiation therapy, e.g. irradiation of the thorax or abdomen, such as in the treatment of cancer; poisons; toxins such as toxins caused by metabolic disorders or by infection, e.g. gastritis, or released during bacterial or viral gastrointestinal infection; pregnancy; vestibular disorders, such as motion sickness, vertigo, dizziness and Meniere's disease; post-operative sickness; gastrointestinal obstruction; reduced gastrointestinal motility; visceral pain, e.g. myocardial infarction or peritonitis; migraine; increased intercranial pressure; decreased intercranial pressure (e.g. altitude sickness); opioid analgesics, such as morphine; and gastro-oesophageal reflux disease, acid indigestion, over-indulgence of food or drink, acid stomach, sour stomach, waterbrash/regurgitation, heartburn, such as episodic heartburn, nocturnal heartburn, and meal-induced heartburn and dyspepsia; central nervous system disorders, in particular psychoses such as schizophrenia, mania, dementia or other cognitive disorders e.g. Alzheimer's disease; anxiety; ATDS-related dementia; diabetic neuropathy; multiple sclerosis; depression; Parkinson's disease; and dependence on drugs or substances of abuse; allergic disorders, in particular allergic disorders of the skin such as urticaria, and allergic disorders of the airways such as rhinitis; gastrointestinal disorders, such as irritable bowel syndrome; skin disorders, such as psoriasis, pruritis and sunburn; vasospastic diseases, such as angina, vascular headache and Reynaud's disease; cerebral ischaemia, such as cerebral vasospasm following subarachnoid haemorrhage stroke, epilepsie, head trauma, spinal cord trauma and ischemic neuronal damage; fibrosing and collagen diseases, such as scleroderma and eosinophilic fascioliasis; disorders related to immune enhancement or suppression, such as systemic lupus erythematosus; rheumatic diseases, such as fibrositis; -18- - neoplastic disorders; - cell proliferation; and - cough. The compounds of the present invention have a favourable metabolic stability and exhibit good oral availability. They also have an advantageous onset and duration of action. In view of the utility of the compounds of formula (I), there is provided a method of treating warm-blooded animals, including humans, suffering from tachykinin-mediated diseases as mentioned hereinabove, in particular, asthma. Said method comprises the systemic administration of an effective tachykinin antagonizing amount of a compound of formula (I), a W-oxide form, a pharmaceutically acceptable addition salt or a possible stereoisomeric form thereof, to warm-blooded animals, including humans. Hence, the use of a compound of formula (I) as a medicine is provided, and in particular a medicine to treat asthma. For ease of administration, the subject compounds may be formulated into various pharmaceutical forms for administration purposes. To prepare the pharmaceutical compositions of this invention, a therapeutically effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable solutions containing compounds of formula (I) may be formulated in an oil for prolonged action. -19- Appropriate oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soy bean oil, synthetic glycerol esters of long chain fatty acids and mixtures of these and other oils. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment. Acid or base addition salts of compounds of formula (I) due to their increased water solubility over the corresponding base or acid form, are obviously more suitable in the preparation of aqueous compositions. In order to enhance the solubility and/or the stability of the compounds of formula (I) in pharmaceutical compositions, it can be advantageous to employ a-, p- or y-cyclodextrins or their derivatives, in particular hydroxyalkyl substituted cydodextrins, e.g. 2-hydroxy-propyl-p-cyclodextrin. Also co-solvents such as alcohols may improve the solubility and/or the stability of the compounds of formula (I) in pharmaceutical compositions. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof. Those of skill in the treatment of tachykinin mediated diseases could determine the effective therapeutic daily amount from the test results presented hereinafter. An effective therapeutic daily amount would be from about 0.001 mg/kg to about 40 mg/kg body weight, more preferably from about 0.01 mg/kg to about 5 mg/kg body weight. It may be appropriate to administer the therapeutically effective dose once daily or as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 0.05 mg to 500 mg, and in particular, 0.5 mg to 50 mg of active ingredient per unit dosage form. -20- The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient as well as other medication the patient may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated patient and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore only guidelines. The following examples are intended to illustrate and not to limit the scope of the present invention. Experimental Part Hereinafter, "DIPE" means diisopropylether, "RT" means room temperature. Of some compounds of formula (I) the absolute stereochemical configuration was not experimentally determined. In those cases the stereochemically isomeric form which was first isolated is designated as "A" and the second as "B", without further reference to the actual stereochemical configuration. A. Preparation of the intermediates Example Al A mixture of (±)-1,1 -dimethylethyl 7-(phenylmethyl)-l ,4-dioxo-8-azaspiro[4.5]~ decane-8-carboxylate (33.34 g) in HC1 (6N; 250 ml) was stirred at 70 °C for 1.5 hour. The mixture was cooled, CH2CI2 (100 ml) was added and NaOH was added while cooling to RT. The organic layer was separated and the aqueous layer was extracted with CH2CI2. Triethylamine (20.2 g), followed by 3,5-bis(trifIuoromethyl)-benzoylchloride (27.7 g) dissolved in CH2CI2 were added and the mixture was stirred for 2 hours. Water was added and the layers were separated. The organic layer was dried, filtered and the solvent evaporated. The residue was crystallized from DIPE, the precipitate was filtered off and dried, yielding 18.34 g of fraction 1. The solvent of the mother layer was evaporated and the residue was crystallized from DIPE. The precipitate was filtered off and dried, yielding 6.51 g of fraction 2. The two fractions were put together and taken up in water and CH2CI2- NaOH was added and the mixture was extracted. The organic layer was dried, filtered and the solvent evaporated, yielding 16.14 g (38%) of (±)-l-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenyImethyl)-4-piperidinone (interm. 1; mp. 102.5 °C). -21- Example A2 a) A mixture of (±)-1,1 -dimethylethyl 7-(hydroxyphenylmethyl)-1,4-dioxa-8- azaspiro[4.5]decane-8-carboxylate (183.6 g) and potassium tert-butoxide (6 g) in toluene (900 ml) was stirred and refluxed for 2 hours. The solvent was evaporated and the residue was stirred in petrol ether and water. The mixture was decanted and the residue was stirred up in DIPE. The precipitate was filtered off and dried, yielding 127.4 g (92%) of (±)-tetrahydro-l'-phenylspiro(lJ3-dioxolan-2)7l(8l//)-3H-oxazo]o[3,4- a]pyridin)-3'-one (interm. 