Title of Invention

1-(1,2-DISUBSTITUTED PIPERIDINYL)-4-SUBSTITUTED PIPERAZINE DERIVATIVES.

Abstract

the N-oxide forms, the pharmaceutically acceptable addition salt and stereoisomeric forms thereof, wherein n is 0, 1 or 2; m is 1 or 2, provided that if m is 2, then n is 1; p is 1 or 2; =Q is =0 or =NR3; X is a covalent bond or a bivalent radical of formula-O-, -S-,-NR3-; R1 is Ar1, Ar1C1-6alkyl or di(Ar1)C1-6alkyl, wherein each C1-6alkyl group is optionally substituted with hydroxy, C1-4alkoloxy, oxo or a ketalized oxo substituent; R2 is Ar2 , Ar2 C1. 6alkyl, Het1 or Het1 C1-6alkyl; R3 is hydrogen or C1-6alkyl; L is hydrogen; Ar3 ; C1-6alkyl; C1-6alkyl substituted with 1 or 2 substituents selected from hydroxy, C1-6alkyloxy, Ar3, Ar3C1-6alkyloxy and Het2;C3-6alkenyl; Ar3C3. 6alkenyl; di(Ar3)C3-6alkenyl or a radical of formula (a-1), (a-2), (a-3), (a-4) or (a-5);Ar1 , Ar2 and Ar3 are each phenyl or substituted phenyl; Het and Het are each monocyclic or a bicyclic heterocycles; as substance-P antagonists; their preparation, compositions containing them and their use as a medicine.

