Title of Invention

"SUBSTITUTED 1-PIPERIDIN-4-YL-4-PYRROLIDIN-3-YL-PIPERRAZINE COMPOUND OF FORMULA (I) AND PROCESS THEREOF"

Abstract

This invention concerns substituted I-piperidin-4-yl-4-pyrrolidin-3-yl-piperazine derivatives having neurokinin antagonistic activity, in particular NK1 antagonistic activity, a combined NK1/NK3 antagonistic activity and a combined NK1/NK2/NK3 antagonistic activity, their preparation, compositions comprising them and their use as a medicine, in particular for the treatment of schizophrenia, anxiety, depression, emesis and IBS. The compounds according to the invention can be represented by general Formula (I) and comprises also the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form Thereof and prodrugs thereof, wherein all substituents are defined as in Claim 1. In view of their capability to antagonize Ihe actions of tachykinins by blocking the neurokinin receptors, and in particular antagonizing the actions of substance P and Neurokinin B by blocking the NK1, NK2 and NK3 receptors, the compounds according to the invention are useful as a medicine, in particular in the prophylactic and therapeutic treatment of tachykinin-mediated conditions, such as, for instance CNS disorders, in particular schi/.oaiieclive disorders, depression, anxiety disorders, stress-related disorders, sleep disorders, cognitive disorders, personality disorders, eating disorders, neurodegenerative diseases, addiction disorders, mood disorders, sexual dysfunction, pain and other CNS-related conditions ; inflammation ; allergic disorders ; emesis ; gastrointestinal disorders, in particular irritable bowel syndrome (IBS); skin disorders ; vasospastic diseases ; fibrosing and collagen diseases ; disorders related to immune enhancement or suppression and rheumatic diseases and body weight control.