2). b) A mixture of intermediate (2) (137 g) in methanol (700 ml) was hydrogenated at 50°C overnight with palladium on activated carbon (10%; 5 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in water and extracted with CH2CI2. The organic layer was dried, filtered and the solvent evaporated, yielding 99 g (85%) of (±)-7-(phenyImethyl)-l ,4-dioxa-8-azaspiro[4.5]decane (interm 3). c) A mixture of intermediate (3) (13 g) in HC1 (6N; 130 ml) was stirred and refluxed for 3 hours. The mixture was cooled, decanted, alkalized with NaOH 50% and extracted with CH2CI2. The organic layer was dried and filtered, yielding (±)-7-(phenylmethy])-l,4-dioxa-8-azaspiro[4.5]decanein CH2CI2 (interm. 4). d) A mixture of intermediate (4), 3,5-dimethylbenzoylehloride (7.4 g) and triethylamine (11 ml) was stirred overnight at RT. The reaction mixture was washed with dilute NaOH and the organic layer was separated, dried, filtered and the solvent evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried, yielding 7.44 g (58 %) of (±)-l-(3,5-dimethylbenzoyl)-2-(phenylmethyl)-4- piperidinone (interm. 5; mp. 107.8 °C). Example A3 a)(±)-l,l~dimethylethyl ?mn^-4-amino-2-(phenylmethyl)-l-piperidinecarboxylate (5 g), l-(2-ethoxyethyi)-2-chloro-lH-benzimidazole (4.5 g) and copper (L28 g) were stirred at 150 °C for 4 hours. The mixture was taken up in CH2O2 and filtered. The filtrate was washed with water/NH3. The organic layer was dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 98/2). The pure fractions were collected and the solvent evaporated, yielding 6 g (73.7 %) of (±)-t4-ditnethyJethyl rmn^-4-[[l-(2-ethoxyethyI)-lH-beTi2:imidazol-2-yl]amino3-2"(phenylmethyl)-l~piperidme- carboxylate (interm. 6). b) Intermediate (6) was added and the mixture was stirred and refluxed for 1 hour. The solvent was -22- evaporated, the residue was taken up in diluted NaOH, and extracted with CH2CI2. The organic layer was separated and purified on a glass filter over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 95/5). The pure fractions were collected and evaporated. The residue was crystallized from DIPE, yielding 3 g (63.4 %) of (±Hra".y-l-(2-ethoxy-ethyl)-A42-(phenylmethyl)-4-piperidinyI]- l//-benzimidazol-2-amine (interm. 7). Example A4 a) 1,1-dimethylethyl l,3-dioxa-8-azaspiro[4.5]decane-8-carboxylate (24.3 g) in diethyl ether (150 ml) and AW./V',/V'-tetramethylethylenediamine (32 ml) was stirred and cooled under N2 on a 2~propanol/C02 bath, jec-buthyllithium (1.4 M; 85.7 ml) was added dropwise at a temperature below -60°C and the mixture was stirred at -60°C for 3 hours. 3,4-Dimethoxybenzaldehyde (19.94 g) in .yec-buthyllithium was added and the mixture was stirred at -60°C for 1 hour. The mixture was brought to RT and stirred overnight. The mixture was decomposed with water, DIPE was added and the ether layer was decanted twice. The precipitate and the aqueous layers were extracted with CH2CI2. The organic layer was separated, dried, filtered and the solvent evaporated. The residue was crystallized from DIPE and the precipitate was filtered off, yielding 2.7 g (8%) of (±)-l-(3,4-dimethoxyphenyl)tetrahydrospiro[l,3-dioxolane-2,7'(r//)-oxazolo[3,4-a]pyridin]-3'(3'H>one (interm. 8; mp. 162.6 °C). b) Trifluoroacetic acid (5 ml) was added to a mixture of intermediate (8) (1 g) in CH2CI2 (25 ml) and the mixture was stirred at RT for a few hours. The mixture was poured into alkalic water and extracted with CH2CI2. The organic layer was separated, dried, filtered and the solvent evaporated. The residue was suspended in DIPE, filtered off and dried. The residue was recrystallized from CH3CN, filtered off and dried, yielding 0.19 g of (±)-l-(3,4~dimethoxyphenyl)tetrahydro-3/f-oxazolo[3,4-alpyridine- 3,6(lff)-dione (interm. 9; mp. 180.2 °C). c) A solution of intermediate (9) (9 g) in methanol (250 ml) was hydrogenated at 50 °C with palladium on activated carbon (10 %; 3 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3 7N) 95/5). The pure fractions were collected and evaporated, yielding 3 g (40%) of (±)-2-[(3,4-dimethoxyphenyl)methyl]-4-piperidinone (interm 10). Example A5 a) A solution of benzaldehyde (10.6 g) and 2-methyl-l,3-dioxolane-2-ethanamine (13.1 g) in toluene (100 ml) was stirred for 16 hours at RT. This solution was added at 100 °C to a solution of 4-methylbenzenesulfonic acid (34.4 g) in toluene (100 ml) and -23- fhe mixture was stirred for I hour at 100 °C The mixture was poured into an ice/water bath, K2CO3 was added to a pH of about 8 and extracted with ethyl acetate. The organic layer was dried, filtered and the solvent evaporated, yielding 14.3 g (70%) of (±)-7-phenyI-I,3-dioxa-8-azaspiro[4.53decane (interm. II). b) A mixture of intermediate (11) (14.5 g) in HO (6 N; 150 ml) was stirred and heated at 60 °C for a few hours. The mixture was cooled, poured into a saturated K2CO3 solution and extracted with CH2CI2. The organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2CI2/CH3OH-NH3 95/5). The pure fractions were collected and evaporated, yielding 7.3 g (57%) (±)-2-phenyl-4-piperidinone (interm, 12). Exaxririej&fi a) Iodine (crystals) was added to magnesium turnings (8.63 g) in diethyl ether under N2. Benzyl bromide was added and the Grigward reaction was started. Benzyl bromide (60.65 g) in diethyl ether (443 ml) was added dropwise si reflux temperature white stirring, the reaction mixture was refiuxed for 1 hour. The Grignard reagens was added dropwise to a suspension of 4-methQxy-MphenyImethyI)pyridinium bromide (75 g) m diethyl ether (1200 ml) and the mixture was stirred at RT for 18 hours. The mixture was poured into ECl (12M; 150 ml) and water (600 ml), alkalized with NH4OH and NaOH and extracted with CH2CI2- The combined organic layers were washed with water, dried, filtered and the solvent was evaporated, yielding 76 g (100%) of (±)-l,2-dihydro-4-methoxy-I>bis(phenylrnethyl)pyridme (interm 13), b) NaOH (370 mi} was added to intermediate (13) (76 %) in methanol (1100 ml) assd the mixture was stirred and refluxed for 1.5 hours. The solvent was evaporated and the residue was extracted with CH2CI2. The organic layer was washed with water, dried, filtered and the solvent evaporated. The residue was purified by column chromato graphy over silica gel (eluent; CH2CI2/CH3OH 95/5). The pure fractions were collected md the solvent evaporated. The residue was taken up in toluene, filtered and the solvent evaporated, yielding 40 g (54.3%) of (±)-2,3-dihydn>-1,2-bi$tpfienyl- meihyiH(lH)~pytidirione (interm. 14). c) Intermediate (H) (40 g) was hydrogenated in methanol (600 ml) with Raney nickel (5 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent; CHsClj/CCHsOH/NHs) 95/5). The pure fractions were collected and the solvent evaporated. The residue was crystallised from CH3CN, yielding 5.4 g (19,6%) of (±)-m>2-(phenylmeth>l>>4-piperidinc^ (inferm. 15; mp, 113.9 °C). -24- Examgfe^A?. A mixture of intermediate (10) (2.8 g) in CHtCh (50 mi) was stirred and 3,5~bis(trifluoromethyl)benzoyi chloride (3.32 g) was added. While stirring, triethylamine (2.8 ml) was added and the mixture was stirred at RT for 3 hours. The mixture was washed with diluted NaOH 50%, then with water, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eiuent: CHzCh^CBsOB 95/5). The pure fractions were collected and the solvent evaporated. The residue was suspended in DIPE, filtered and dried. The solvent was evaporated and the residue was dried, yielding 3.25 g (59.3%) of (±)-l-[3,5-bis(trifluoromethyI)benzoyI3"2-t(3i4-dimethoxyphenyl)methyi3-4-piperidinone (interm. 