Full Text

-lA- This invention concerns l-(l,2-disubstituted piperidinyl)-4-substituted piperazine 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 by Ciba-Geigy Corp., discloses 1-acylpiperidine compounds, in particular 2-arylalkyl-l-arylcarbonyl-4-piperidinamine derivatives, and their use as substance-P antagonists. EP-0,655,442-A, published on May 31,1995 by Fujisawa Pharmaceutical Co. Ltd., discloses piperazine derivatives having tachykinin antagonistic activity. The present compounds differ therefrom in that they invariably contain a 4-substituted-(piperazine or homopiperazine)-moiety in the 4-position of a piperidine- or homopiperidine group or in the 3-position of a pyrrolidine group, and by their favourable farmacological properties. The present invention concerns compounds of formula -2- 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; p is 1 or 2; =Q is=O or=NR3; X is a covalent bond or a bivalent radical of formula -0-, -S-, -NR3-; R1 is Ar1, Ar1C1-6alkyl or di(Ar1)C1-6alkyl, wherein each C1-6alkyl group is optionally substituted with hydroxy, C1-4alkyloxy, oxo or a ketalized oxo subsiituent of formula -O-CH2-CH2-O- or -O-CH2-CH2-CH2-O-; R2 is Ar2, Ar2C1-6alkyl, Het1 or Het1C1-6alkyl; R3 is hydrogen or C1-6alkyl; L is hydrogen; Ar3; C1-6alkyl; C1-6alkyl substituted with 1 or 2 substiluents selected from hydroxy, C1-6alkyloxy, Ar3, Ar3C1-6alkyloxy and Het2; C3-6alkenyl; Ar3C3-6alkenyl; di(Ar3)C3-6alkenyl or a radical of formula wherein each q independently is 2, 3 or 4; each r is 0, 1, 2, 3 or 4; each Y1 independently is a covalent bond, -O- or NR3; Y2 is a covalent bond, C1-4alkanediyl or -C1-4alkylNR3; -3- each -A=B- independently is a bivalent radical of formula -CH=CH-, -N=CH- or -CH=N-; each R4 independently is hydrogen, C1-6alkyl, Ar2 or Ar2C1-6alkyl; R5 is hydrogen, C1-6alkyl or Ar3; R6 is C1-6alkyl, Ar3, Ar3C1-6alkyl, di(Ar3)C1-6alkyl, Ar3C3-7cycloalkyl, or indolyl; R7 is Ar3; Ar3C1-6alkyl; di(Ar3)C1-6alkyl; C1-6alkyl; C3-7cycloalkyl; C3-7Cycloalkyl substituted with Ar3; oxazolyl; oxazolyl substituted with halo or C1-6alkyl; thiazolyl; thiazolyl substituted with halo or C1-6alkyl; imidazolyl; imidazolyl substituted with Ar3, C1-6alkyl, Ar3C1-6alkyl or halo; indolinyl; indolinyl substituted with C1-4alkyl; 2,3.4-trihydroquinoIinyl; pyrrolidinyl or furanyl; each R8 independently is hydrogen, C1-6alkyl, C3-7cycloalkyl or a radical of formula -Alk-R11 (b-l)or -Alk-Z-Rl2 (b-2); wherein Alk is C1-6alkanediyl; Z is a bivalent radical of formula -0-, -S- or -NR3-; R11 is phenyl; phenyl substituted with 1 or 2 substituents selected from halo, C1-6alkyl or C1-6alkyloxy; furanyl; furanyl substituted with 1 or 2 substituents selected from C1-6alkyl or hydroxyC1-6alkyl; thienyl; thienyl substituted with 1 or 2 substituents selected from halo or C1-6alkyl; oxazolyl; oxazolyl substituted with 1 or 2 C1-6alkyl substituents; thiazolyl; thiazolyl substituted with 1 or 2 C1-6alkyl substituents; pyridinyl or pyridinyl substituted with 1 or 2 C1-6alkyl substituents; R12 is C1-6alkyl or C1-6alkyl substituted with hydroxy, carboxyl or C1-6alkyloxycarbonyl; Ar1 is phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, C1-4alkyl, haloC1-4alkyl, cyano, aminocarbonyl, C1-4alkyloxy or haloC1-4alkyloxy; Ar2 is naphtalenyl; phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from hydroxy, halo, cyano, nitre, amino, mono- or di(C1-4aikyl)amino, C1-4alkyl, haloC1-4alkyl, C1-4alkyloxy, haloC1-4alkyloxy, carboxyl, C1-4alkyloxycarbonyl, aminocarbonyl and mono- or di(C1-4aIkyl)aminocarbonyl; -4- Ar3 is phenyl or phenyl substituted with 1, 2 or 3 substit^ents selected from halo, hydroxy, amino, nitro, aminocarbonyl, C1-6alkyl, haloC1-6alkyl or C1-6alkyl-oxy; Het1 is a monocyclic heterocycle selected from pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyi, 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, C1-4alkyl or mono-, di- or tri(halo)methyl; and Het2 is a heterocycle selected from 1.4-dihydro-5-oxo-tetrazol-l-yI, imidazo[1,2-]-pyridinyl, oxazolyl or imidazolyl; each of said heterocycles may be substituted with 1 or where possible 2 substituents selected from C1-4alkyl and Ar3. The heterocycles in the definition of Het1 are preferably connected to the rest of the molecule, i.e. X, -C(=Q)- or C1-6alkyl, by a carbon atom. As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C2-4alkyl defines straight and branched chain saturated hydrocarbon radicals having from 2 to 4 carbon atoms such as, for example, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl and the like; C1-4alkyl is meant to include C2-4alkyl and methyl; C1-5alkyl is meant to include C1-4alkyl and the higher homologues thereof having 5 carbon atoms such as, for example, pentyl, 2-methylbutyl and the like; C1-6alkyl is meant to include C1-5alkyl and the higher homologues thereof having 6 carbon atoms such as, for example, hexyl, 2-methylpentyl and the like; C1-4alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methylene, 1,2-ethanediyl, i,3-propanediyi, 1,4-butanediyl, and the like; C1-6alkanediyl is meant to include C1-4alkanediyl 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; C3-6alkenyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 3 to 6 carbon atoms such as, for example, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-meiyl-2-butenyl, 3-hexenyl and the like; and the carbon of said C3-6alkenyl connected to the nitrogen atom of the piperazine or homopiperazine preferably is saturated. As used in the foregoing definitions and hereinafter, haloC1-4alkyl is defined as mono- or polyhalosubstituted C1-4alkyl, in particular C1-4alkyl substituted with 1 to 6 halogen -5-atoms, more in particular difluoro- or trifluoromethyl. The pharmaceurically acceptable addition sails 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 hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxy ace tic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, mahc, tartaric, citric, meihanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosahcylic, pamoic and the like acids. The pharmaceurically 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, N-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 mixwre, of all possible stereochemically and conformationally isomeric forms, said mixtures containing all diastereomers, enantiomers and/or conformers of the basic molecular structure. More in -6- particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic saturated radicals may have either the cis- or trans-configaration; >C=NR3 and C3-6aIkenyl radicals may have the E- or Z-configuration. The compounds of fomula (I) have at least two stereogenic centers; thus for compounds of which the actual stereochemical configuration is known, the relative stereodescriptors R* and S* may be used in accordance with the Chemical Abstracts rules (Chemical Substance Name Selection Manual (CA), 1982 Edidon, Vol. III, Chapter 20). In those cases where the :ompounds of formula (I) were separated into its racemic cis and racemic trans isomers, or in those cases where the racemic cis or racemic trans isomers were separated into its pure enantiomeric forms, the stereochemically isomeric form which was first isolated was designated as "A" and the second as "B". 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 L is a radical of formula (a-1) wherein R5 is hydrogen, or a radical of (a-2) or (a-3) wherein Y1 is -NH-, or a radical of fomiula (a-5) wherein R3 is hydrogen may exist in their corresponding tautomeric form. Also compounds of formula (I) wherein X is -NH- and =Q is =0 may exist in their corresponding tautomeric form. The N-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 N-oxide, particularly those N-oxides wherein one or more of the piperazine-nitrogens are iV-oxidized. Whenever used hereinafter, the term "compounds of formula (I)" is meant to also include their N-oxide forms, their pharmaceutically acceptable addition salts, and their stereochemically isomeric forms. A special group of compounds are those compounds of formula (I) wherein L is hydrogen; C1-6alkyl; C1-6alkyl substituted with hydroxy; C3-6alkenyl; Ar3; Ar3C1-6alkyl; di(Ar3)C1-6alkyl; Ar3C3-6alkenyl; di(Ar3)C1-6alkenyl; or a radical of formula (a-1), (a-2), (a-4) or (a-5) wherein R7 is Ar3; Ar3C1-6alkyl; di(Ar3)C1-6alkyl; C1-6alkyl; C3-7Cycloalkyl; C3-7cycloalkyl substituted with Ar3; oxazolyl; oxazolyl substituted with halo or C1-6alkyl; thiazolyl; -7- thiazolyl substituted with halo or C1-6alkyl; imidazolyl; imidazolyl substituted with Ar3, C1-6alkyl. Ar3C1-6alkyl or halo; pyrrolidinyl or furanyl; Ar3 is phenyl or phenyl substituted with 1, 2 or 3 substituents selected from halo, hydroxy, amino, aminocarbonyl, C1-6alkyl, haloC1-6alkyl or C1-6alkyloxy; Het1 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, 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, C1-4alkyl or mono-, di- or tri(halo)methyI. 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 Ar1C1-6alkyl; or b) R2is Ar2, Ar2C1-6alkyl orHet1; in particular, phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, cyano, nitro, amino, C1-4alkyl, haloC1-4alkyl, C1-4alkyloxy and C1-4alkyloxycarbonyl, more in particular, phenyl substituted with 2 substituents selected from methyl and trifluoromethyl; or c) n is 0 or 1, in particular n is 1; or d) m is 1; or e) p is 1 or 2, in particular pis I; or f) =Qis=0;or g) X is a covalent bond, -O- or -NR3-, in panicular a covalent bond. A second group of interesting compounds consists of those compounds of formula (I) wherein L is hydrogen, Ar3; Ar3C1-6alkyl; di(Ar3)C1-6alkyl; Ar3C3-6alkenyl; C1-6alkyl substituted with hydroxy; or a radical of formula (a-2) wherein R4 is hydrogen or Ar2; r is 0 or 1; Y1 is a covalent bond, -O- or -NR3-; and R7 is Ar3, C3-7cycloalkyl substituted with Ar3, di(Ar3)methyl, pyrrolidinyl or furanyl; or a radical of formula (a-4) wherein Y2 a covalent bond or methylene; -A-B- is -CH=CH- or -N=CHs and R8 hydrogen, a radical of formula (b-1) wherein R11 is methyl substituted oxazolyl, or a radical of formula (b-2) wherein Z is -O- and R12is C1-6alkyl; or a radical of fomula (a-5) wherein R4 is hydrogen; q 2; and R3 is hydrogen. A third group of interesting compounds consists of those compounds of formula (I) wherein q is 2 or 4; -A=B- is -CH=CH- or -N=CH-; R4 is hydrogen or Ar2; R5 is hydrogen; R6isC1-6alkylorAr3; R7is Ar3; di(Ar3)C1-6alkyl; C1-6alkyl; C3-7ycloalkyl substituted with Ar3; thiazolyl; imidazolyl substituted with C1-6alkyl or Ar3C1-6alkyl; indolinyl; indolinyl substituted with C1-4alkyl; 2,3,4-trihydroquinolinyl; pyrrolidinyl or furanyl; Zis-O-; R11 is phenyl substituted with halo; oxazolyl substituted with C1-6alkyl; or R12isC1-6alkyl. Of special interest are those compounds of formula (I) wherein R1 is Ar1C1-6alkyl, R2is phenyl substituted with 2 substituents selected from methyl or trifluoromethyl, X is a covalent bond and =Q is =0. Further of special interest are those compounds of formula (I) wherein n and m are 1 and p is 1 or 2. Particular compounds are those compounds of formula (I) wherem R1 is phenylmethyl; R2 is phenyl substituted with 2 substituents selected from methyl or trifluoromethyl; n, m and p are 1; X is a covalent bond; and =Q is =0. Also particular compounds arc those compounds of formula (I) wherein L is a radical of formula (a-2) wherein R4 is hydrogen or phenyl; r is 0or l; Y1 is a covalent bond, -O- or -NH-; R7 is pyrrolidinyl; furanyl; 1-phenylcyclohexanyl; diphenylmethyl; or phenyl substituted with 1, 2 or 3 substituents each independently selected from methyl, methoxy or chloro. Preferred compounds are those particular compounds that have a trans configuration. Other preferred compounds are those particular compounds that have a cis configuration. Still other preferred compounds are those compounds of formula (I) wherein Rl is phenylmethyl; R2 is phenyl substituted with 2 substituents selected from methyl or trifluoromethyl; n, m and p are 1; X is a covalent bond; =Q is =0; L is a radical of formula (a-2) wherein R4 is hydrogen; r is 1; Yl is -NH-; and R7 is phenyl substituted with 2 methyl substituents. Most preferred are those compounds selected from 4-[l-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethyI- phenyl)-l-piperazine acetamide; 4-[l-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(l-phenyl- cyclohexyl)-l-piperazine acetamide; l-[3,5-bis(trifluoromethyl)benzoy]]-2-(phenylmethyl)-4-[4-[a-(l-pyn"olidinylcarbonyl)- benzyl]-l-piperazinyl]piperidine; l-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-fl-[(2-methyl-5-oxazolyl)methyl]-lH- benzimidazol-2-yl]-1 -piperazinyl]-2-(phenylmethyl)piperidine; 4-[l-[3,5-bis(trifluoromethyl)benzoyl]-2-[(4-trifluoromethylphenyl)methyl]-4- piperidinyl]-N-(2,6-dimethylphenyl)-l-piperazine acetamide; -10- 4-[l-[3,5-bis(trifluoromethyl)ben2oyI]-2-[(3,4-dichlorophenyl)methyl]-4-piperidinyl]-A'-(2,6-dimethylphenyl)-l-piperazine acetamide; the TV-oxides, the stereoisomeric forms and the pharmaceutically acceptable addition salts thereof. Particularly interesting stereoisomeric forms are (+)-(B)-trans-4-[l-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenyimethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-l-piperazine acetamide; and (-)-(B)-cis-4-[i-[3,5-bis(trifluoromethyl)-benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethyIphenyl)-l-piperazine acetamide, and the pharmaceutically acceptable addition salts thereof, especially the (L)-malic acid form. The compounds of formula (I) can be prepared by reductively N-alkylating an intermediate of formula (III) with an intermediate of formula (IT). Said reductive N-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 an appropriate reducing agent such as, for example, a borohydride, e.g. sodium borohydride, sodium cyano-borohydride or triacetoxy borohydride. In case a borohydride is used as a reducing agent, it may be convenient to use a complex-forming agent such as, for example, titanium (I V)isopropylate as described in J. Org. Chem, 1990,55, 2552-2554. Using said complex-forming agent may also result in an improved cis/trans ratio in favour of the trans isomer. It may also be convenient to 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 hydj'ogen is used as reducing agent, it may be advantageous to add a dehydrating agent to the reaction mixture such as, for example, aluminium rerf-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. 