Full Text

SUBSTITUTED 1-PIPERJDIN-4-YL-4-PYRROLIDIN-3-YL-PIPERAZINE DERIVATIVES AND THEIR USE AS NEUROKININ ANTAGONISTS Field of the Invention This invention concerns substituted 1 -piperidin-4-yl-4-pyrrolidm-3-yl-piperazine derivatives having neurokinm antagonistic activity, in particular NKj antagonistic activity, a combined NK]MK3 antagonistic activity and a combined NKi/NK2/NK3 antagonistic activity, their preparation, compositions comprising them and their use as a medicine, in particular for the treatment of schizophrenia, emesis, anxiety and depression, irritable bowel syndrome (IBS), circadian rhythm disturbances, visceral pain, neurogenic inflammation, asthma, micturition disorders such as urinary incontinence and nociception. Background of The Invention Tachykinins belong to a family of short peptides that are widely distributed in the mammalian central and peripheral nervous system (Bertrand and Geppetti, Trends Phai-macol. Sd. 17:255-259 (1996) ; Lundberg, Can. J. Physiol. Pharmacol 73:908-914 (1995) ; Maggi, Gen. Pharmacol. 26:911-944 (1995) ; Regoli etal., Pharmacol. Rev. 46 (1994)). They share the common C-terminal sequence Phe-Xaa-Gly-Leu-Met-NH2. Tachykinins released from peripheral sensory nerve endings are believed to be involved in neurogenic inflammation. In the spinal cord/central nervous system, tachykinins may play a role in pain transmission/perception and in some autonomic reflexes and behaviors. The three major tachykinins are Substance P (SP), Neurokinin A (NKA) and Neurokinin B (NKB) with preferential affinity for three distinct neurokinin receptor subtypes, termed NKi, NK2, and NK3, respectively. However, functional studies on cloned receptors suggest strong functional cross-interaction between the 3 tachykinins and their corresponding neurokinin receptors (Maggi and Schwartz, Trends Pharmacol. Sci. 18: 351-355 (1997)). Species differences in structure of NKi receptors are responsible for species-related potency differences of NKi antagonists (Maggi, Gen. Pharmacol. 26:911-944 (1995); Regoli et al, Pharmacol. Rev. 46(4):551-599 (1994)). The human NK, receptor closely resembles the NKi receptor of guinea-pigs and gerbils but differs markedly from the NKi receptor of rodents. The development of neurokinin 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. etaL, DN&P 8(l):5-23 (1995)). The tachykinins are involved in schizophrenia, depression, (stress-related) anxiety states, emesis, inflammatory responses, smooth muscle contraction and pain perception. Neurokinin antagonists are in development for indications such as emesis, anxiety and depression, irritable bowel syndrome (IBS), circadian rhythm disturbances, visceral pain, neurogem'c inflammation, asthma, micturition disorders, and nociception. In particular, NKi antagonists have a high therapeutic potential in emesis and depression and NKa antagonists have a high therapeutic potential in asthma treatments. NK^ antagonists seem to play a role in the treatment of pain/inflammation (Giardina, G. et al. Exp. Opin. Ther. Patents, 10(6): 939-960 (2000)) and schizophrenia. Schizophrenia The NK3 antagonist SR142801 (Sanofi) was recently shown to have antipsychotic activity in schizophrenic patients without affecting negative symptoms (Arvantis, L. ACNP Meeting, December 2001). Activation of NKi receptors causes anxiety, stressfull events evoke elevated substance P (SP) plasma levels and NKi antagonists are reported to be anxiolytic in several animal models. The NKj antagonist from Merck, MK-869 shows antidepressant effects in major depression, but data were not conclusive due to a high placebo response rate. Moreover, the NKi antagonist from Glaxo-Welcome (S)-GR205,171 was shown to enhance dopamine release in the frontal cortex but not in the striatum (Lejeune et al. Soc. Neurosci, November 2001). It is therefore hypothesized that NKs antagonism in combination with NKi antagonism would be beneficial against both positive and negative symptoms of schizophrenia. Anxiety and depression Depression is one of the most common affective disorders of modem society with a high and still increasing prevalence, particularly in the younger members of the population. The life time prevalence rates of Major depression (MDD, DSM-IV) is currently estimated to be 10-25 % for women and 5-12 % for men, whereby in about 25 % of patients the life time MDD is recurrent, without full inter-episode recovery and superimposed on dysthymic disorder. There is a high co-morbidity of depression with other mental disorders and, particularly in younger population high association with drug and alcohol abuse. In the view of the fact that depression primarily affects the population between 18-44 years of age e.g. the most productive population, it is obvious that it imposes a high burden on individuals, families and the whole society. Among all therapeutic possibilities, the therapy with antidepressants is incontestably the most effective. A large number of antidepressants have been developed and introduced to the market in the course of the last 40 years. Nevertheless, none of the current antidepressants fulfill all criteria of an ideal drug (high therapeutic and prophylactic efficacy, rapid onset of action, completely satisfactory short- and long-term safety, simple and favourable pharmacokinetics) or is without side effects which in one or the other way limits their use in all groups and subgroups of depressed patients. Since no treatment of the cause of depression exists at present, nor appears imminent, and no antidepressant is effective in more than 60-70 % of patients; the development of a new antidepressant which may circumvent any of the disadvantages of the available drugs is justified. Several findings indicate involvement of SP in stress-related anxiety states. Central injection of SP induces a cardiovascular response resembling the classical "fight or flight" reaction characterised physiologically by vascular dilatation in skeletal muscles and decrease of mesenteric and renal blood flow. This cardiovascular reaction is accompanied by a behavioural response observed in rodents after noxious stimuli or stress (Oilman and Unger, Can. J. Physiol. Pharmacol. 73:885-891 (1995)). In mice, centrally administered NKi agonists and antagonists are anxiogenic and anxiolytic, respectively (Teixeira et al, Eur. J. Pharmacol. 