16; mp. 132.7 °C). In a similar way were prepared (i)-I-f34-bis(trifluoromethyl)benzoyl]-2-(imidazo[l,2-a]pyridin-3-yI)-^piperidiBOf3e (interm. 17) (±}-cis-1 -(315-dimethylbenzoyi)-2'(pheny]methyI)-4-piperidino] (interm. 18; mp, 178,1 °C); (±)-t-[3,5-bis(trifluoromethyl)benzoyl]~2"phenyl-4-piperidinone (interm. 19; mp. 119,4 °C); (±)~trans- 1 -(3,5-dimethylbenzoyl)~2-(phenyJmethy))-4-pipefidmol (interm. 20; mp. 153.2 °C). Example A8 Triethyl amine (7 ml) and methanesulfonyl chloride (3.4 ml) were added to a mixture of intermediate (18) (13 g) in CH2CI2 (200 ml) and the mixture was stirred at RT for 3 hours. The mixture was washed with water, NaOH 50% and again with water. The organic layer was dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2CI2/CH3OH 99/1). The pure fractions were collected and the solvent evaporated, yielding 14.4 g (90%) of (±)-c"-l-(3f5-dimethylbenzoyl)-2-(phenylmethyl)-4-piperidinol methanesulfonate(ester) (interm. 21). Example A9 a) A mixture of (±)-ethyl 4-oxo-2-(phenylmethyl)~l-piperidinecarboxylate (10 g) and benzylamine (4 g) was hydrogenated at 5Q°C In thiophene (4% solution; 1 ml) and methanol (150 ml) with palladium on activated carbon (10%; 3 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off and the solvent was evaporated, yielding (±)-ethyl 2-(phenylmethyl)-4-[(phenylmethyl)amino]-l-piperidme-carboxylate (interm, 22). -25- b) A mixture of intermediate (22) (12 g) was hydrogenated at 50 °C in methanol (150 ml) with palladium on activated carbon (10%; 2 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2CI2/ (CH3OH/NH3) 97/3 to 95/5). The pure fractions were collected and the solvent evaporated, yielding 6 g (67%) of (±)-ethyI 4-amino-2-(phenylmethyl)-l~piperidinecarboxylate (interm. 23). c) Intermediate (23) (15.1 g), 2-chIoro-l-(2-ethoxyethyl)-lH-benzimidazol (13.5 g) and copper (3.84 g) were stirred at 350 °C for 4 hours. The mixture was taken up in CH2CI2 and filtered. The filtrate was washed with a NH4OH solution and with water. The organic layer was dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2C12/ CH3OH 97/3). The pure fractions were collected and the solvent evaporated, yielding 20 g (77%) of (±)-ethyl ci>^f[l-(2^thoxyethyI)-lH-benzxmidazol-2-yl]arriino3-2-(pheny!methyl>- 1-piperidinecarboxylate (interm, 24). Example A10 l-(2-ethoxyethyI)-lff-benzimidazoI-2-amine (8.2 g) was added to (±)-ethy3 2~[(3,4-dichlorophenyI)methylH-oxo-l-piperidinecarboxylate (13.2 g) in CH2C12 (20 ml). Titaniurn(IV)isopropoxide (13,64 g) was added and the mixture was stirred for 3 hours at RT. Sodiumborohydride (1.82 g) in ethanol (20 ml) was added and the reaction mixture was stirred overnight at RT. Water (20 ml) was added and the mixture was stirred for 5 minutes. CH2CI2 (200 ml) was added and the mixture was stirred, dried, filtered, and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2CI2/ CH3OH 98/2, upgrading to 97/3). The desired fractions were collected and the solvent was evaporated, yielding 2.6 g of (±)-ethyl /ra"5-2-[(3)4-dichlorophenyl)methyl]-4-i;[l-(2-ethoxyethyl)-lH-benzirnidazol-2-yl]amino]-l-piperidinecarboxylate (interm. 25), and 6.2 g of (±)-ethyl ds-2-[(3,4-dichlorophenyl)methyl3-4-[[l-(2-ethoxyethyl)-lH-benximidazol-2" yl]amino3-l-piperidinecarboxylate (interm. 26), Example All (±)-1,1-dirnethylethyi £ranM-hydroxy-2~(phenylmethyl)-1 -piperidinecarboxylate (25.6 g) was dissolved in MA^-dimethylformamide (256 mi). Sodiumhydride (4.24 g) was added and the mixture was stirred at RT for 1.5 hours. 2-chloro-l-(2-ethoxyethyi> lH-benzimidazoI (24.8 g) was added and the mixture was stirred at 70°C for 18 hours. The solvent was evaporated, the residue taken up in water and CH2CI2 and the layers were separated. The organic layer was dried, filtered and the solvent evaporated, -26- yielding 50 g (100%) of (±)-lfl-dimethylethyl f"ww-4-[[l-(2-ethoxyethyI)-lff-benzimidazol-2-yI]oxy]-2-(phenylmethyl)-l-piperidine-carboxylate(interm27). Example A12 A mixture of (±)-ethyl rran5-2-[(3,4-dichIorophenyl)methyl]-4-[[l-(2-ethoxyethyl)-l#-benzimidazol-2-yI]amino]-l-piperidinecarboxylate (2.5 g) and KOH (2.8 g) in 2-propanol (50 ml) was stirred and refluxed for 48 hours. The solvent was evaporated. The residue was partitioned between water and CH2CI2. The organic layer was separated, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 95/5, upgrading to 90/10). The pure fractions were collected and the solvent was evaporated, yielding 1.1 g (49.2%) of (±)-frart^-A'r-[2-[(3,4-dichlorophenyl)methy]]-4-piperidinyl]-l-(2-ethoxyethyl)-lff-benzimidazol-2-amine (interm. 28). In a similar way were prepared : (±)-cw-W-[2-[(3,4-dichlorophenyl)methyl]-4-piperidinyl]-l-(2-ethoxyethyl)-l/f-benzimidazol-2-amine dihydrochloride.monohydrate.2-propanolate(2:l) (interm. 29); and (±)-cw-l-(2-ethoxyethyl)-N^-[2-(phenylmethyl)-4-piperidinyl]-l//-benzimidazol-2-amine ethanedioate(l:2) (interm. 30). Example A13 A mixture of (±)-cw-7V-[l,2-bis(phenylmethyI)-4-piperidinyI]-l-methyl-l^-benzimidazol-2-amine (4.7 g) in methanol (200 ml) was hydrogenated with palladium on activated carbon (10%; 2 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eleunt: CH2CI2/CH3OH 95/5). The pure fractions were collected and the solvent evaporated. The residue was suspended in DIPE, filtered and dried, yielding 0.6 g (17%) of (±)-cw-l-methyl-W-[2-(phenylmethyl)-4-piperidinyl]-lff-benzimidazol-2-amine (interm. 31; mp. 86.3 °C). Example A14 (±)-1,1 -dimethylethyl transA-{[\-(2-ethoxyethyl)-l#-benzimidazol-2-yI]amino]-2-(phenylmethyl)-l-piperidinecarboxylate (6 g) was taken up in methanol (160 ml). HC1 in 2-propanol (16 ml) was added and the mixture was stirred and refluxed for 1 hour. The solvent was evaporated, the residue was taken up in water, diluted NaOH and extracted with CH2CI2. The organic layer was separated and purified on a glass filter over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 95/5). The pure fractions were collected and the solvent evaporated. The residue was crystallized from DIPE, yielding -27- 3 g (63.4%) (±)-/ra"1y-l-(2-ethoxyethyl)-A^-[2-(phenylmethyl)-4-piperidinyI]-l^-benzimidazol-2-amine (interm. 32). In a similar way were prepared : (±)-/ran1y-l-(2-ethoxyethyl)-2-[[2-(phenylmethyl)-4-piperidinyl]oxy]-l^-benzimidazole (interm. 33); (±)-/rattj-A^-[2-(phenylmethyl)-4-piperidinyl]-l-(2-thienylme%l)-lff-benzimidazoI-2-amine (interm. 34); (±)-f/-an^-l-[(4-fluorophenyl)methyl]-A^-[2-(phenylmethyl)-4-piperidinyl]-l/?- benzimidazol-2-amine (interm. 35; mp. 127.2 °C); (±)-rra/i5-l-E(2-methoxyphenyl)methyl]-7^-[2-(phenylmethyl)-4-piperidinyI]-lff-benzimidazol-2-amine (interm. 36); (±)-rranj-N-[2-(phenylmethyl)-4-piperidinyl]-l -methyl- l#-benzimidazol-2-amino (interm. 37); (±)-rra/i1y-l-[(2-methyI-5-oxazolyl)methyl]-//-[2-(prienylmethyl)-4-piperidinyl]-l/f-benzimidazol-2-amine (interm. 38); (±)-/ra"^-l-[(5-methyl-2-furanyl)methyl]-A^-[2-(phenylmethyl)-4-piperidinyl]-l/f-2-benzimidazol-2-amine (interm. 