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 -11- chromatography. The compounds of formula (I) can also be prepared by reacting an intermediate of formula (IV) 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 benzenesulfonyloxy, with an intermediate of formula (V). The reaction can be performed in a reaction-inert solvent such as, for example, a chlorinated hydrocarbon, e.g. dichloromethane, an alcohol, e.g. ethanol, or a ketone, e.g. methyl isobuty Ike tone, 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 conveniendy be carried at a temperature ranging between room temperature and reflux temperature. The compounds of formula (I) may also be converted into each other following art-known transformations. In particular, the compounds of formula (I) wherein L is other than hydrogen, said L being represented by L" and said compounds being represented by formula (I-a), can also be prepared by reacting a compound of formula (I) wherein L is hydrogen, said compounds being represented by formula (I-b), with an intermediate of formula (VI) wherein W2 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 benzenesulfonyloxy, at reaction conditions which are similar to those for the reaction between intermediates of formula (IV) and (V). The compounds of formula (I) may also be converted into each other following art-known iransformations. In particular, the compounds of formula (I) wherein L is other than hydrogen, said L being represented by L" and said compounds being represented by formula (I-a), can also be prepared by reacting a compound of formula (I) wherein L is hydrogen, said compounds being represented by formula (I-b), with an intermediate of formula (VI) wherein W^ 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 benzenesulfonyloxy, at reaction conditions which are similar to those for the reaction between intermediates of formula (IV) and (V). Compounds of formula (I-b) may be prepared by reductively N-alkylating a piperazine derivative of formula (VII) wherein pi is a protective group such as, for example, benzyl, with an intermediate of fonnula (II). Said reaction may be performed in a similar way as described hereinabove for the reductive N-alkylation using intermediates (II) and (III). The thus formed compound of formula (l-c) may then be deprotected using art- -12- known deprotection techniques. Depending on the nature of the protective group P1 compounds of formula (I-c) may be part of the scope of the compounds of formula (I). Alternatively, compounds of formula (I-b) may be prepared by first reductively N-alkylating a piperazine derivative of formula (VII) wherein P1 is a protective group such as, for example, halo, with an intermediate of fonnula (VIII) using the same procedure as described hereinabove for the reductive N-alkylation using intermediates (II) and (in). The thus formed intermediate of formula (XI) may then be reacted with an intermediate of formula (IV) in a reaction-inen solvent and optionally in the presence of a suitable base such as, for example, triethylamine, to fonn a compound of formula (I-c), which may then be deprotected using an-known deprotection techniques. The compounds of formula (I-b) are deemed to be of particular use in the synthesis of other compounds of formula (I). The compounds of formula (I) may also be converted to the corresponding N-oxide -13- forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting materiai 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. tert-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 (IH), (IV) and (VI) may be prepared according to an-known procedures. Intermediates of formula (II) may be prepared by condensing an intermediate of formula (IV) with an intermediate of formula (VIII) analogous to the procedure described in EP-0,532,456-A. The preparation of intermediates of formula (VIII) is also described in EP-0,532,456-A. However, intermediates of formula (VIII) wherein R1 is optionally substituted Ar1C1-6alkyl or di(Arl)C1-6alkyl, said R1 being represented by -CH(Rla)2 and said intermediates being represented by formula (VIII-a), may also be prepared as depicted in scheme 1. -14- In scheme 1, the intermediates of formula (IX-b) may be prepared by reacting an intermediate of formula (IX-a) with an aldehyde or a ketone of formula (X). The C1-6alkylcarbamate moiety in the intermediates of formula (IX-b) may be converted into a fused oxazolone which in turn may be reduced to an intermediate of formula (IX-d). Said intermediate (IX-d) may in turn be deprotected, thus forming an intermediate of formula (VIII-a). Subsequently, intermediates of formula (VIII-a) may be reacted with an intermediate of formula (IV) to prepare intermediates of formula (II) wherein R1 is defined as -CH(R1a)2, said intermediates being represented by formula (Il-a). Said intermediates of formula (II-a) may also be prepared by first reacting intermediate (IX-d) with intermediate (IV) in the presence of a suitable base to form an intermediate of formula (XII), which may subsequently be deprotected. These reactions and those performed in scheme 1 may all be conducted following conventional methods that are generally known in the art. -15- Intermediates of formula (V) may suitably be prepared by reacting an intermediate of formula (VIII-1), being a protected intermediate of formula (VIII) with a protecting group p2 such as, for example, a C1-6alkyloxycarbonyl group, with an intermediate of formula (III) according to the previously described reductive N-alkylation procedure, and subsequently deprotecting the thus formed intermediate. In particular, intermediates of formula (V) wherein R1 is -CH(R1a)2, said intermediates being represented by formula (V-a), may be prepared as is depicted in scheme 2. The ketalized intermediate of formula (IX-c) may be transformed to the corresponding ketone of formula (IX-e) which subsequently may be reductively aminated with a piperazine- or homopiperazine derivative of formula (III). The thus obtained intermediate may then be reduced with a suitable reducing agent to an intermediate of formula (V-a). 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. -16- The compounds of formula (1) as prepared in the hereinabove described processes are generally racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I) which are sufficiently basic or acidic may be converted into the corresponding diasiereomeric 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 stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomeric ally 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-media ted 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, NK1, NK2 and NK3 receptors. Substance P displays highest affinity for NKj receptors, whereas NKA preferendally 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 -17- activation of the immune system. A number of diseases are deemed to be engendered by activation of neurokinin receptors, in particular the NK1 receptor, by excessive release of substance P and other neurokinins in panicular cells 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 NK1 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, or the antagonism of drug-induced emesis in ferrets (Watson et al., Br. J. Pharmacol. 115, 84-94, 1995). 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 NK1 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 -18- 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 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, cannustine, lomusune and chlorambucil; cytotoxic antibiotics, e.g. dactinomycin, doxorubicin, milomycin-C and bleomycin; antimetabolites, 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 motihty; 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; AIDS-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; -19- - stroke, epilepsie, head trauma, spinaJ cord trauma and ischemic neuronal damage; - fibrosing and collagen diseases, such as sclerodemia and eosinophilic fascioliasis; - disorders related to immune enhancement or suppression, such as systemic lupus erythematosus; - rheumatic diseases, such as fibrositis; - 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. The compounds of formula (I) also have the ability to penetrate the central nervous system as may be demonstrated in vivo by their inhibitory effect on the change in behaviour induced by intracerebroventricular-applied substance P in the gerbil. 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, pain, emesis or asthma. Said method comprises the systemic admini.stration of an effective tachykinin antagonizing amount of a compound of formula (T), a TV-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 (F) as a medicine is provided, and in particular a medicine to treat pain, emesis or 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 -20- 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 pan, 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. 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-, ^ or y-cyclo-dextrins or their derivatives, in particular hydroxyalkyi substituted cyclodextrins, e.g. 2-hydroxypropyl-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. -21- 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. 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 "RT" means room temperature, "THF" means tetrahydrofuran, "DIPE" means diisopropylether, "DCM" means dichloromethane and "DMF" means N,N-dimethylformamide. A. Preparation of the intermediate compounds Example A.l a) A mixture of (+)-1,1-dimethyl 7-(phenylmethyl)-l,4-dioxa-8-azaspiro[4,5]decane-8-carboxylate (13 g; prepared according to the method described in EP-A-532,456) in HCl (6N; 130 ml) was stirred and refluxed for 3 hours. The reaction mixture was cooled, alkalized with aqueous NaOH (50 %) and extracted with DCM. The organic layer was separated, dried, filtered, and the filtrate, which contained (±)-2-(phenylmethyl)-4-piperidinone (intermediate 1), was used in next reaction step. b) A mixture of the filtrate obtained in the previous reaction step, 3,5-dimethylbenzoyl chloride (7.4 g) and triethylamine (11 ml) was stirred overnight at RT. The reaction mixture was extracted with dilute NaOH solution. The organic layer was separated, dried, filtered and the solvent evaporated. The residue was crystallized from DIPE. The -22- precipitate was filtered off and dried, yielding 7.44 g (58%) of (±)- ]-(3,5-dimethyl-benzoyl)-2-(phenylmethyl)4-piperidinone (intermediate 2; mp. 107.8°C). Example A. 2 a) A mixture of (±)-1,1-dimethyl 7-(phenylmethy])-l,4-dioxa-8-a2aspiro[4,5]decane-8-carboxylate (33.34 g; prepared according to the method described in EP-A-532,456) in HCl (6N; 250 ml) was stirred at 70 °C for 1 hour and 30 minutes. The mixture was cooled, alkalized with NaOH while cooling to 25°C, and extracted with DCM (100 ml). The organic layer was separated and the aqueous layer was extracted with CH2Cl2. Triethylamine (20.2 g), followed by 3,5-bis(trifluoromethyi)ben2oyl chloride (27.7 g) dissolved in a little DCM were added and the mixture was stirred for 2 hours. The mixture was extracted with water, 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 product. The mother layer was evaporated and the residue was crystallized from DIPE. The precipitate was Filtered off and dried, yielding 6.51 g of product. The two fractions were put together and taken up in water and DCM, 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-(trifIuoromethyl)benzoyl]-2-(phenylmethyi)-4-piperidinone (intermediate 3; mp.102.50C). Example A.3 A mixture of pyrrolidine (2.13 g) and triethylamine (6.06 g) in DCM (100 ml) was stirred at -10°C. 2-chloro-2-phenylacetylchloride (5.67 g) was added slowly and dropwise. The mixture was allowed to warm to RT and was then stirred overnight. The mixture was extracted with water and K2CO3. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was crystallized from DIPE and the precipitate was filtered off and dried, yielding 3.25 g (48 %) of firaction I. The mother layer was separated and the solvent was evaporated. The residue was crystallized froro DIPE and the precipitate was filtered off and dried, yielding 0.29 g (5 %) of fraction 2. Both fractions were combined, thus yielding 3.54 g (53 %) of (±)-l-(2-chloro-2-phenyl-acetyl)pyrrolidine (intermediate 4; mp. 88.5 °C). Example A.4 Sodium hydride (2 g) was added ponionwise 10 a solution of 3,5-dimethylphenol (6.1 g) in DMF (50 ml). The mixture was stirred for 30 minutes and added dropwise at a temperature below 30 °C to a solution of 2-chtoro-2^phenylacetylchloride (9.45 g) in DMF (50 ml). The mixture was stirred overnight, decomposed with water (5 ml) and -23- the solvent was evaporated. Water was added and the mixture was extracted with DCM. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent; hexane/DIPE 100/0, 98/2 and 95/5). The pure fractions were collected and the solvent was evaporated [residue; yielding 10.82 g (79%) ]. A small amount of the obtained residue was crystallized from DIPE, the precipitate was filtered off and the solvent was evaporated, yielding 1 g of (±)-3,5-dimethyIphenyl a-chlorobenzeneacetate (intermediate 5; mp. 79.0 0C). Example A.5 a) A mixture of (±)-l-[3.5-bis(trifluoromethyl)benzoyl]-2-(pheny]methyl)-4-(l-piperazinyl)piperidine (0.0127 mol), chloroacetonitrile (0.013 mol) and sodium carbonate (0.013 mol) in methylisobuty] keton (l00ml) was stirred and rcfluxed. The mixture was cooled and water was added. The organic layer was separated, dried, fihered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 100/0, 99.5/0.5 and 99/1). The pure fractions were collected and the solvent was evaporated, yielding 3.64g (53%) of (±)-dj-l-[3,5-bis-(trifluoromethyl)benzoy]]-4-r4-(cyanomeihyl)-l-piperazinyl]-2-(phenylmethyl)pipeT)dine (intermediate 6). b) A mixture of intermediate 6 (0.0067 mol) in THE (150 ml) was hydrogenated at 200C with Raney Nickel (1 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated, yielding 3.77 g of (±)-cis-4-[4-(2-aminoethyl)-l-piperazinyl]-l-[3,5-(trifluoromeihy!)benzoyl]-2-(phenylmethy])piperidine fintermediate 7). Example A.6 A mixture of l-(phenylmethyl)-4-piperidinone (0.2 mol) and l-methylpiperazine (0.2 mol) in methanol (500 ml) was hydrogenated for 8 hours with palladium on activated carbon (10%, 2.5 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. A mixture of di-tert -butyl dicarbonate (0,2 mol) in THE (500 ml) was added to the residue and hydrogenated again with palladium on activated carbon (10%, 2.5 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. Tlie residue was purified over silica gel on a glass filter (eluent: CH2C12/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated, yielding 45.3 g (80%) of 1,1-dimethylethyl 4-(4-methyl-1 -piperazinyl)-1 -piperidinecarboxyiate (intermediate 8). Example A.7 a) A mixture of 4-methoxypyridine (0.4 mol) in THE (1000 ml) was stirred and cooled in -24- a 2-propanol/C02 bath. Ethyl chloroformate (0.4 mol) was added dropwise and the mixture was stirred for 3 hours while cooling (mixture I). In another round-bottom flask, the Grignard-reagent was prepared: Mg (0.44 mol) was stirred in a small amount of (C2H5)20. Some I2 was added. A small amount of 1,2-dichloro-4-(chloromethyl)-benzene was added. Then, l,2-dich!oro-4-(chloromethyl)benzene (0.4 mol) in (C2H5)2O (600 ml) was added dropwise at reflux temperature. The mixture was stirred for one hour (mixture II). The Grignard-reagent was decanted off, added to mixture I at b) Intermediate 9 (0.176 mol) in THF (880 ml) was stirred under a N2 flow, and cooled to -78 °C. L-selectride (0.264 mol) was added dropwise at -78 °C. The reaction mixture was stirred for 1 hour, then poured out into water. DIPE was added. The organic layer was separated, washed with an aqueous NaHCOs solution, with an aqueous NaCl solution, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 90/10). The desired ft-actions were collected and the solvent was evaporated, yielding 20.2 g (34.8%) of (±)-ethyl 2-[(3,4-dichlorophenyl)methyl]-4-oxo-I-piperidinecarboxyIate (intermediate 10). c) Titanium(IV)isopropoxide (0.0269 mol) was added to a mixture of intermediate 10 (0.0224 mol) and intermediate 10 (0.0224 mol) in DCM (11 ml). The mixture was stirred at RT for 3 hours. Sodium cyanoborohydride (0.0224 mol) and then ethanol (10 ml) were added. The mixture was stirred at RT for 48 hours. Water was added and the mixture was stirred. CH2CI2 was added and the mixture was stirred. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by HPLC over silica gel (eluent: CH2CI2/CH3OH 100/0 and 98/2). The pure fractions were collected and the solvent was evaporated. The residue was purified by reversed phase chromatography (eluent: NH4OAc(0.5% in H2O)/CH3OH 20/80). Two pure fractions were collected and their solvents were evaporated. The residue was dried and ground, yielding 2 g (16%) of (±)-ethyl trans/25-2-[(3,4-dichlorophenyl)methyl]-4-[4-[2- [(2,6-dimethylphenyl)amino]-2-oxoethylJ-l-piperazinyl]-l-piperidinecarboxylate (intermediate 11) and 3.5g (28%) of (±)-ethyl cis-2-[(3,4-dichlorophenyl)methyl]-4-[4- [2-[(2,6-dimethylphenyl)amino]-2-oxoeEhylj-1 -piperazinyl]-1 - p iperidi nee arboxy late (intermediate 12). -25- d) A mixture of intemiediate 11 (0.0034 mol) and potassium hydroxide (0.034 mol) in 2-propanoJ (150 ml) was stirred and refluxed for 4 days. The solvent was evaporated The residue was taken up in CHsClz/water. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromato-graphy over silica gel (eluent: CH2Cl2/(CH30H/NH3) 95/5). The pure fractions were collected and the solvent was evaporated, yielding 0.5 g (30%) of (±)-trans-4-[2-[(3,4- dichlorophenyl)methyl]-4-piperidinyl]-N-(2,6-dimelhylphenyl)-l-piperazineacetamide (intermediate 13). Example A.8 a) Sec-butyllithium (0.066 mol) was added to a mixture of 1,1-dimethylethyl 1,4-dioxo-8-azaspiro[4.5]-8-carboxylate (0.06 mol) in N'N'N'N'-tetramethylethylenediamine (22.6 ml) and (C2H5)20 (100 ml). The mixture was stirred at -70°C for 3 hours. 3,5-difluorobenzaldehyde (0.07 mol) was added dropwise at -70°C. The mixture was allowed to warm to RT. Water (50 ml) and DIPE were added. The aqueous layer was separated and extracted with CH2C12- The combined organic layer was dried, filtered and the solvent was evaporated. Toluene was added and evaporated again, yielding 23 g of (±)-1,1 -dimethylethyl 7-[(3,5-difluorophenyl)hydroxymethyl]-l,4-dioxo-8-azaspiro[4.5]-8-carboxylate (intemiediate 14) b) A mixture of intermediate 14 (0.06 mol) and 2-methyl-2-propanol, potasssium salt (0.72 g) in toluene (110 ml) was stirred and refluxed for 2 hours. The solvent was evaporated. The residue was stirred in petroleum ether and a small amount of water, and decanted. The residue was dissolved in CH2Cl2, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2CI2/CH3OH 100/0, 99/1 and 98/2). Two pure fracdons were collected and their solvents were evaporated, yielding 9.2 g (49%) of (±)-3-(3,5-dinuorophenyl)ietrahydro-spiro[l,3-dioxolan-2.5'(3'H)-lH.oxazolo[3,4-a]pyridin]-l-one (intermediate 15) c) A mixture of intermediate 15 (0.03 mol) in methanol (250 ml) was hydrogenated at 50°C 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 over silica gel on a glass filter (eluent: CH2CI2/CH3OH 100/0,98/2 and 95/5 and CH2Cl2/(CH3OH/NH3) 95/5). The desired fractions were collected and the solvent was evaporated, yielding 1.9 g (39 %) of (±)-7-[(3,5-difluorophenyl)methyl]-l,4-dioxo-8-azaspiro[4.5]decane (intermediate 16). d) A mixture of intermediate 16 (0.012 mol) in HCl 6N (30ml) was stirred ai75°C for 2 hours. The mixture was cooled, poured out into ice and a NaOH solution and extracted with CH2Cl2. The organic layer was separated, dried and filtered, yielding -26- 2.7 g of (±)-2-[(3,4-difluorophenyi)methy]]'4'piperidinone (intermediate 17). e) A mixture of 3,5-trifluoromethyJbenzoyl chloride (0.012 mol) in a small amount of CH2Cl2 was added dropwise to a stirred mixture of intermediate 17 (0.012 mol) and N,N-diethylethanamine (0.024 mol). The mixture was stirred at RT for 1 hour and water was added. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2CI2/ CH3OH 100/0 and 99.5/0.5). The pure fractions were collected and the solvent was evaporated, yielding 2.7g (48%) of (+)-l-[3,5-bis(trifiuoromethyI)benzoyl]-2-[(3,5-difluorophenyl)methyI]-4-piperidinone (intermediate 18). Example A.9 Sec-butyllithium (0.63 mol) was added at -780C under N2 flow ro a solution of 1,1-dimethylethyl l,4^dtoxo-8-azasp.ro[4.5]-8-carboxylate (0.57 mol) and N,N,N'N-~ tetramethylethylenediamine (1.14 mol) in (C2H5)20 (1000 ml). One hour after complete addition, a mixture of 3-(trifluoromethyI)benzaldehyde (0.57 mol) in (C2H5)20 (200 ml) was added. The mixture was allowed to warm 10 RT and then stirred at RT for 16 hours. The solvent was evaporated. A mixture of 2-methyl-2-propanol, potassium salt (0.2 mol) in toluene (500 ml) was added. The mixture was stirred at 800C for 5 hours. The solvent was evaporated. The residue was heated with a saturated NH4Cl solution and extracted with CH2Cl2- The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was suspended in DIPE, filtered off and dried. This fraction was dissolved in CH3OH (230 ml) and the mixture was hydrogenated with palladium on activated carbon (10%, 3 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was purified over silica gel on a glass filter (eluent; CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. This fraction was dissolved in HCl (6N, 100 ml) and CH3OH (100 ml) and the mixture was stirred at 50°C for 8 hours. The organic solvent was evaporated. The concentrate was washed with a saturated K2CO3 solution and extracted with CH2Cl2- The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 95/5)- The pure fractions were collected and the solvent was evaporated. yielding 48.5 g (70 %) of (±)-2-[[4-(trifluoromethyl)phenyl]methyl]-4-piperidinone (intermediate 19). Example A.10 a) A mixture of ethyl -oxobenienebutanoate (0.5 mol) and benzenemethanamine (0.5 mol) in toluene (500 ml) was hydrogenated at 120°C (pressure = 100 kg) overnight in the presence of Cu2Cr2O5 (5 g) and CaO (10 g). After uptake of hydrogen, the -27- catalyst was filtered off and the filtrate was evaporated, yielding 29.7 g of (±)-ethyl N,2-bis(phenylmethyl)-ß-alanine (intermediate 20), b) Ethyl chloroacetate (0.3 mol) was added to a mixture of intermediate 20 (0.2 mol) in DMF (250 ml). The mixture was stirred and trielhylamine (0.4 mol) was added. The mixture was stirred at 60°C overnight. The solvent was evaporated and the residue was taken up in water/CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 76.6 g of (±)-ethyI 3-[(2-ethoxy-2-oxoethyl)(phenyl-methyl)amino]ben2enebutanoate (intennediate 21). c) Intermediate 21 (0.2 mol) was heated to 80°C under N2 flow. NaOCHs (44 g) was added. The mixture was stirred at 80°C for 30 minutes. The solvent was evaporated and water (170 ml) and HCl (6N, 60 ml) were added. The mixture was stirred and refluxed for 1 hour, then cooled, alkalized with NaOH and extracted with CH2Cl2. The organic layer was separated, washed with water and a saturated NaCl solution, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3CN 100/0 to 96/4). The pure fractions were collected and the solvent was evaporated, yielding 7.8 g of (±)-l,5-bis(phenylmethyl)-3-pyrrolidinone (intermediate 22). d) A mixture of intermediate 22 (0.027 mol) and CH3SO3H (0.03 mol) in THF (200 ml) was hydrogenated with palladium on activated carbon (10%, 2 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off, yielding (±)-5-(phenyImethyl)-3-pynrolidinone methanesulfonate(l:l) (intermediate 23). e) 3,5-di(trifluoromethyl)benzoyl chloride (0.03 mol) was added to intermediate 23 (0.027 mol). The mixture was stirred and triethylamine (0.1 mol) was added. The mixture was stirred at RT for 18 hours and then washed with water, NaOH and a saturated NaCl solution. The organic layer was separated, washed with a saturated NaCl solution, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2CI2/CH3OH 98/2). The pure fractions were collected and the solvent was evaporated, yielding 1.4 g of (±)-l-[3,5-bis(trifluoromethyl)benzoyl]-5-(phenylmethyl)-3-pyrrolidinone (intermediate 24). B. Preparation of the compounds of formula (1) Example B.l a) Titanium(IV)isopropoxide (16.5 g) was added to a mixture of intermediate 3 (21.5 g) and l-(phenylmethyl)piperazine (8.81 g) in DCM (35 ml). The mixture was stirred for 3 hours at RT. Sodium cyanoborohydride (2.85 g) and ethanol (70 ml) were added and the resulting reaction mixture was stirred overnight at RT. Water (5 ml) and DCM were added. The biphasic mixture was filtered over dicalite, and the filter residue was washed -28- I with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was crystallized from CH3CN and the precipitate was filtered off and dried] yielding 7.93 g (26.9 %) of (±)-m-I-[3,5-bis(trifluoromethyl)benzoyl]-2- (phenylmethyl)-4-[4-(phenylmeihyI)-l-pipera2inyl]piperidine (compound 16; mp. 143.8 °C). b) The mother liquor was concentrated and the residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 100/0, then 99/1, 98/2, 97/3). The desired fractions ((A) and (B)) were collected and their solvent was evaporated. The A-isomer was crystallized from CH3CN, filtered off and dried, yielding 1.11 g (4 %) of compound 16. The pure fractions of the B-isomer were concentrated, yielding 5.9 g (20%)of (±)-trans-l-[3,5-bis(trifluoromethyl)ben2oyI]-2-(phenylmethyl)-4-[4-(phenyl-methyl)-l-piperazinyl]piperidine. The impure fractions of the B-isomer were collected and the solvent was evaporated. The residue was converted into the fumaric acid salt (1:2) in ethanol, The precipitate was filtered off and dried, yielding 1.89 g (±)-trans-l-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenyImethyl)-4-[4-(phenylmethyl)-l-piperazinyl]-piperidine (E)-2-butenedioate(l:2) (compound 17; mp. 240.3 °C). Example B.2 A mixture of compound 16 (8.4 g) in methanol (250 ml) was hydrogenated at 50 °C with palladium on activated carbon (10 %) (2 g) as a catalyst. After uptake of H2, the catalyst was filtered off and the filtrate was evaporated, yielding 7 g (100 %) of (±)-l-[3,5-bis-(trifluoromethy])benzoyl]-2-(phenylmethyl)-4-(l-piperazinyl)piperidine (compound 15). Example B.3 a) Titanium(IV)isopropoxide (13.2 g) was added to a mixture of intermediate 3 (17.16 g) and N-(2,6-dimethylphenyl)-l-piperazineacetamide (9.88 g) in DCM (20 ml). This mixture was stirred for 3 hours at RT. Sodium cyanoborohydride (2.52 g) in ethanol (20 ml) was added and the resulting reaction mixture was stirred overnight at RT. Water (10 ml) was added and the reaction mixture was extracted with DCM (800 ml). The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was taken up into water and this mixture was extracted with DCM. The separated organic layer was dried, filtered, and the solvent evaporated. The residue was pre-purified by column chromatography over silica gel (eluent: CH2CI2/CH3OH 97/3). The desired fractions were collected and the solvent was evaporated, giving 4 g of the trans-racemate. Resolution was obtained by purification over stationary phase Chiralcel OD (eluent: CH3OH 100%). Two desired trans-fraction groups were collected and their solvent was evaporated, yielding 1.75 g fraction 1 and 2 g fraction 2. Fraction 1 was dissolved in DCM, filtered and the filtrate was evaporated. The residue was dried. -29- yielding 1.55 g (6%) (-)-(A)-trans-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenyl-methyl)-4-piperidinyl]-A'-(2,6-dimethylphenyl)-I-piperazine acetamide (compound 26; mp. 97.4 °C; [a]20D = -5.81° (c = 1 % in DMF)). Fraction 2 was dissolved in DCM, filtered and the filtrate was evaporated. The residue was dried, yielding 1.70 g (6%) (+)- (B)-trans-4-[l-[3,5-bis(trifluoromethy]}benzoy]]-2-(phenylmethyl)-4-piperidinyl]-N- 20 (2,6-dimethylphenyl)-l-piperazine acetamide (compound 27; mp. 96.8°C; [a]D, = +5.71° (c = l % in DMF)). b) Compound 27 was dissolved in wann 2-propanol and convened into the (L)-malic acid salt with a solution of (L)-malic acid in 2-propanol. The mixture was stirred for 2 hours and the precipitate was filtered off and dried, yielding (-H)-(B)-trans-4-[1-[3,5- bis(trifluoromethyl)benzoyl]-2-(plienylmethyl)-4-piperidinyl]-A/-(2,6-dimethylphenyl)-l' piperazine acetamide (L)-malic acid (1:1) (compound 95). Example B.4 A mixture of compound 15 (2.5 g), intermediate 5 (1.65 g) and sodium carbonate (0.64 g) in methylisobutylketon (50 ml) was stirred and refluxed for 3 hours. The reaction mixture was washed and the separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH l00/0 and 99.5/0.5). The pure fractions were collected and the solvent was evaporated, yielding 1.59 g (43%) of (±)-3,5-dimethylphenyl cis-4-[l-[3,5-bis-(trifluoromethyl)benzoyl]-2-(phenylmethy!)-4-piperidinyl]-a-phenyl'l-piperazineacetate (compound 43; mp. 88.1 °C). Example B.5 A mixture of intermediate 2 (3.2 g), l-(diphenylmethyl)piperazine (2.5 g) and aluminum tributoxide (2 g) in toluene (250 ml) was hydrogenated for 48 hours at 50 °C, with palladium on activated carbon (10 %; 2 g) as a catalyst in the presence of thiophene (4 % solution; 1 ml). After uptake of hydrogen (] equiv), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by high-performance liquid chromatography over silica gel (eluent: CH2Cl2/CH3OH 100/0, upgrading to 90/10). Two pure fractions were collected and their solvent was evaporated, resulting in residue 1 and residue 2. Residue 1 was suspended in DIPE. The precipitate was filtered off and dried, yielding 0.94 g (17%) of (±)-cis-l-(dimethylbenzoyl)-4-[4-(diphenylmethyl)-l-piperazinyl]-2-(phenylmethyl)piperidine (compound 12; mp. 1(X).8°C). Residue 2 was dried, yielding 0,2 g (3.6%) of (±)-trans-l-(dimethylbenzoyl)-4-[4-(diphenylmethyl)-l-piperazinyi]-2-(phenylmethyl)piperidine (compound 13). -30- Example B.6 A mixture of compound 15 (0.005 mol) and l,2-epoxyethy]ben2ene (0.006 mol) in methanol (50 ml) was stirred at RT for 1 hour. The mixture was stirred and refluxed for 3 hours. The solvent was evaporated and the residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 100/0, 99/1 and 98/2). The pure fractions were collected and the solvent was evaporated. The residue was purified by HPLC over silica gel (eluent: CH2Cl2/CH3OH 98/2 to 95/5). Two pure fractions were collected and their solvents were evaporated. Each residue was dried, yielding 0.7 g (23%) of (±)-cis-l-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(2-hydroxy~2-phenylethyl)-l-piperazinyl]-2-(phenylmethyl)piperidine (compound 60) and 0.23 g (7%) of (±)-d.y-l-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(2-hydroxy-l-phenylethyl)-l-piperazinyl]-2-(phenylmethyl)piperidine (compound 61). Example B.7 Compound 15 (0.005 mol), 2-chloro-l-[(2-methyl-5-oxazolyl)methyl]-lH-benzimidazole (0.005 mol) and Cupper (0.005 mol) were stirred at 140°C for 2 hours. The mixture was cooled, dissolved in CH2Cl2, filtered and washed with CH2Cl2 and a diluted NH4OH solution. The organic layer was separated, washed with a diluted NH4OH solution, dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 100/0,99.5/0.5,99/1, 98.5/1.5 and 98/2). The pure fractions were collected and the solvent was evaporated. The residue was dried, yielding 1.42 g (40%) (±)-cis-l-[3,5-bis(trifluoromethyl)-benzoyl]-4-l4-[l-[(2-methyl-5-oxazolyl)methyl]-lH-benzimidazol-2-yl]-l-piperazinyl]- 2-(phenylmethyl)piperidine (compound 70), Example B.8 A mixture of intemediate 7 (0.0033 mol) and 3,5-dimethylben2oyl chloride (0.0035 mol) in DCM (50 ml) was stirred at RT for 15 minutes. Triethylamine (0.007 mol) was added and the mixture was stirred at RT for 1 hour. Water was added. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was convened into the fumajic acid salt (1:1) with 2'propanol. The precipitate was filtered off and dried. The residue was converted intothe free base with NaOH. The precipitate was filtered off and dried. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 100/0,99.5/0.5,99/1,98/2 and 97/3). The pure fractions were collected and tlie solvent was evaporated. The residue was dried, yielding 0.8 g (36%) (±)-cis-N-[2-[4-ll-(3,5-bis(trinuoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-l-piperazinyl]ethyl]-3,5-diniethylbenzamide (compound 116). -31- Example B.9 A mixture of compound 74, prepared according lo example B.4, (0.004 mol) in methanol (150 ml) was hydrogenated at 50°C with palladium on activated carbon (10 %; 1 g) as a catalyst in the presence of thiophene (4 % solution, 1ml). After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off, washed with DIPE and dried. This fraction was dissolved in toluene. The mixture was filtered and the solvent was evaporated. The residue was suspended in DIPE. The precipitate was filtered off and dried. This fraction was converted into the fumaric acid salt (1:2) with a warm solution of fumaric acid (0.52g) in ethanol. The mixture was stirred for 6 hours. The precipitate was filtered off and dried, yielding 0.91 g (25%) of (+)-cis-N-(4-amino-2,6-dimethylphenyl)-4-[l-[3,5-(trifluoromethyl)benzoyl]-2-(phenylmethy])-4-piperidinyl]-]-piperazineacetamide (E)-2-butenedioate(l:2) (compound 129). Example B. 10 Sec-butyllihium (0.055 mol) was added at -78°C under N2 flow to a solution of 1,1-dimethylethyl 4-(4-methyI-l-piperazinyl)-l-piperidinec£irboxylate (0.05 mol) and N'N'N'N'-tetramethyleihylenediamine (0.1 mol) in (C2H5)20 (50 ml). 2 hours after complete addition, a mixture of benzaldehyde (0.05 mol) in (C2H5)20 (50 ml) was added. The mixture was allowed to waiin to RT and then stirred at 25°C for 16 hours. The solvent was evaporated and the residue was washed with a saturated NH4CI solution and extracted with CH2C12- The organic layer was separated, dried, filtered and the solvent was evaporated. A solution of 2-methyl-2-propanol, potassium salt (0.02 mol) in toluene (ICX) ml) was added to this fraction and the mixture was stirred at 100°C for 2 hours. The solvent was evaporated. The residue was washed with a saturated NH4CI solution, extracted with CH2Cl2 and decanted. The organic layer was dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2CI2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. This fraction was dissolved in methanol (150 ml) and hydrogenated with palladium on activated carbon (10%, 3g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was purified over silica gel on a glass filler (eluent: CH2CI2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. This fraction was dissolved in DCM (20 ml) and Triethylamine (2 ml). 3,5-di(trifluoromethyl)benzoyl chloride (0.0087 mol) was added at 0°C. 1 hour after complete addition, water was added and the mixture was extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: -32- CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. This fraction was converted into the (E)-2-butenedioic acid salt (1:2) with ethanol. The precipitate was filtered off and dried, yielding 4.7 g (74%) of (±)-m-l- [3,5-bis(trifluoron:iethyl)benzoyl]-4-(4-methyl-l-piperazinyl)-2-(phenylniethyl)pjperidine (E)-2-butenedioate(l:2) (compound 130). Example B.ll A mixture of compound 15 (0.005 mol), A'-12-(3,4-dichlorophenyl)-4-[(methylsuIfonyl)-oxy]butyl]-A'-methyl benzamide (0.0055 mol) and NaHCO3 (0.0055 mol) in ethanol (50 ml) was stirred and refluxed for 6 hours. The solvent was evaporated, the residue was taken up in water and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2CI2/CH3OH 100/0, 99/1, 98/2 and 97/3). The pure fractions were collected and the solvent was evaporated. The residue was converted into the fumaric acid salt (1:2) with ethanol. The precipitate was filtered off and dried, yielding 1.42 g (27%) of (±)-cis-N-[4-[4-[l-[3,5-bis(trifluonomethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-l-piperazinyl]-2-(3,4-dichlorophenyl)butyl]-N-methyl-benzamide (E)-2-butenedioate(l:2) (compound 93). Examples. 