39). B. Preparation of the compounds of formula (I) Example B1 A mixture of intermediate (1) (6.44 g) and l-(2-ethoxyethyl)-iV-piperidin-4-yl-l//-benzimidazol-2-amine (4.33 g) in thiophene (4 % solution; 2 ml) and toluene (450 ml) was hydrogenated with palladium on activated carbon (10 %; 1 g) as a catalyst in autoclave at 125°C and under a pressure of 50 kg overnight. After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 98/2). Fraction 1 was collected and evaporated. The residue was crystallized from CH3CN, the precipitate was filtered off and dried, yielding 2.14 g (20 %) of (±)-cw-l-[l,3-bis-(trifluoromethyl)benzoyl]-4-[4-[[l-(2-ethoxyethyl)-l//-benzimidazol-2-yl]amino]-l-piperidinyl]-2-(phenylmethyl)piperidine (comp. 5; mp. 201.5 °C). Fraction 2 was collected and evaporated. The residue was stirred up in petrol ether, the precipitate was filtered off and dried, yielding 1.04 g (10 %) of (±)-fra"^-l-[l,3-bis(trifluoromethyl)-benzoyl]-4-[4-[[l-(2-ethoxyethyl)-l//-benzimidazol-2-yl]amino]-l-piperidinyl]-2-(phenylmethyl)piperidine (comp. 6; mp. 174.5 °C). Example B2 Titanium(IV)isopropoxide (3.55 g) was added to a mixture of intermediate (7) (3.78 g) and intermediate (1) (2.74 g) in ethanol (10 ml) and the mixture was stirred at RT for -28- 6 hours. Sodium cyanoborohydride (0.65 g) in ethanol (5 ml) was added and the mixture was stirred at RT overnight. Water (10 ml) was added, stirred for 15 minutes, CH2CI2 (200 ml) and MgSC>4 were added and the mixture was stirred for 15 minutes. The mixture was filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2CI2/CH3OH 98/2). The pure fractions were collected and evaporated. The residues (fraction A and fraction B) were purified by HPLC (eluent: toluene/2-propanol 95/5). The pure fractions were collected and evaporated. The residues were suspended in petrol ether, filtered off and dried, yielding 0.55 g (7 %) of 2a,4a-fra/iy-l-[3>5-bis(trifluoromethyl)benzoyl]-4-[4-[[l-(2-ethoxyethyI)-l//-benzimidazol-2-yl]amino]-2-(phenyImethyl)-l-piperidinyl]-2-(phenylmethyl)piperidine (comp. 13; mp. 115.3 °C) and 0.74 g (9.3 %) of 2a,4p-/ran^-l-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-[[l-(2-ethoxyethyl)-l//-benzimidazoI-2-yI]amino]-2-(phenylmethyI)-l-piperidinyl]-2-(phenylmethyl)piperidine (comp. 14; mp. 105.9 °C). Example B3 a) 3,5-bis(trifluoromethyl)benzoyl chloride (1.52 g) was added, followed by triethyl- amine (1.4 ml) to intermediate (7) (1.9 g) dissolved in CH2CI2 (100 ml) and the mixture was stirred overnight. The mixture was washed with water and the layers were separated. The organic layer was dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2CI2/ (CH3OH/NH3) 98/2). The pure fractions were collected and the solvent evaporated. The residue was crystallized from DIPE, yielding 2.47 g (80%) of {±)~trans-1 -[3,5-bis(trifluoromethyl)benzoyl]-4-[[ 1 -(2-ethoxyethyl)-1 ff-benzimidazol-2-yl]amino]-2-(phenylmethyl)piperidine (comp. 85; mp. 177.8°C). b) Compound (85) (0.5 g) was separated in its optical isomers by column chromato graphy Chiracel AD over silica gel (eluent: hexane/C2H5OH 80/20) (20 jam). The pure fractions were collected and the solvent was evaporated, yielding 0.21 g (42.4%) of (A-trans)-1 -[3,5-bis(trifluoromethyl)benzoyl]-4-[[ 1 -(2-ethoxyethyl)- \H- benzimidazol-2-yl]amino]-2-(phenylmethyl)piperidine (comp. 94; mp. 110.0°C; 20 [a]D = -22.97° (cone. = 1% in CH3OH)) and 0.24 g (48.5%) of (B-rra".y)-l-[3,5-bis- (trifluoromethyl)benzoyl]-4-[[l-(2-ethoxyethyl)-l//-benzimidazol-2-yI]amino]-2- 20 (phenylmethyl)piperidine (comp. 95; mp. 111.5°C; [cc]D = + 22.96° (cone. = \% in CH3OH)). -29- Example B4 3-methyl-2-benzofurancarboxylic acid (0.100 g) and l~hydroxy-l#-benzotriazole (0.070 g) were added to (±)-trans-l-[(2-methyI-5-oxazolyl)methyl]-A'-tl-[2-(phenyImethyI)-4-piperidiny]]-4-piperidinyl]-lH-benzimidazoI-2-amine (0.100 g) in CHZC12 (5 ml). The mixture was stirred under N2 atmosphere. A solution of triethylamine (0.5 ml) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1:1) (0.080 g) in CH3C12 (10 ml) was added dropwise and the reaction mixture was stirred overnight at RT, under Nr Then, the compound was isolated and purified by column chromato-graphy (eluent gradient: (0.5% ammoniumacetate in HaO)/CH3OH/CH3CN 70/15/15 upgrading over 0/50/50 to 0/0/100). The desired fractions were collected and the solvent was evaporated, yielding 0.060 g of (±>trans-l-[(3-methyI-2~benzofuranyl)-carbonyl]-4-[4-[[H(2-methyl-5-oxazoIyl)methyl]-1 H~benzimidazol-2-yl]amino]-1 -piperidinyl]-2-(phenylmethyl)piperidine. Example B5 A mixture of (±)-trans-iV-[3!5-bis(trifluoromethyl)phenyl3-4-[4-[[l-[(2-inethyl-5-oxazolyl)methyl]-lAr-benzimidazol-2-ylJamino]-l-piperidinylJ-2-(phenyImethyl)-l-piperidinecarboxamide (0.100 g) and 3,5-bis(trifIuoromethyl) benzeneisocyanato (10 drops) in CEfi^ (2 ml) was stirred overnight at RT. Then, the compound was isolated and purified by column chromatography (eluent gradient: (0.5% ammonium-acetate in H2O)/CHjOH/CH3CN 70/15/15 upgrading over 0/50/50 to 0/0/100), The desired fractions were collected and the solvent was evaporated, yielding 0.050 g (±)-trans-iV"[3,5-bis(trifluoromethyl)phenyl3-444-[[l-[(2-methy]-5-oxazolyl)methylJ-lH-benzimidazol-2-yl]amino]-l-piperidinyI]-2-(phenyImethyI)-l-piperidine-carboxamide (comp.52). Example B6 (±ycis-l -(3,5-dimethylbenzoyl)-2-(phenylmethyl)-4-piperidinamine (1.2 g), 2-chloro-H2-thienyIrnethyl)-ltf~benzimidazole (2,24 g) and copper (0.6 g) were stirred at 150°C for 5 hours. The mixture was taken up in CH2CI2 and filtered. The filtrate was washed with diluted NH4OH and stirred. The organic jayer was separated, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent; CH2Ci2/(CH3OH/NH3> 97/3). The pure fractions were collected and the solvent evaporated. The residue was crystallized from CH3CN, yielding 1.87 g (35%) of (±)-cr>-l-(3,5-dirnethylbenzoyl)-2-(phenylmethyl)~iV-[l-(2-thienylmethyl> lK-benzimidazoI-2-yl]-4-piperidinamine (comp. 76; mp. 201.4°C). -30- ExatnpleB? A mixture of (±)~ 1 ~[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyI)-4-piperidinone (4.29 g), 3-(2-furanylmethyl)-3^-imicIazo[4,5-b]pyridin-2-amine (2.14 g) and titanium(IV)isopropoxide (3.41 g) in CH2CI2 (5 ml) was stirred at RT for 3 hours. A mixture of sodium cyanoborohydride (0.628 g) in ethanol (5 ml) was added. The mixture was stirred at RT overnight. Water (5 ml) and CH2CI2 (300 ml) were added. The mixture was stirred for 15 minutes. The biphasic mixture was dried, filtered and the filtrate was evaporated. The residue was purified by HPLC (eluent: 0.5% NH4OC(O)CH3/CH3CN 40/60). Two desired fractions were collected and their solvent was evaporated. Each residue was dried and ground, yielding 1.22 g (19.4%) of(±)-cJ5443?5-bis(trifluoromethyl)berizoyU-44[3 mp. 1O8.3°C). Example B8 (±ycisA-(3,5~dimuhylbenzoyiy2'(phmylmethyl)~4~pipendinol (2.6 g) dissolved in A^AMimethylformamide (100 ml) was stirred under N2. Sodium hydride (60%) (0.36 g) was added and the mixture was stirred at 40°C for 1 hour. 2-Chloro-l~ [(4-fIuorophenyl}--methyl3~lH~benziiHidazoIe (2.6 g) was added and the mixture was stirred at 60°C for 20 hours. The solvent was evaporated and the residue was taken up in water and CH2CI2. The organic layer was separated, dried, filtered and the solvent evaporated. The residue was purified by column chrornatography over silica gel (eluent: CH2CI2/CH3OH 97/3). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE, yielding 2.85 g (65%) of (±)~ds~ 1 -(3,5-dimethy Ibenzoy l)-4-[[ 1 -[(4-fluorophenyI)methyl]-1 #-benzimidazol~2-yl]oxy ]~2~ (phenylmethyl)piperidine (comp. 70; mp. 154.1°C). Example B9 A mixture of l~(2-ethoxyethyl)-lH-benzimidazole-2-thiol (4.44 g), intermediate (21) (6 g) and potassium carbonate (2.76 g) in ethanol (300 ml) was stirred and reftoxed overnight. The solvent was evaporated, the residue was taken up in water and extracted with CH2CI2. The organic layer was dried, filtered and the solvent evaporated. The residue was purified by HPLC (eluent: CH3OH/(H2O/NH4OC(O)CH3 0.5%) 75/25). The pure fractions were collected and their solvent evaporated. The residue was separated by column chrornatography over silica gel (eluent: CH2CI2/CH3OH 98/2 to 96/4). The pure fractions were collected and their solvent evaporated. Residue 1 was -31- dried and grinded, yielding 0.71 g of (±)-c/5-l-(3,5-dimethylbenzoyl)-4-[[l-(2-ethoxy-ethyl)-l^T-benzimidazoI-2-yl]thio]-2-(phenyImethyI)piperidine (corop. 105). Residue 2 was dried and grinded, yielding 1.72 g of (±)-/ra"5-l~(3,5-dimethylbenzoy!)-4-[f l-(2-ethoxyethyl)-l/f-benzinudazoI-2-yl]thio]-2-(phenylniethyl)piperidine(comp. 106; mp. 147.3°C). Example BIO Sodium hydride (0.22 g) was added to a mixture of compound (85) (2.8 g) in MAf-di-methyiformamide (100 ml) and stirred. The mixture was stirred at 60°C for 45 minutes. lodomethane (0.78 g) was added and the mixture was stirred at 70°C overnight. The solvent was evaporated and taken up in CH2CI2 and water. The organic layer was separated, dried, filtered and the solvent evaporated. The residue was purified on a glass filter over silica gel (eluent: CH2CI2/CH3OH 97/3). The pure fractions were collected and their solvent evaporated. The residue was crystallized from DIPE, filtered and dried, yielding 1.19 g (42%) of (±)-*ra"^H3>bis(triflu me%l)benzoyl]-4-[[l-(2^^ (phenylmethyDpiperidine (comp. 108; mp. 155.2°C). ExampIeBll 3-Chlorobenzenecarboperoxoic acid (0.173 g) was added to a mixture of compound (106) (0.5 g) in CH2CI2 (10 ml) and the mixture was stirred for 2.5 hours at RT. The mixture was washed with diluted NaOH, dried and the solvent evaporated. The residue was crystallized from CH3CN. The residue was purified by HPLC (eluent; CH2Q2/ CH3OH 98/2). The pure fractions were collected and their solvent evaporated. The residues were dried, yielding 0.11 g of (A-/ran^)-l-(3,5-dimethylben2oyl)-4-[[l-(2-ethoxyethyl)- li?-benzimidazol-2-yl]sulfinyl]-2-(phenylmethyl)piperidine (comp. 109) and 0.33 g of (B-?m/i5)-l-(3J5-dimethylbenzoyl)-4-[[l-(2"ethoxyethyl)-lH-benzimidazol~2-yl]suIfinyl]-2-(phenylmethyl)piperidine (comp. 110). Isatoic anhydride (0.49 g) was added to a mixture of (±)-?mn^-l-(2^thoxyethyl)-iV~ E2-(phenylmethyl)-4-piperidinyl]-tH-benzimidazol-2-amine (1.14 g) in CH2CI2 (150 ml), the mixture was stirred for 3 hours and then refluxed for 3 hours. The solvent was evaporated, 2-propanoI (100 ml) was added to the residue and the mixture was refluxed for 18 hours, Isatoic anhydride (0.2 g) was added again and the mixture was refluxed for 4 hours. The solvent was evaporated and the residue was purified by column crtromatography over silica gel (eluent; CH2CI2/CH3OH 95/5), The pure fractions were collected and evaporated. The residue was crystallized from DIPE, -32- yielding 0.5 g (33,4%) of (±)-frsn5--I~[2-aminobenzoyI]-4-E[l-(2-ethoxyethyl)-lH-benzimidazol-2~yl]amino]-2~(phenylrnethyl)piperidine (comp 123; mp. 197.4°C). The following tables list compounds that were prepared according to one of the above examples (Ex.). Table 1 Co. Ex P R A Y R4 R6 Physical Data No, (nip, in °C) 1 Bl 1 CH3 CH NH CH2-CH2-O-CH2-CH3 H (±hcisf 102.0 2 Bl 1 CH3 CH NH CH2-CH2-O-CH2-CH3 F H Ct)-/mnff/98.8 3 Bl 1 CH3 CH NH H (±)-cis/134.5 4 Bl 1 CH3 CH NH F H {±)-trans 11203 5 Bl 1 CF3 CH NH CH2-CH2-O-CH2-CH3 H {±)-cisf 201.5 6 Bl 1 CF3 CH NH CH2-CH2-O-CH2-CH3 H (±)-trans /174.5 7 B2 1 CH3 CH NH H (±)~cis? 121.8 8 B2 1 CH3 CH NH H (±)-tmnsl 139.6 9 B2 1 CH3 CH NH -CH3-^ N H (±)-cis/ 134.1 10 B2 1 CH3 CH NH -CH2-^ -N H (±>/m/w/134.9 11 B2 1 CH3 CH CH2 /V"! H (±)-c/5/90.6 12 B2 1 CH3 CH CH2 ssyc"' _CH2-Ii N H (±)-transl95,X 13 B2 1 CF3 CH NH CH2-CH2-O-CH2-CH3 benzyl 2a, 4a iran^ / 115.3 Co. No. Ex P R A Y R4 R6 Physical Data (mp. in °C) 14 B2 1 CF3 CH NH (CH2)2-O-CH2- benzyl 2 "CH2U H 105.9 (±hcisf 149.0 16 B2 1 CF3 CH NH 0 CH3 "CH2"(Y \l-N H {±)~trans 17 B2 1 CF3 N NH ~CH2\Y I. L rj H (±)-cisf 123.5 18 B2 1 CF3 N NH 0NyCH3 H (±)-trans/153.8 H3C 19 B2 1 CF3 N NH H (±)-cis/148.1 20 B2 1 CF3 N NH -CH2-^ >-CH3 H (±>mws /107.6 21 B2 1 CF3 CH CHOH H A-m/110.2 22 B2 1 CF3 CH CHOH A ~CH2"C |PCH3 H B-ds/108.7 23 B2 1 CF3 CH CHOH ^°-CH2-~CH3 H (±)-rran^/185.5 24 B2 1 CF3 CH O _ CHr/ \__P H (±)-ciiF/130.9 25 B2 1 CF3 CH O -CH2-^ ^-F H (±ytransf 168.8 26 B2 1 CF3 CH NH -CH2~# ^ F H (±)-cr> / 220.6 27 B2 1 CF3 CH NH -CHa"^ ^ F H (±)-trwisf 126 A 28 29 B2 1 B2 1 CF3 CF3 CH CH NH NH A -CH2~ (jtytrans/ 130.0/ hydrate (1:1) 30 31 B2 0 B2 0 CF3 CF3 N N NH NH A H H (±)-cw/90.8 (±)-trans I 80.7 hydrate (1:1) / -34- Co. No. 32 ' ii ¦ Ex -^*-^" B3 - i P 1 '- - R 1 -¦ CH3 ¦ ' ' II ¦- A ~ i* ¦ in ii cn ""II "¦ im- Y NH R4 -CHiT 1 - - I-.. -^ H -- .-.--____ Physical Data (mP- in °C) ""'¦¦I""J- ¦-~ f 1 . . (±)-tran$ 33 B2b 1 CF3 CH CH2 H {±)~trans 34 B2a 1 CF, CH S H (±)-cis 35 B2a 1 CF CH s -Ofy-P \-F H (±)-trans 36 B2a CF CH 0 *' TJ H (±)-cis 37 B2a ¦ CF CH 0 IN H (&)-tmns 38 3a H CH NH "-K H (±)~tmns 40 2b CF CH CU, -'CH2~\ y F H (±)~cis 41 2a CF CH CH2 _CHr-^ V"CH3 l. H {±ytrans 42 2a CF CH CH2 H (±ycis 43 2a CF CH NH -CH2- 44 B2a ¦ CF CH NH H (±)~cis Co. No. Ex A*. X R2 R Physical Data (mp. in °C) 45 46 47 48 B3a B3a B3a B3a direct bond direct bond direct bond * ¦ \ direct bond 2-naphalenyl 2-furanyl phenyl .-. CH3 € N>-CH- direct bond direct bond direct bond direct bond (±)-trans (±)-trans (±)-trans (±)-trans -35- Co. Ex X R2 R Physical Data No. (mp. in °C) 49 B3a NH 3,5-bis (trifluoro- irect bond (±)-trans methyl)phenyl 50 B4 irect bond 6-benzothiazolyJ irect bond (±}-trans 51 B4 irect bond 5-fluoro-2~indo]yl irect bond ±ytrans 52 B5 NH 3,5-bis (trifluoro- -piperidinyJ ±)- trans methyOphenyl 53 B3a irect bond -cyanophenyl -piperidiny! ±)-trans 54 B3a irecf bond -(1-methyiethoxy}- -piperidinyl ±)-trans henyJ 55 B3a irect bond ,5~dichlorophenyl -piperidinyl ±)-trans 56 B3a irect bond -thienyJ -piperidinyl ±)-trans 57 B3a irect bond 2-quinolinyl -piperidinyl ±)-trans 58 B3a irect bond 3,4,5-trimethoxy- -piperidinyl ±)-cis )henyl 59 B3a direct bond 2-thienyl -piperidinyl ±)-cis 60 B3a direct bond 5~methyl-3-isoxaEolyl -piperidinyl ±)-cis 61 B3a direct bond 2,6-dichloropyridinyl -piperidinyl ±)-cis 62 B3a direct bond 2-quinoxalinyl -piperidinyl (±)-cis 63 B3a direct bond 3-(l-methylethoxy)- -piperidinyl {±)-cis shenylmethyl 64 B3a S phenyl 4-piperidinyl (±)-cis 65 B4 direct bond 2,4-dimethyl-5- 4-piperidinyl (±)-cis thiazolyl B4 direct bond 5-roethyl-2-pyrazinyI 4-piperidinyl (±)-trans 00 67 XJ"T B4 direct bond 3~methyl-2-benzo~ 4-piperidinyl (±)-trans 68 ' B4 direct bond_ S-fluoro-2-indolM 4-piperidinyl_ Tablel -36- Co. No. Ex. No. R1 R" --y R4 -A=B- Physical data (mp. in °C) 69 B8 -CH3 -CH3 -O- -CH3 -CH=CH- 171.1; (±)-cis 70 B8 -CH3 -CH3 -O- (4-fluorophenyl)methyl -CH=CH- 154.1; (±)-cis 71 B8 -CH3 -CH3 -O- 2-methoxyphenyl)methyl -CH=CH- 151.7; (±)-cis 72 B8 CH3 -CH3 -0- -CH3 -CH=CH- 185.6; {±)~trans 73 B3a CH3 -CH3 -NH- -CH3 -CH=CH- 185.9; (±)-cis 74 B3a CH3 -CH3 -NH- -(CH2)2-O-CH2-CH3 -CH=CH- 166.4; (±)-trans 75 B3a CH3 CH3 -NH- -(CH2)2-O-CH2-CH3 CH=CH- 123.9; (±)-cis 76 B6 CH3 CH3 -NH- 2-thienylmethyI CH=CH- 201.4; (±)-cis 77 B3a CH3 CH3 -NH- (4-fluorophenyl)methyI CH=CH- 249.9; (±)-trans 78 B3a CH3 CH3 -NH- 2-thienylmethyl CH=CH- 250.7; (±)-trans 79 B3a CH3 -CH3 -NH- 2-methoxyphenyl)methyl CH=CH- 154.1; {±)~trans 80 B8 CH3 CH3 -0- -(CH2)2-O-CH2-CH3 CH=CH- 67.2; (±)-cis 81 B8 CH3 CH3 -O- 2-thienylmethyl CH=CH- 196.0; (±)-trans 82 B8 CH3 CH3 -0- -(CH2)2-O-CH2-CH3 CH=CH- 55.9; {±)-trans 83 B3a CH3 CH3 -NH- " -CH3 CH=CH- 151.7; (±)-trans H2O 84 B3a CH3 CH3 -NH- (2-methyl-5-oxazolyl)-methyl CH=CH- 226.3; (±)~trans 85 B3a CF3 -CF3 -NH- -(CH2)2-O-CH2-CH3 -CH^CH- 177.8; (±)-trans 86 B3a -H -H -NH- -(CH2)2-O-CH2-CH3 -CH=CH- ±)-trans 87 B3a -H -CH3 -NH- -(CH2)2-O-CH2-CH3 -CH=CH- (±)-trans 88 B3a -H -CN -NH- -(CH2)2-O-CH2-CH3 -CH=CH- (±)-trans 89 B3a -H -CF3 -NH- -(CH2)2-O-CH2-CH3 -CH=CH- [±)-trans 90 B3a oca -OCH3 -NH- -(CH2)2-O-CH2-CH3 -CH=CH- (±)-trans 91 B3a -ci -Cl -NH- -(CH2)2-°-CH2-CH3 -CH=CH- (±)-trans 92 B3a -F -F -NH- -(CH2)2-O-CH2-CH3 -CH=CH- 173.7; (±)-trans 93 B8 -CH3 -CH3 -0- (2-methyl-5-oxazolyl)-methyl -CH=CH- 155.1; {±)-trans 94 B3b -CF3 -CF3 -NH- -(CH2)2-O-CH2-CH3 -CH=CH 110.0; [a]D = -22.97 (cone. = l%inCH3OH); 4 i \ A-trans; 95 B3b -CF3 -CF3 -NH- -(CH2)2-O-CH2-CH3 -CH=CH 20 111.5; [a]D = +22.96 (cone. = l%inCH3OH); * B-trans -37- Co. No. Ex. No. R1 R" y R4 -A=B- Physical data (mp. in °C) 96 B3a -CF3 -CF3 -O- -(CH2)2-O-CH2-CH3 -CH=CH- 115.9; (±)-trans 97 B3 -CF3 -CF3 -NH- ¦(CH2)2-O-CH2-CH3 -CH=CH- 77.5; [a]^° = -5.99° (cone. = 1% in CH3OH); B-cis 98 B3a -CF3 -CF3 -NH- (2-methyl-5- -CH=CH- 204.8; (±)-trans furanyl)methyl 99 B3a -CF3 -CF3 -NH- (2-methy!-5- -CH=CH- 211.0; (±)-trans furanyl)methyl 100 B3a -CH3 -CH3 -NH- (2-methyl-5- -CH=CH- 188.0; {±)-trans furanyl)methyl 101 B3a -OCH; -OCH3 -O- -(CH2)2-O-CH2-CH3 -CH=CH- (±)-trans 102 B3a -Cl -Cl -O- -(CH2)2-O-CH2-CH3 -CH=CH- (±)-trans 103 B3a -H -CF3 -O- -(CH2)2-O-CH2-CH3 -CH=CH- (±)-trans 104 B3a -F -F -O- -(CH2)2-O-CH2-CH3 -CH=CH- (±)-trans 105 B9 -CH3 -CH3 -S- -(CH2)2-O-CH2-CH3 -CH=CH- (±)-cis 106 B9 -CH3 -CH3 -S- -(CH2)2-O-CH2-CH3 -CH=CH- 147.3; (±)-trans 107 B3 -CF3 -CF3 -NH- -(CH2)2-O-CH2-CH3 -CH=CH- 80.4; A-cis 108 BIO -CF3 -CF3 -N-CH3- -(CH2)2-O-CH2-CH3 -CH=CH- 115.2; (±)-trans 109 Bll -CH3 -CH3 -SO- -(CH2)2-O-CH2-CH3 -CH=CH- A-trans 110 Bll -CH3 -CH3 -SO- -(CH2)2-O-CH2-CH3 -CH=CH- B-trans 111 B3a -CF3 -F -NH- -(CH2)2-O-CH2-CH3 -CH=CH- (±)-trans 112 B7 -CF3 -CF3 -NH- 2-furanyImethyI -N=CH- 108.7; (±)-cis 113 B7 -CF3 -CF3 -NH- 2-furanylmethyl -N=CH- 108.3; (±)-trans 114 B3 -CF3 -CF3 -NH- (2-methyl-5- -CH=CH- 108.2, [a]p° = oxazolyl) methyl +24.77° (cone. = 1% in CH3OH); A-trans 115 B3 -CF3 CF3 -NH- (2-methyl-5- -CH=CH- 110-120, [a]D = oxazolyl)methyl -25.07° (cone. = 1% in CH3OH); B-trans Table 4 -38- Co. Ex, m n X& R2 ^ysical Data No. (mp. in °C) 116 13a 1 1 d.b. -NH- phenylmethyl 2,4-dichIorophenyl (±)-trans 117 13a 1 1 d.b. -NH- phenyimethyl 4-chlorophenylmethyl {±)-trans 118 13a 1 1 d.b. ¦NH- phenyimettiyl 2-naphtalenyJ {±)-trans 119 13a 1 1 d.b. ¦NH- phenylmethyl 2-naphtalenylmethyI {±)-trans 120 13a 1 1 -0- NH~ phenylmethyl phenylmethyl i±)-trans 121 13a 1 1 d.b. NH- phenyimethyl 1-phenylethyi (±)-trans; mp. 74.9 122 13a 1 1 d.b. NH- phenylmethyl 1 -methy 1-2-pyrrolyl (±)-trans; mp. 117.6 123 20 1 1 d.b. NH- phenylmethyl 2-aminophenyl (±)~trans; mp. 197.4 124 [3a 1 1 d.b. NH- phenylmethyl 3-(2-propoxy>- (±)-trans; phenylmethyl mp. 55.3 125 13a 1 1 d.b. -O- phenylmethyl 3,4-dichlorophenyl (±)-trans 126 3a 1 1 d.b. -o- pfienyhnethyi 2-naphtalenyl (±)-trans 127 3a 1 1 d.b. -o- phenylmethyl l-phenylethyl (±)-trans 128 3a 1 1 d.b. -o- phenylmethyl 4-chlorophenylmethyl (±)-trans 129 3a 1 1 d.b. o- phenylmethyl 2-quinolinyl (±)-trans 130 3a 1 1 d.b. -o- phenylmethyl 2-naphtalenylmethyl {±)-trans 131 15 1 1 d.b. NH- phenyl 3,5-bis(trifluoro)pheny 1 ±)-tis; mp. 84.9 132 13a 1 I d.b. NH- phenylmethyl 2,4-bis(trifluoro)phenyl (±)-trans 133 3a 1 1 d.b. HH- phenylmethyl 2-trifluorophenyl {±ytrans 134 13a 1 1 d.b. NH- phenylmethyl 2-trifluoro-4~fiuorophenyl {±)-trans 135 13a 1 1 d.b. NH- phenylmethyl 2,5-bis(trifluoro)phenyl {±)-trans 136 13a 1 1 d.b. NH- phenylmethyl 2-fluoro-6~trifluorophenyI (±ytrans 137 13a 1 1 d.b. NH- phenylmethyl 2-fluoro-3-triflnorophenyI (±)-trans 138 13a 1 1 d.b. NH- phenylmethyl 3-trifluorO"4-fluoropheny) (±)-trans 139 13a 1 1 d.b. -NH- phenylmethyl 2-fluoro-5-trifluorophenyI (±)-trans 140 13a 1 1 d.b. -NH- (3,4-dichloro- 3,5-bis(trifluoro)phenyl (±)-cis; mp. phenyl)methyl 88.3 141 13a 1 1 d.b. -NH- (3,4-dichloro-phenyl)methyl 3,5-bis(trifluoro)phenyl (±)-trans; mp. 194.9 142 15 1 1 d.b. -NH- (3,4-dimethoxy-phenyl)methyi phenylmethyl 3,5-bis(trifluoro)phenyl (±)-trans 143 13a 1 i*"ni* 1 d.b. -NH- -¦ I"I* 2,6-bis(trifluoro)phenyI {±)~trans; mp. 212.1 ¦> J ¦ "¦ j -39- Co. No. Ex. m n X& R2 Physical Data (mp. in °C) 144 B3a 1 1 d.b. -NH- 4-chlorophenyl- methyl 2,5-bis(trifluoro)phenyl (±)-trans 145 B3a 1 1 d.b. -NH- 4-chlorophenyl-methyl 2,5-bis(trifluoro)phenyl (±)-cis 146 B2a 1 1 d.b. -NH- 4-(trifluoro)-phenylmethyl 3,5~bis(trifluoro)pheny 1 (±)-cis 147 B2b 1 1 d.b. NH 3,4-difluoro-phenylmethyl 3,5-bis(trifluoro)phenyl (±)-trans 148 B2b 1 1 d.b. NH 3,4-difluoro-phenylmethyl 3,5-bis (trifluoro)pheny 1 (±)-cis 149 B2a 1 2 d.b. NH phenylmethyl 3,5-bis(trifluoro)phenyI (±)-(cis + trans) 150 B2a 2 1 d.b. NH phenylmethyl 3,5 -bis(trifluoro)phenyl (±)-(cis + trans) d.b. means direct bond C. Pharmacological examples Example Cl : Antagonism of substance P induced relaxation of the pig coronary arteries Segments of coronary arteries taken from pigs (killed by injection of an overdose of sodium pentobarbital) were inverted and mounted for recording of isometric tension in organ baths (volume 20 ml) with the endothelium at the outside. The preparations were bathed in Krebs - Henseleit solution. The solution was kept at 37 °C and gassed with a mixture of O2 / CO2 (95/5). After stabilisation of the preparations, prostaglandin F2a (10~^ M) was administered to induce a contraction. This was repeated until contractile responses became stable. Then prostaglandin F2a was again administered and substance P (3xl0~10 M and 10"9 M cumulatively) was added. Substance P induced endothelium dependent relaxations. After washing away the agonists, a known concentration of a compound of formula (I) was added. After an incubation period of 30 minutes, prostaglandin F2oc (10"^ M) and the same concentrations of substance P as described above were again administered in the presence of the compound to be tested. Relaxations caused by substance P were expressed as relaxations under control conditions, and the percentage inhibition (% inhibition) of the response to 10"9 M substance P was taken as a measure of the antagonistic activity of the compound to be tested. The results for the compounds of the present invention at a certain test concentration are listed in table 5. -40- Table 5 Comp. Concentration % No. test compound inhibition 1 3 x 10-8 15.0 2 3 x 10-8 41.1 3 3 x 10-7 35.2 4 3 x lO"8 10.2 5 3 x 10-8 80.7 6 3 x 10"8 85.3 7 3 x lO"8 54.0 8 1 x 10"8 14.7 9 3 x 10"8 78.1 10 3 x 1O"8 89.3 11 3 x 10-8 81.1 12 3 x 10-8 92.3 13 3 x lO"8 19.9 14 3 x lO-8 53.3 15 3 x 10"8 84.6 16 3 x lO-8 88.8 17 3 x lO-8 94.5 18 3 x lO"9 73.7 19 3 x 10-9 79.5 20 3 x lO"9 68.9 21 3 x 10"8 95.8 22 3 x lO9 89.4 23 3 x 10"9 94.3 24 3 x lO-8 100 25 3 x 10"8 100 26 3 x 10"8 82.2 27 3 x lO-8 92.8 28 3 x 10"8 100 Comp. Concentration % No. test compound inhibition 29 3 x lO-8 65.6 30 3x lO-8 87.5 31 3 x lO"9 90.6 44 3 x lO-8 91.5 43 3 x 10"8 85.2 150 3 x lO-8 98.1 149 3 x 10-8 12.7 . 