12 A mixture of (±)-l-[3,5-bis(trifluoromeihyl)benzoyl]-2-[(3,5-difluorophenyl)methyl]-4-piperidinone (0.0058 mol), A'-(2,6-dimethylphenyl)-l-piperazineacetamide (0.0058 mol) and titanium(IV)isopropoxide (0.0064 mol) in 2-propanol (5 ml) was stirred at RT overnight. NaBH4 (0.0116 mol) and ethanol (15 ml) were added. The mixture was stirred for 2 days. Water (5 ml) was added and the mixture was stirred for 10 minutes. CH2Cl2 (200 ml) was added. The organic layer was separated, dried, filtered and the solvent was evaporated. This fraction was purified by HPLC over silica gel (eluent: CH2Cl2/CH3OH 98/2 to 90/10 over a 30-minute period). Two pure fractions (Fl and F2) were collected and their solvents were evaporated. Fl was purified by column chromatography over RPl 8 (eluent: NH4OAC (0.5% in H20)/CH3CN 40/60). The pure fractions were collected and the solvent was evaporated. The residue was dried, yielding 0.33 g (8%) of (±)-cis-4-[l-[3,5-bis(trifluoromethyl)benzoyl]-2-[(3,5-difluorophenyl)-methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-l-piperazineacetamide (compound 132). F2 was purified by column chromatography over silica gel (eluent: CH2CI2/CH3OH 100/0 to 92/8 over a 30-minute period). The pure fractions were collected and the solvent was evaporated. The residue was dissolved in CH2Cl2, filtered and the solvent was evaporated. The residue was dried, yielding 0.24 g (6%) of (±)-trans-4-[l-[3,5-bis-(trifluoromethyl)benzoyl]-2-[(3,5-difluorophenyl)methyl]-4-piperidinyl]-N- -33- (2,6-dimethylphenyl)-1-piperazineacetamide (compound 133). Example B.13 3,5 di(trifluonnethyi)benzoyl chloride (0.0011 mol) was added to a mixture of (±)-trans 4-[2-[(3,4-dichloropheny])methyl]-4-piperidinyl]-N-(2,6-dimethyIphenyl)-]-piperazine-acetamide (0.001 mol) in DCM (20ml). The mixture was stirred for 5 minutes. Triethyl-amine (2ml) was added. The mixture was stin-ed at RT for 3 hours, washed with a diluted NaOH solution and with water, and then dried. The solvent was evaporated. The residue was purified by column cliromatography over silica gel (eluent: CH2Cl2/ CH3OH 96/4). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 0.32 g (44%) of (±)-trans-4-[l-[3,5-bis(trifluoromethyl)benzoyl]-2-[(3,4-dichloropheny])methyl]-4-piperidinyl]-N-(2,6-dimethy]phenyl)-l-piperazineacetamide (compound 139). Example B 14 A mixture of compound 15 (0.01 moi) and imidazo[l,2-a]pyridin-2-carboxa]dehyde (0.01 mol) in methanol (250 ml) was hydrogenated at RT overnight with palladium on activated carbon (10%, 2 g) as a catalyst in the presence of thiophene (4% solution, 2 ml). After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/ CH3OH 100/0, 99/1, 98/2, 97/3 and 96/4). The pure fractions were collected and the solvent was evaporated. The residue was converted into the fumaric acid salt (1-.2) from ethanol. The precipitate was filtered off and dried, yielding 2.8 g (32%) of (±)-cis-l-[3,5-bis(trifluoromethyl)benzoyI]-4-[4-(imidazo[l,2-a]pyridin-2-ylmethyl)-l-piperazinyl]-2-(phenylmethyI)piperidine (E)-2-butenedioate(l:2) (compound 111), Examples. 15 (+)-(B-trans)-4-[l-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-l-piperazineacetamide (0.003 mol) was dissolved in ethanol (20 ml). A solution of fumaric acid (0.003 mol) in ethanol (15 ml) was added and the mixture was stood for 7 days. The precipitate was filtered off and dried, yielding 1.2 g of(B-trans)-4-[l-[3,5-bis(trifluoromethyl)benzoyl]'2-(phenylmethyl)-4-piperidinyl]-N- (2,6-dimethylphenyl)-l-piperazineacetainide (E)-2-butenedioate(l:l) (compound 128). Example B. 16 A mixture of (±)-l -[3,5-bis(trifluoromethyl)benzoyl]-5-(phenylmethyl)-3-pyrrolidinone (0.0037 mol) and N-(2,6-dimethylphenyl)-l-piperazirneacetamide (0.0037 mol) in -34- methanol (150 ml) was hydrogenated at 50°C with palladium on activated carbon (10%, 1 g) as a catalyst in the presence of tiophene solution (1 ml). After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gei (eiuent: CH2Cl2/CH3OH 95/5). The desired fractions were collected and the solvent was evaporaied. The residue was dried and then crystallized from DIPE. The precipitate was filtered off and dried, yielding 0.35 g (15 %) of (±)-cis-4-[l-(3.5-bis(trifluoromethyl)benzoyl]-5-(phenylmethyl)-3-pyrrolidinyl]-N-(2,6-dimethylpheny)- l-piperazineacetamide (compound 131). Example B.17 (±)-cis-l-(phenylmethyl)-4-[2-(phenylmethyl)-l-piperidinyi]piperazine (0.00043 mol) was added to 3,4-dichlorobenzeneacetic acid (± 0.0004 mol) and l-hydroxybenzotriazole hydrate (0.080 g) in DCM (5 ml). The mixture was stirred and cooled on an ice/ethanoJ-bath, under N2 flow. Triethylamine was added dropwise. A solution of l-(3-dimethyI-aminopropyl)"3-ethylcarbodiinnide hydrochloride (0.120 g) in DCM (5 ml) was added and the reaction mixture was allowed to wann to RT, under N2. The reaction mixture was stirred overnight. The mixture was diluted with CH2Cl2, until a 15-ml total volume was obtained. Then, the compound was isolated and purified by HPLC over silica gel (eiuent: CH2Cl2 to CH2Cl2/CH3OH 90/10 over 20 minutes at 125 ml/minute). The desired fractions were collected and the solvent was evaporated, yielding 0.020 g of (±)-cis-l-[(3,4-dichlorophenyl)acetyll-2-(phenylmelhyl)-4-[4-(phenylmethyl)-l- piperazinyl]piperidine (compound 181). Examples. 18 3,5-di(trifluoromethyl)-l-isocyanatobenzene (0.0025 mol) in DCM (10 ml) was added to a mixture of (±)-trans-N-(2,6-dimethylphenyl)-4-[2-(phenylmethyl)-4-piperidinyl]-l-piperazineacetamide (0.0025 mol) in DCM (15 ml), The mixture was stirred at RT overnight. The precipitate was filtered off and dried, yielding 0.66 g (40%) of (±)-trans 4-[l-[[[3,5-bis(trifluoromethyl)phenyl]amino]carbonyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-l-piperazineacetamide (compound 143). Examples. 19 A mixture of (±)-l-[3,5-bis(trifluoromethyl)benzoyl]-24[3-fluoro-5-(trifluoromethyl) phenyl]methyl]-4-piperidinone (0.01 mol) and N-(2,6-dimethylphenyl)-l-piperazineacetamide (0.01 mol) in 2-propanol (150 ml) was hydrogenated at 50°C with platinum on activated carbon (5 %; 2 g) as a catalyst in the presence of titanium(IV)isopropoxide (2.84 g)and thiophene soludon (1 ml). After uptake of hyrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in CH2Cl2 and H2O. The -35- organic layer was separated, washed several times with H2O, dried, filtered over dicalite and the solvent was evaporated. This fraction was purified by HPLC over silica gel (eluent: CH2Cl2/CH3OH 98/2). Two pure fractions were collected and their solvents were evaporated. The residue was dried, yielding 0.72 g (10 %) of (±)-c/j-4-[l-[3,5-bis(trifluoromethyl)benzoyl]-2-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-l-piperazineacetamide (compound 140) and 0.88 g (12 %) of (±)-trans-4-[l-[3,5-bis(trifluoromethyl)benzoyl]-2-[[3-fluoro-5-(trifluoro)-methyl)phenyl]methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-l-piperazineacetamide (compound 141). Tables 1 to 4 list compounds of fonnula (I) that were prepared according to one or more of the foregoing examples (Ex.). Table 1 -36- -38- -39- -40- -41- -42- -43- -44- -45- -46- -47- -49- -50- Co. No. C H N Exp Theor Exp Theor Exp Theor 47 63.46 63.63 5.84 5.80 8.39 8.48 48 65.16 65.53 6.38 6.20 7.71 7.84 49 65.43 65.53 6.25 6.20 7.81 7.84 50 63.71 63.63 5.64 5.80 8.40 8.48 51 61.79 61.62 5.46 5.48 8.31 8.45 52 64.50 64.71 5.70 5.87 7.92 8.16 53 63.77 63.63 5.90 5.80 8.25 8.48 54 63.54 64.53 5.15 5.29 5.19 5.37 55 67.97 68.56 5.65 5.60 6.02 6.31 56 63.34 63.46 5.39 5.49 6.79 6.94 57 63.54 63.46 5.43 5.49 6.97 6.94 59 63.58 63.63 5.75 5.80 8.37 8.48 60 64.13 63.97 5.61 5.69 6.60 6.78 61 63.41 63.97 5.65 5.69 6.60 6.78 62 62.65 62.87 5.76 5.72 9.97 10.18 63 58.77 58.92 5.14 5.19 4.99 5,03 65 63.78 64.08 6.24 5.98 7.97 8.30 66 62.89 64.22 5.41 5.39 11.03 10.96 67 63.06 64.22 5.18 5.39 10.62 10.96 69 60.74 61.28 5.57 5.68 11.15 11.28 70 62.34 62.53 4.81 5.11 11.62 11.82 71 54.59 54.69 4.03 4.20 7.04 7.29 72 59.45 59.57 5.01 5.28 9.71 9.92 74 54.84 54.85 4.18 4.47 9.28 9.41 76 59.66 60.19 6.21 6.06 8.93 9.36 78 63.95 64.08 5.90 5.98 8.23 8.30 79 55.18 55.25 4.08 4.38 7.04 7.16 82 62.65 63.63 5.80 5.80 8.22 8.48 83 61.84 63.63 5.91 5.80 8.00 8.48 84 58.20 58.49 5.21 5.38 12.81 13.20 85 61.55 62.53 5.15 5.11 11.53 11.82 86 63.82 63.97 5.58 5.69 6.73 6.78 87 67.38 68.37 5.48 6.15 5.48 5.70 92 61.87 61.95 5.17 5.32 6.32 6.72 93 57.14 57.47 4.71 4.92 5.02 5.26 -53- Co. No. C H N Exp Theor Exp Theor Exp Theor 94 66.62 66.84 5.55 5.75 7.23 7.60 95 58.94 58.94 5.60 5.58 6.97 7.05 96 52.25 52.35 4.82 4.97 11.15 11.25 97 62.54 62.35 5.26 5.37 11.64 11.79 98 63.86 63.82 5.30 5.51 8.39 8.51 99 64.29 64.28 5.40 5.69 8.17 8.33 100 62.13 62.35 5.16 5.37 11.59 11.79 101 64.49 64.28 5.68 5.69 8.08 8.33 102 67.17 66.84 5.82 5.75 7.36 7.60 103 58.42 58.69 5.39 5.47 6.15 6.08 104 64.16 64.28 5.73 5.69 8.31 8.33 105 63.95 64.08 6.01 5.98 8.25 8.30 106 62.27 62.65 5.37 5.42 8.84 8.86 107 63.76 63.82 5.54 5.51 8.45 8.51 108 54.46 54.69 4.08 4.20 7.20 7.29 109 58.46 58.49 5.19 5.38 12.90 13.20 110 56.57 57.14 4.58 4.80 7.96 8.13 111 56.80 57.14 4.59 4.80 7.99 8.13 112 56.42 56.33 4.73 4.88 10.77 10.95 114 54.52 54.17 4.61 4.82 5.75 5.74 115 64.06 64.08 6.07 5.98 8.16 8.30 116 63.87 64.08 5.89 5.98 8.11 8.30 117 55.13 55.25 4.18 4.38 7.05 7.16 118 57.96 58.41 4.90 5.12 6.06 6.19 119 60.60 60.60 5.45 5.42 9.12 9.42 120 59.92 59.72 4.73 4.70 6.20 6.53 121 63.51 63.82 5.60 5.51 8.43 8.51 122 63.53 63.82 5.77 5.51 9.05 8.51 123 64.81 65.00 5.75 5.75 10.17 10.24 131 63.23 63.15 5.72 5.61 8.51 8.66 132 60.00 60.34 4.90 5.21 7.76 8.04 133 59.93 60.34 5.17 5.21 7.94 8.04 134 60.22 60.34 5.22 5.21 7.94 8.04 135 60.87 60.34 5.44 5.21 7.97 8.04 137 59.04 59.34 5.01 5.12 7.43 7.69 Co. No. C H N Exp Theor Exp Theor Exp 138 57.81 57.62 4.76 4.97 7.54 7 68 139 57.28 57.62 4.73 4.97 7.25 7.68 140 57.53 57.91 4.88 4.86 7.18 7.50 141 57.45 57.91 4.79 4.86 7.21 7.50 142 73.32 74.19 8.25 7.96 9,28 9.61 143 61.66 62.21 5.77 5.82 10.21 10.36 144 75.31 75.54 7.76 7.68 10.28 10.68 145 76.49 77.32 7.43 7.37 9.33 9.75 170 53.73 55.03 4.46 4.62 7.14 7.40 192 64.48 65.13 6.20 6.33 7.84 7.99 -55- Table 6 Co. No. IC50 (in 10-9M) 5 4.61 17 1.68 19 0.54 22 0.37 24 0.64 25 0.79 26 2.75 27 0.13 28 13.3 29 0.45 33 0.60 34 0.35 35 17.0 36 2.31 37 9.60 38 0.86 42 0.93 43 5.63 44 8.34 45 0.15 46 0.42 48 0.26 49 0.59 50 2.43 Co. No IC50 (in 10-9M 51 1.35 52 1.10 53 0.35 55 2.8 56 3.25 58 0.24 59 1.20 61 15.2 62 0.24 63 8.38 65 6.39 68 5.88 69 1.57 70 0.29 73 5.73 76 14.1 85 0.15 86 2.13 87 1.90 91 0.07 92 0.78 93 4.99 94 0.42 95 0.10 Co. No. IC50 (in 10-9M) 97 1.58 99 1.46 101 0.75 102 1.85 104 0.30 105 1.05 107 0.96 115 2.23 119 2.81 120 0.82 121 2.77 122 1.68 124 0.06 128 0.35 132 2.08 133 0.62 134 0.04 135 0.01 136 0.31 137 0.23 138 0.16 139 0.13 Example C.2 : Antagonism of substance P induced plasma extravasation in guinea-pigs Plasma extravasation was induced by injection of substance P (2 mg/kg) in the femoral artery of female guinea-pigs. Evans Blue dye (30 mg/kg) was injected simultaneously. The test compound or solvent was administered 1 hour prior to substance P injection. 10 minutes after challenge, the animals were checked for blue colouring (a direct measure for plasma extravasation) of the nose, the forepaws, and the conjunctiva. 