42 3 x lO-8 96.9 41 3 x 10"9 82.6 36 3 x 10"9 66 145 3 x 10"9 92.2 40 3 x 10-8 93.3 33 3 x 10"9 56.8 144 3 x lO-9 88.4 147 3 x lO-8 95.6 148 3 x 10"8 100 34 3 x 10-8 69.6 35 3 x 10-8 88.5 146 3 x 10"9 51.8 37 3 x lO"9 70.5 32 3 x 10"9 20.1 54 3xlO"9 7.3 55 3 x 10"9 28.1 56 3 x 10-9 8.7 65 3 x lO"9 9.7 52 3 x 10"9 6.3 46 3 x 10"9 17.6 45 3 x 10-9 13.1 D. Composition examples "Active ingredient" (A.I.) as used throughout these examples relates to a compound of formula (I) a pharmaceutically acceptable addition salt, a stereochemically isomeric form thereof or a iV-oxide form thereof. -41- Example D.I : ORAL SOLUTION Methyl 4-hydroxybenzoate (9 g) and propyl 4-hydroxybenzoate (1 g) were dissolved in boiling purified water (41). In 3 1 of this solution were dissolved first 2,3-dihydroxy-butanedioic acid (10 g) and thereafter A.I (20 g). The latter solution was combined with the remaining part of the former solution and 1,2,3-propanetriol (12 1) and sorbitol 70% solution (3 1) were added thereto. Sodium saccharin (40 g) were dissolved in water (500 ml) and raspberry (2 ml) and gooseberry essence (2 ml) were added. The latter solution was combined with the former, water was added q.s. to a volume of 20 1 providing an oral solution comprising 5 mg of the active ingredient per teaspoonful (5 ml). The resulting solution was filled in suitable containers. Example D.2 : FILM-COATED TABLETS Preparation.qftablet.cpre A mixture of A.I. (100 g), lactose (570 g) and starch (200 g) was mixed well and thereafter humidified with a solution of sodium dodecyl sulfate (5 g) and polyvinyl- pyrrolidone (10 g) in water (200 ml). The wet powder mixture was sieved, dried and sieved again. Then there was added microcrystalline cellulose (100 g) and hydrogenated vegetable oil (15 g). The whole was mixed well and compressed into tablets, giving 10.000 tablets, each containing 10 mg of the active ingredient. Coating To a solution of methyl cellulose (10 g) in denaturated ethanol (75 ml) there was added a solution of ethyl cellulose (5 g) in CH2C12 (150 ml). Then there were added CH2CI2 (75 ml) and 1,2,3-propanetriol (25 ml). Polyethylene glycol (10 g) was molten and dissolved in CH2C12(75 ml). The latter solution was added to the former and then there were added agnesium octadecanoate (2.5 g), polyvinylpyrrolidone (5 g) and concentrated colour suspension (30 ml) and the whole was homogenated. The tablet cores were coated with the thus obtained mixture in a coating apparatus. Example D.3 : INJECTABLE SOLUTION Methyl 4-hydroxybenzoate (1.8 g) and propyl 4-hydroxybenzoate (0.2 g) were dissolved in boiling water (500 ml) for injection. After cooling to about 50°C there were added while stirring lactic acid (4 g), propylene glycol (0.05 g) and the A.I. (4 g). The solution was cooled to RT and supplemented with water for injection q.s. ad 1 1, giving a solution comprising 4 mg/ml of A.I.. The solution was sterilized by filtration and filled in sterile containers. -49- Claims 1. A compound of formula a W-oxide form, a pharmaceutically acceptable addition salt' or a stereoehernically isornericform thereof, wherein n is 0,1 or 2; m is 1 or 2, provided that if m is 2, then n is 1; X is a covalent bond or a bivalent radical of formula -O~, -S-, -NR3-; =Q is =0 or =NR3; R1 is AT1, Ar^Ci-ealkyl or diCAr^Ci-eaikyl wherein the Cj^alkyl group is optionally substituted with hydroxy, C^alkyloxy, oxo or a ketalized oxo substituent of formula -O-CH2~CH2-O- or -O-CH2-CH2~CH2-O-; R2 is Ar2, Ar^Ci-ealkyl, Hct or HetCi-gaUsyl; L is a radical of formula wherein p is 0, 1 or 2; ^.Y_ js a bivalent radical of formula -CH2-, -CH(OHh -C(=OK -O-, -S-, -S(=O)-; "S(=O)2% -NR3-, -CH2-NR3- or -C(=0)~NR3-; or a trivalent radical of formula =CH-; -A=B- is a bivalent radical of formula -CH=€H~, -N=CH- or -CH"N-; R3 independently is hydrogen or Ci^alkyl; R4 is hydrogen, Ci-6alkyl, C3.7cycloalkyl or a radical of formula -Alk-R? (c-l)or -Alk-Z~R8 (c-2); wherein Alk is Ci-galkanediyl; Z is a bivalent radical of formula -O-, -S- or -NR3-; R7 is pfaenyl; phenyl substituted with i or 2 substituents selected from halo, Cvgalkyl or Ci-ealkyloxy; furanyl; furanyl substituted with 1 or 2 substituents selected from Ct-ealkyl or hydroxyCi^alkyl; thienyl; thienyl substituted with 1 or 2 substituents selected from halo or Ci-galkyl; 43- oxazolyl; oxazolyl substituted with 1 or 2 Chalky! substituents; thiazolyl; thiazolyl substituted with 1 or 2 Cj.$aikyl substituents; pyridinly or pyridinyl substituted with 1 or 2 Chalky 1 substitu tents; R8 is Ci.6alkyl or Chalky! substituted with hydroxy, carboxyl or Cuealkyloxycarbonyl; R5 is hydrogen, halo, hydroxy or Ci^alkyloxy; R6 is hydrogen, C^alkyl or A^C^alkyl; Ar1 is phenyl; phenyl substituted with 1,2 or 3 substituents each independently selected from halo, CMalkyl, haloCMalkyi, cyano, minocarbonyl, CMaikyloxy orhaloCMalkyloxy; Ar2 is naphtalenyl; phenyl; phenyl substituted with 1,2 or 3 sabstituents each independently selected from hydroxy, halo, cyano, nitro, amino, mono- or di(CMaBcyI)anino, Ci^alkyl, haloCMalkyl, CMalkyloxy, haloCMalkyloxy, carboxyl CMalkyloxycarbonyl, aminocarbonyl and mono- or di(CMalkyl)amfflocarbonyh and Het is a monocyclic heterocycle selected from pyrrolyl, pyrazolyl, imidazolyl, furanyl, thieny], oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyi, pyrazinyi and pyridazisyl; or a bicyclic heterocycle selected from qumolinyl, quinoxalinyl, indolyl, beazimidazolyl, benzoxazolyt, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuraiyl and benzothienyl; each monocyclic and bicyclic heterocycle may optionally be substituted on a carbon 44 atom by 1 or 2 substituents selected from halo, Chalky 1 or mono-, di-ortri(halo)m ethyl. 2. A compound as claimed in claim 1 wherein L is a radical of formula (A) and Het is a monocyclic heterocycle selected from pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyi, pyrazinyl and pyridazinyl; or a bicyclic heterocycle selected from quinoiinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzothiazolyl, benzisothiazolyl, benzofuranyl and benzothienyl; each monocyclic and bicyclic heterocycle may optionally be substituted on a carbon atom by 1 or 2 substituents selected from halo, CMalkyl or mono-, di- or tri(halo)methyl. 3. A compound as claimed in claim 1 wherein L is a radical of formula (B) and Het is a monocyclic heterocycle selected from pyrrolyi, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocycle selected from quinolinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl and benzothienyl; each monocyclic and bicyclic heterocycle may optionally be substituted on a carbon atom by 1 or 2 substituents selected from halo, Chalky! or mono-, di- or tri(halo)m ethyl. - 45 4, A compound as claimed in any one of claims 1 to 3 wherein L is a radical of formula (A) and p is 0 or 1. 5. A compound as claimed in any one of claims I to 4 wherein L is a radical of formula (B), n is I or 2, and m is 1 or 2, provided thai if m is 2* then n is 1. 6. A compound as ciairaed m any one of claims i to 5 wherein R1 is Ar'Ct.tf&ikyl, R2 is phenyl substituted with 2 sabstituents selected from methyl or trifhoroniethyl X is a covaient bond and ~Q is 7- A compound as claimed in any one of claims 1 to 6 whereia - Y Is -NH* or -0-; - A-B. is -CH-CH- or -N-CH-; U4 is a radical of formula (c-1) wherein R? is oxa^olyl s"bstitated with 1 or 2 Ct. (ialkyi snbstituents, fiirasyl substituted with Ci-Salkyl or hydroxyCt. 6alkyl; or R^is a radical of formula (c-2) wherein Z is a bivalent radical of formula -0-, and R8 is Cj^aOcyU R1 is hydrogen; and Rs is hydrogen- 8. A compound as claimed in claim 1 selected from l-[l,3-bis(tnHuoroBiethyl)benzoyI]-4-[4-[[I-(2-ethoxyethyl)-lif- benzimidazoi-2-y!]smino]-l-piperidkyl]*2- (pheaytaethyl)piperidme; -46- l-[3,5-bis(trifluororaethyl)benzoyl]-4-[4-[[l-(2-methyi-5- oxazoIyl)methyl]-ll//'-benzimidazol-2-yl]amino]-l-piperidinyl]-2- (phenylmethyl)piperidine; l-l^^-bisftrifluoromethylJbenzoylJ^-^-flS-CS-methyl^-furanyl)- 3//-unidazo[4,5-b]pyridin-2-yI]amino]-l-piperidinyI]-2- (phenylmethyl)piperidine; l-[3>5-bis(trifluororaethyl)benzoyl]-4-[3-[[3-[(5-methyl-2- fu ran yl)m ethyl] 3/f-imidazo[4,5-b]pyridin-2-yl]amino]-l- pyrrolidinyl]-2-(phenylmethyl)piperidine; l-[3,5.bis(trifluoromethyl)benzoyl]-4-[4-[[l-[(5- methyt-2- furanyl)methyI]-l/f-benzimidazol-2-yl]amino]-l- piperidinyi]piperidine; i-[3,5-bis(trmuoromethyl)benzoyl]-4-[[l-2-ethoxyethyl)- IH- benzimidazol-2-yI]amino]-2-(phenylmethyl)piperidine; l-[3>5-bis(triiluoromethyl)benzoyl]-4-[[l-(2-methyl-4- oxazolyl)raethyl]-li/-benzimidazol-2-yl]aaaiBo]-2- (phenylmethyl)piperidine; l-[3s5-bis(trifluoromethyl)benzoyl]-4-[[l-[(5-methyI-2. furanyl)m ethyl]- l/f-benzimidazoI-2-yl]amino]-2- (phenylmethyi)piperidine; a stereoisomeric form or a pharmaceutically acceptable acid addition salt thereof. 47- 9. A pharmaceutical composition comprising a phannaceiitically acceptable carrier, and as active ingredient a therapemically effective amount of a compound as claimed in any one of claims 1 to 8. 10. A process of preparing a composition as claimed in claim 9, wherein a phannaceutically acceptable carrier is intimately mixed with atherapeutically effective amount of a compound as claimed in any one of claims 1 to 8. 11. A compound as claimed in any one of claims 1 to 8 for use as a medicine. 12. A process of preparing a compound as claimed in claim I5 wherein a) reacting an intermediate of formula (II) wherein R2, X and Q are defined as in claim 1 and W1 is an appropriate leaving group, with an intermediate of formula (III) wherein n, m" L and R1 are defined as in claim I, in a reaction-inert solvent, mid in the presence of a suitable base; 48 b) redsctively N-alkylattag an intermediate of formula (V) wherein p" - Y " -A^B-, R4, R5 and R6 are defined as in claim 1, with an intermediate of formula (IV) wherein R1, R2" X, Q. n and m are defined as in claim 1, in a reaction-inert solvent, in the presence of a reducing agent and optionally k the presence of a suitable catalyst; thus forming a compound of formula (1-A); 49 c) reductively iV-alkylating an intermediate of formula (VI) wherein -A=B-, R3, R4 and R5 are defined as in claim 1, with an intermediate of formula (IV) wherein R1, R2, X, Q, n and m are defined as hYcIaim 1, in a reaction-inert solveriV in the presence of a.reducing agent and optionally in the presence of a suitable catalyst; thus forming a compound of formula (I-B-l); d) reacting an intermediate of formula (VII) wherein R1, R2, R3, X, Q, n and m are defined as in claim 1. with an intermediate of-formula (Vim wherein W2 is an appropriate leaving group and -A=B-, R4 and R5 are defined as in claim 1, in the presence of a suitable catalyst Jtnd optionally in a reaction-inert^ solvent; thus forming a compound of formula (I-B-l); e) reacting an intermediate of formula (IX) wherein W3 is a suitable leaving group and R1, R2, X, Q, n and m are defined as in claim 1, with an intermediate of formula (X) wherein -A=B-, R4 and R3 are defined as in claim 1, in a reaction-inert solvent,'and in the presence of a suitable base; thus forming a compound of formula (I-B-2); f) reacting an intermediate of formula (XI) wherein R1, R2, X, Q, n and m are defined as in claim 1, with an intermediate of formula (VHI) 50 wherein W2 is an appropriate leaving group and -A=B-, R4 and R5 are defined as in claim 1, in a reaction-inert solvent and in the presence of a Suitable base; thus forming a compound of formula (I-B-3); and, if desired, converting compounds of formula (I) into each other following art-known transformations, and further, if desired, converting the compounds of formula (I), into a therapeutically active non-toxic acid addition salt by treatment with ^an acid, or into a therapeutically active non-toxic base addition salt by treatment with a base, or conversely, converting the acid addition salt form into the free base by treatment with alkali, or converting the base addition salt into the free acid by treatment with acid; and, if desired, preparing stereochemically isomeric forms or N-oxide forms thereof. This invention concerns the compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein n is 0, 1 or 2; m is 1 or 2, provided that if m is 2, then n is 1; X is a covalent bond or a bivalent radical of formula -O-, -S-, -NR3-; =Q is =O or =NR3; R1 is Ar1, Ar1C1-6alkyl or di(Ar1)C1-6alkyl wherein the C1-6alkyl group is optionally substituted; R2 is Ar2, Ar2C1-6alkyl, Het or HetC1-6alkyl; L is a benzimidazole or imidazopyridine derivative of formula (A) or (B) Ar1 is optionally substituted phenyl Ar2 is naphtalenyl or optionally substituted phenyl; and Het is an optionally substituted monocyclic or bicyclic heterocycle; as substance P antagonists; their preparation, compositions containing them and their use as a medicine. |
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| Patent Number | 209255 | |||||||||||||||
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| Indian Patent Application Number | 02225/CAL/1996 | |||||||||||||||
| PG Journal Number | 34/2007 | |||||||||||||||
| Publication Date | 24-Aug-2007 | |||||||||||||||
| Grant Date | 23-Aug-2007 | |||||||||||||||
| Date of Filing | 23-Dec-1996 | |||||||||||||||
| Name of Patentee | JANSSEN PHARMACEUTICA N.V. | |||||||||||||||
| Applicant Address | TURNHOUTSEWEG 30, B-2340 BEERSE, BELGIUM | |||||||||||||||
Inventors:
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| PCT International Classification Number | A 61K 31/4418 | |||||||||||||||
| PCT International Application Number | N/A | |||||||||||||||
| PCT International Filing date | ||||||||||||||||
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