30 minutes after challenge, the animals were sacrificed by CO2 gas inhalation and checked for blue colouring of the trachea and the urinary bladder. Doses which actively inhibit substance -56- P-induced plasma extravasation are defined as thoses doses at which only 1/3 or less of the total surface area of the nose, forepaws, conjunctiva, trachea or urinary bladder are coloured blue by an intensive exuavasation. Table 7 lists the lowest active doses (LAD) in mg/kg for the tested compounds. Table 7 Co. No. LAD (in m g/kg) nose forepaws conjunctiva trachea urinary bladder 8 10.0 10.0 10.0 >40.0 >40.0 12 >40.0 >40.0 >40.0 >40.0 40.0 16 40.0 40.0 40.0 >40.0 >40.0 17 10.0 10.0 10.0 >40.0 10.0 19 2.50 2.50 2.50 10.0 >40.0 21 10.0 10.0 10.0 >40.0 10.0 22 2.50 2.50 2.50 10.0 >40.0 23 10.0 10.0 >40.0 >40.0 >40.0 24 2.50 2.50 10.0 10.0 >40.0 25 2.50 2.50 10.0 >40.0 >40.0 26 10.0 10.0 20.0 40.0 20.0 27 0.63 0.63 0.63 0.63 0.63 33 2.50 10.0 2.50 >40.0 >40.0 34 2.50 10.0 2.50 10.0 10.0 38 10.0 10.0 10.0 >40.0 >40.0 40 10.0 10.0 10.0 >40.0 >40.0 42 1.25 1.25 2.50 5.00 5.00 45 0.63 0.63 0.63 >40.0 2.50 46 0.63 0.63 0.63 >40.0 0.63 47 40.0 40.0 40.0 >40.0 >40.0 48 2.50 2.50 2.50 2.50 2.50 49 2.50 2.50 2.50 10.0 >40.0 50 10.0 10.0 10.0 10.0 >40.0 52 0.63 0.63 2.50 10.0 10.0 53 1.25 1.25 1.25 2.50 2.50 56 10.0 10.0 10.0 40.0 2.50 59 2.50 2.50 2.50 5.00 5.00 68 10.0 10.0 >40.0 >40.0 >40.0 70 10.0 10.0 10.0 10.0 10.0 -57- Co. No. LAD (in m g/kg) nose forepaws conjunctiva trachea urinary bladder 73 10.0 10.0 10.0 >40.0 >40.0 74 10.0 10.0 10.0 >40.0 >40.0 82 2.50 2.50 2.50 10.0 >40.0 83 0.63 0.63 2.50 >40.0 0.63 85 2.50 2.50 2.50 2.50 10.0 87 10.0 10.0 10.0 10.0 >40.0 90 10.0 10.0 10.0 10.0 >40.0 94 2.50 2.50 2.50 10.0 10.0 95 0.31 0.31 0.31 0.63 2.50 96 10.0 10.0 10.0 >40.0 >40.0 101 10.0 10.0 10.0 >40.0 >40.0 103 2.50 2.50 2.50 10.0 2.50 105 2.50 2.50 2.50 >40.0 >40.0 107 2.50 2.50 2.50 2.50 10.0 119 2.50 2.50 2.50 10.0 >40.0 128 0.63 0.63 0.63 >40.0 10.0 132 10.0 10.0 10.0 10.0 10.0 133 2.50 2.50 2.50 10.0 10.0 134 10.0 10.0 10.0 10.0 10.0 135 0.63 0.63 0.63 2.50 >40.0 136 2.50 2.50 2.50 2.50 2.50 137 2.50 2.50 2.50 2.50 2.50 138 2.50 2.50 2.50 10.0 >40.0 139 2.50 2.50 2.50 2.50 2.50 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 N-oxide form thereof. Example D.l : ORAL DROPS 500 Grams of the A.L was dissolved in 0.5 1 of 2-hydroxypropanoic acid and 1.5 1 of the polyethylene glycol at 60-80°C. After cooling to 30~40°C there were added 35 1 of polyethylene glycol and the mixture was stirred well. Then there was added a solution of 1750 grams of sodium saccharin in 2.5 1 of purified water and while stirring there were added 2,5 1 of cocoa flavor and polyethylene glycol q.s. to a volume of 50 1, providing an oral drop solution comprising 10 mg/ml of A.L The resulting solution was filled into suitable containers. -58- Example D.2 : ORAL SOLUTION 9 Grams of methyl 4-hydroxybenzoate and 1 gram of propyl 4-hydroxy ben zoate were dissolved in 41 of boiling purified water. In 3 1 of this solution were dissolved first 10 grams of 2,3-dihydroxybutanedioic acid and thereafter 20 grams of the A.I. The latter solution was combined with the remaining part of the former solution and 121 1,2,3-propanetriol and 3 1 of sorbitol 70% solution were added thereto. 40 Grams of sodium saccharin were dissolved in 0.5 1 of water and 2 ml of raspberry and 2 ml of gooseberry essence were added. The latter solution was combined with the former, water was added q.s. to a volume of 201 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.3 : FILM-COATED TABLETS Preparation of tablet-core A mixture of 100 grams of the A.I.,, 570 grams lactose and 200 grams starch was mixed well and thereafter humidified with a solution of 5 grams sodium dodecyl sulfate and 10 grams polyvinylpyrrolidone in about 200 ml of water. The wet powder mixture was sieved, dried and sieved again. Then there was added 100 grams microcrystalline cellulose and 15 grams hydrogenated vegetable oil. 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 10 grams methyl cellulose in 75 ml of denaturated ethanol there was added a solurion of 5 grams of ethyl cellulose in 150 ml of dichloromethane. Then there were added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 Grams of polyethylene glycol was molten and dissolved in 75 ml of dichloromethane. The latter solution was added to the former and then there were added 2.5 grams of magnesium octadecanoate, 5 grams of polyvinylpyrrolidone and 30 ml of concentrated colour suspension and the whole was homogenaied. The tablet cores were coaled with the thus obtained mixture in a coating apparatus. Example D.4 : INJECTABLE SOLUTION 1.8 Grams methyl 4-hydroxybenzoate and 0.2 grams propyl 4-hydroxybenzoate were dissolved in about 0.5 1 of boiling water for injection. After cooling to about 50°C there were added while stirring 4 grams lactic acid, 0.05 grams propylene glycol and 4 grams of the A.I.. The solution was cooled lo room temperature 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. 59 We Claim: an N-oxide form, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein n is 0 or 1; m is 1; p is 1 or 2; =Q is=0; X is a covalent bond or a bivalent radical formula -O-or-NR^-; R1 isAr1C1-6alkyl; R2 is Ar2, Ar2C1-6alkyl or Het'; R3 is hydrogen or C1-6alkyl; L is hydrogen; Ar3; C1-6alkyl; C1-6alkyl; substituted with 1 or 2 substituents selected from hydroxy Ar , Ar C1-6alkyloxy and Het ; Ar3 C3-6alkenyl; or a radical of formula 60 wherein each q independently is 2; each r is 0, 1 or 3; 1 "Z each Y independently is a covalent bond, -O- or NR ; Y2 is a covalent bond or-C1-4alkyl NR3-; each-A=B-independently is a bivalent radical of formula-CH=CH-or-N-CH-; each R4 independently is hydrogen, or Ar2; R5 is hydrogen or C1-6alkyl; R6 is C1-6alkyl or Ar3 61 R7 is Ar3; di(Ar3)C1-6alkyl; C1-6alkyl;C1-7cycloalkyl substituted with Ar3; thiazolyl; imidazolyl substituted with C1-6alkyl or Ar3 C1-6alkyl; indolinyl; indolinyl substituted with C1-4alkyl; 2,3,4- trihydroquinolinyl; pyrrolidinyl or furanyl; each R8 independently is hydrogen or a radical of formula Alk-R11 (b-1)or Alk-Z-R12 (b-2); wherein Alk is C1-6alkanediyl; Z is a bivalent radical of formula-O-; R11 is phenyl substituted with halo; oxazolyl substituted with 1 C1-6alkyl substituent; R12 is C1-6alkyl; Ar1 is phenyl substituted with 1 or 2 substituents each independently selected from halo or C1-4alkyl; Ar2 is naphtalenyl; phenyl;phenyl substituted with 1,2 or 3 substituents each independently selected from halo, cyano, nitro, amino, C1-. 4alkyl, halo C1-4alkyl, C1-4alkyloxy and C1-4alkyloxycarbonyl; Ar3 is phenyl or phenyl substituted with 1,2 or 3 substituents selected from -halo, hydroxy, nitro, aminocarbonyl,C1-6alkyl, haloC1-6alkyl or C1-6alkyloxy; 62 Het is a monocyclic heterocycle selected from furanyl, thienyl, isoxazolyl, pyridinyl, and pyrazinyl; or a bicyclic heterocycle selected from quinolinyl, quinoxalinyl, indolyl, benzofuranyl and benzothienyl; each monocyclic and bicyclic heterocycle may optionally be substituted on a carbon atom by 1 or 2 substituents selected from halo or C1-4alkyl; and Het2 is a heterocycle selected from l,4-dihydro-5-oxo-tetrazol-l-yl, imidazo [1,2-a] pyridinyl, oxazolyl or imidazolyl; each of said heterocycles may be substituted with 1 or where possible 2 C1-4alkyl substituents. 2. A compound according to claim 1 wherein L is hydrogen; C1-6alkyl; C1-6alkyl substituted with hydroxy; Ar3; Ar3C1-6alkyl; di(Ar3)C1-6alkyl; Ar3 C3-6alkenyl; or a radical of formula(a-l), (a-2) or (a-4) wherein R7 is Ar3 di(Ar3)C1-6alkyl; C1-6alkyl; C3-7cycloalkyl substituted with Ar3; thiazolyl; imidazolyl substituted with C1-6alkyl or Ar3C1-6alkyl;pyrrolidinyl or furanyl; Ar3 is is phenyl or phenyl substituted with 1, 2 or 3 substituents selected from halo, hydroxy, aminocarbonyl, C1-6alkyl, haloC1-6alkyl orC1-6alkyloxy; Het1 is a monocyclic heterocycle selected from furanyl, thienyl. 63 isoxazolyl, pyridinyl, and pyrazinyl; or a bicyclic heterocycle selected from quinolinyl, benzofiiranyl and benzothienyl; each monocyclic and bicyclic heterocycle may optionally be substituted on a carbon atom by 1 or 2 substituents selected from halo or C1-4alkyl; 3. A compound as claimed in claim 1 or 2 wherein R1 is Ar1C1-6alkyl, R2 is phenyl substituted with 2 substituents selected from methyl and trifluoromethyl, X is a covalent bond and =Q is =0. 4. A compound as claimed in any one of claims 1 to 3 wherein n and are 1 and p is 1 or 2. 5. A compound as claimed in any one of claims 1 to 4 wherein R1 is phenylmethyl; R is phenyl substituted with 2 substituents selected from methyl or trifluoromethyl; n, m and p are 1; X is a covalent bond; and =Q is =0. 6. A compound as claimed in any one of claims 1 to 4 wherein L is a radical of formula (a-2) wherein R4 is hydrogen or phenyl; r is 0 or 1; y1 is a covalent bond, -O- or -NH-; R7 is pyrrolidinyl; furanyl; 1-phenylcyclohexanyl; diphenylmethyl; or phenyl substituted with 1,2 or 3 substituents each independently selected from methyl, methoxy or chloro. 64 7. A compound as claimed in claim 5 or 6 wherein the compound has the trans active configuration. 8. A compound as claimed in claim 5 to 6 wherein the compound has the cis configuration. 9. A compound as claimed in claim 1, wherein L is hydrogen. 10.A compound as claimed in claim 1, wherein the compound is 4-[l-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6- dimethylphenyl)-l-piperazine acetamide; 4-[I-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4- piperidinyl]-N-( 1 -phenylcyclohexyl)-1 -piperazine acetamide; l-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-[4-[a-(l- pyrrolidinylcarbonyl)benzyl]-1 -piparazinyljpiperidine; l-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-[l-[(2-methyl-5-oxazolyl)methyl]-lH-benzimidazol-2-yl]-l-piperazinyl]-2-(phenylmethyl)piperidine; 4-[l-[3,5-bis(trifluoromethyl)benzoyl]-2-[(4- trifluoromethylphenyl)methyI]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1 -piperazine acetamide; 4-[l-[3,5-bis(trifluoromethyl)benzoyl]-2-[(3,4-dichlorophenyl)methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-l-piperazine acetamide. 65 11.A compound as claimed in claim 10, wherein the compound is (+)-(B)-trans-4-[l-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1 -piperazine acetamide; (-)-(B)-cis-4-[l-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1 -piperazine acetamide; or (+)-(B)-cis-4-[l-[3,5-bis(trifluoromethyl)benzoyi]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-l-piperazine acetamide, (L)-malic acid (1:1). 12.A process of preparing a composition as claimed in claim 12,characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound as claimed in any one claims 1 to 11. 13.A compound as claimed in any one of claims 1 to 11 for use as a medicine. 14.A process of preparing a composition as claimed in claim 1,characterized by a) reductively N-alkylating an intermediate of formula (III) wherein L and p are defined as in claim 1, with an intermediate of formula (II) 66 wherein R , R , X, Q, n and m are defined as claim 1, in a reaction-inert solvent, in the presence of an appropriate reducing agent and optionally in the presence of a suitable complex-forming agent; b) reacting an intermediate of formula (IV) wherein R , X and Q are defined as in claim 1 and W1 is an appropriate leaving group with an intermediate of formula (V) wherein R1 L, n, m and p are defined as in claim 1, in a reaction-inert solvent and in the presence of a suitable base; 67 c) reductively N-alkylating a piperazine derivative of formula (VII) wherein p is defined as in claim 1 and P1 is a protective group, with an intermediate of formula (II) wherein R1, R2 , X, Q, n and m are defined as in claim 1, in a reaction-inert solvent, in the presence of an appropriate reducing agent and optionally in the presence of a suitable complex-forming agent, thus forming a compound of a formula (I-c); 68 d) reductively N-alkylating a piperazine derivative of formula (VII) wherein p is defined as in claim 1 and P1 is a protective group, with an intermediate of formula (VIII), wherein R1, n, and m are defined as in claim 1, in a reaction-inert solvent and in the presence of a suitable base; thus forming an intermediate of formula (XI); which may subsequently be reacted with an intermediate of formula (IV) wherein W is an appropriate leaving group , and X, Q and R are defined as in claim 1, to form a compound of formula (I-c); 69 e) deprotecting a compound of formula (I-c) using art-known deprotection techniques, thus forming a compound of formula (I-b); f) reacting a compound of formula (I-b) with an intermediate of formula (VII) wherein L' is the same as L as defined in claim 1 but other than hydrogen and W2 is an appropriate leaving group in a reaction-inert solvate and in the presence of a suitable base; thus forming a compound of formula (I-a); 70 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 from 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. Dated this 28th day of October 1996. the N-oxide forms, the pharmaceutically acceptable addition salt and stereoisomeric forms thereof, wherein n is 0, 1 or 2; m is 1 or 2, provided that if m is 2, then n is 1; p is 1 or 2; =Q is =0 or =NR3; X is a covalent bond or a bivalent radical of formula-O-, -S-,-NR3-; R1 is Ar1, Ar1C1-6alkyl or di(Ar1)C1-6alkyl, wherein each C1-6alkyl group is optionally substituted with hydroxy, C1-4alkoloxy, oxo or a ketalized oxo substituent; R2 is Ar2 , Ar2 C1. 6alkyl, Het1 or Het1 C1-6alkyl; R3 is hydrogen or C1-6alkyl; L is hydrogen; Ar3 ; C1-6alkyl; C1-6alkyl substituted with 1 or 2 substituents selected from hydroxy, C1-6alkyloxy, Ar3, Ar3C1-6alkyloxy and Het2;C3-6alkenyl; Ar3C3. 6alkenyl; di(Ar3)C3-6alkenyl or a radical of formula (a-1), (a-2), (a-3), (a-4) or (a-5);Ar1 , Ar2 and Ar3 are each phenyl or substituted phenyl; Het and Het are each monocyclic or a bicyclic heterocycles; as substance-P antagonists; their preparation, compositions containing them and their use as a medicine.

Documents:

01880-cal-1996 abstract.pdf

01880-cal-1996 claims.pdf

01880-cal-1996 correspondence.pdf

01880-cal-1996 description(complete).pdf

01880-cal-1996 form-1.pdf

01880-cal-1996 form-18.pdf

01880-cal-1996 form-2.pdf

01880-cal-1996 form-3.pdf

01880-cal-1996 form-6.pdf

01880-cal-1996 g.p.a.pdf

01880-cal-1996 letter patent.pdf

01880-cal-1996 priority document.pdf

01880-cal-1996 reply f.e.r.pdf

1880-CAL-1996-(29-03-2012)-FORM-27.pdf

1880-CAL-1996-(29-03-2012)-PA.pdf

1880-cal-1996-granted-abstract.pdf

1880-cal-1996-granted-claims.pdf

1880-cal-1996-granted-correspondence.pdf

1880-cal-1996-granted-description (complete).pdf

1880-cal-1996-granted-form 1.pdf

1880-cal-1996-granted-form 2.pdf

1880-cal-1996-granted-form 3.pdf

1880-cal-1996-granted-gpa.pdf

1880-cal-1996-granted-letter patent.pdf

1880-cal-1996-granted-reply to examination report.pdf

1880-cal-1996-granted-specification.pdf

1880-cal-1996-granted-translated copy of priority document.pdf