311:7-14 (1996)). The ability of NKj antagonists to inhibit thumping induced by SP (or by electric shock; Ballard et al., Trends Pharmacol. Sci. 17:255-259 (2001)) might correspond to this antidepressant / anxiolytic activity, since in gerbils thumping plays a role as an alerting or warning signal to conspecifics. The NK| receptor is widely distributed throughout the limbic system and fear-processing pathways of the brain, including the amygdala, hippocampus, septum, hypothalamus, and periaqueductal grey. Additionally, substance P is released centrally in response to traumatic or noxious stimuli and substance P-associated neurotransmission may contribute to or be involved in anxiety, fear, and the emotional disturbances that accompany affective disorders such as depression and anxiety. In support of this view, changes in substance P content in discrete brain regions can be observed in response to stressful stimuli (Brodin et al., Nenropeptides 26:253-260 (1994)). Central injection of substance P mimetics (agonists) induces a range of defensive behavioural and cardiovascular alterations including conditioned place aversion (Elliott, Exp. Brain. Res. 73:354-356 (1988)), potentiated acoustic startle response (Krase et a!., Behav. Brain. Res. 63:81-88 (1994)), distress vocalisations, escape behaviour (Kramer et al., Science 281:1640-1645 (1998)) and anxiety on the elevated plus maze (Aguiar and Brandao, Physiol Behav. 60:1183-1186(1996)). These compounds did not modify motor performance and co-ordination on the rotarod apparatus or ambulation in an activity cage. Down-regulation of substance P biosynthesis occurs in response to the administration of known anxiolytic and antidepressant drugs (Brodin et al., Neuropeptides 26:253-260 (1994); Shirayama etal, Brain. Res. 739:70-78 (1996)). Similarly, a centrally administered NKi agonist-induced vocalisation response in guinea-pigs can be antagonised by antidepressants such as imipramine and fluoxetine as well as L-733,060, an NKi antagonist These studies provide evidence suggesting that blockade of central NKi receptors may inhibit psychological stress in a manner resembling antidepressants and anxiolytics (Rupniak and Kramer, Trends Pharmacol. Sci. 20:1-12 (1999)), but without the side effects of present medications. Emesis Nausea and vomiting are among the most distressing side effects of cancer chemotherapy. These reduce the quality of life and may cause patients to delay or refuse, potentially curative drugs (Kris et al., J. Gin. Oncol., 3:1379-1384(1985)). The incidence, intensity and pattern of emesis is determined by different factors, such as the chemotherapeutic agent, dosage and route of administration. Typically, early or acute emesis starts within the first 4 h after chemotherapy administration, reaching a peak between 4 h and 10 h, and decreases by 12 to 24 h. Delayed emesis (developing after 24 h and continuing until 3-5 days post chemotherapy) is observed with most 'high-emetogenic' chemotherapeutic drugs (level 4 and 5 according to Hesketh et al., J. Clin. Oncol. 15:103 (1997)). ha humans, these 'high-emetogenic' anti-cancer treatments, including cis-platinum, induce acute emesis in > 98% and delayed emesis in 60-90% of cancer patients. Animal models of chemotherapy such as cisplatin-induced emesis in ferrets (Rudd and Naylor, Neuropharmacology 33:1607-1608 (1994) ; Naylor and Rudd, Cancer. Surv. 21:117-135 (1996)) have successfully predicted the clinical efficacy of the 5-HT3 receptor antagonists. Although this discovery led to a successful therapy for the treatment of chemotherapy- and radiation-induced sickness in cancer patients, 5-HT3 antagonists such as ondansetron and granisetron (either or not associated with dexamethasone) are effective in the control of the acute emetic phase (the first 24 h) but can only reduce the development of delayed emesis (> 24 h) with poor efficacy (De Mulder et al, Annuals of Internal Medicine 113:834-840 (1990) ; Roila, Oncology 50:163-167 (1993)). Despite these currently most effective treatments for the prevention of both acute and delayed emesis, still 50% of patients suffer from delayed vomiting and/or nausea (Antiemetic Subcommittee, Annals Oncol. 9:811-8T9 (1998)). In contrast to 5-HT3 antagonists, NKj antagonists such as CP-99,994 (Piedimonte et al., L. Pharmacol. Exp. Ther. 266:270-273 (1993)) and aprepitant (also known as MK.-869 or L-754,030 ; Kramer et al., Science 281:1640-1645 (1998); Rupniak and Kramer, Trends Pharmacol. Sci. 20:1-12 (1999)) have now been shown to inhibit not only the acute but also the delayed phase of cisplatin-induced emesis in animals (Rudd et al.,Br. J. Pharmacol. 119:931-936 (1996) ; Tattersall etal.,Neitropharmacology 39:652-663 (2000)). NKi antagonists have also been demonstrated to reduce 'delayed' emesis in man in the absence of concomitant therapy (Cocquyt et al., Eur. J. Cancer 37:835-842 (2001); Navari eta!., N. Engl. L. Med. 340:190-195 (1999)). When administered together with dexamethasone and 5-HT3 antagonists, moreover, NK] antagonists (such as MK-869 and CJ-11,974, also known as Ezlopitant) have been shown to produce additional effects in the prevention of acute emesis (Campos et al., J. Clin. Oncol. 19:1759-1767 (2001); Hesketh etal, Clin. Oncol. 17:338-343 (1999)). Central neurokinin NKi receptors play a major role in the regulation of emesis. NK] antagonists are active against a wide variety of emetic stimuli (Watson et al., Br. J. Pharmacol. 115:84-94 (1995) ; Tattersall et al., Neuropharmacol 35:1121-1129 (1996) ; Megens etal., J. Pharmacol. Exp. Ther. 302:696-709 (2002)). The compounds are suggested to act by blocking central NKi-receptors in the nucleus tractus solitarius. Apart from NKi antagonism, CNS penetration is thus a prerequisite for the antiemetic activity of these compounds. Loperamide-induced emesis in ferrets can be used as a fast and reliable screening model for the antiemetic activity of NKi antagonists. Further evaluation of their therapeutic value in the treatment of both the acute and the delayed phases of cisplatin-induced emesis has been demonstrated in the established ferret model (Rudd etal., Br. J. Pharmacol. 119:931-936 (1994)). This model studies both 'acute' and 'delayed' emesis after cisplatin and has been validated in terms of its sensitivity to 5-HT3 receptor antagonists, glucocorticoids (Sam et al., Eur. J. Pharmacol. 417:231-237 (2001)) and other pharmacological challenges. It is unlikely that any future anti-emetic would find clinical acceptance unless successfully treating both the 'acute' and 'delayed' phases of emesis. Irritable bowel syndrome (IBS) Patients with irritable bowel syndrome (IBS) experience impaired quality of life, and utilise health care resources extensively as they seek better "solutions" (including unnecessary repeated investigations or even surgery). Although these patients suffer from a 'benign' disorder (in other words, they will never die or develop significant complications), they nevertheless cause a significant economic burden by extensive health care resource utilisation, and absence from work. A reasonable number of pre-clinical publications over the role of NKi receptors in visceral pain has been published. Using NKi receptor knockout mice and NKi antagonists in animal models, different groups have demonstrated the important role played by the NKi receptor in hyperalgesia and visceral pain. The distribution of NKi receptors and substance P favours a major role in visceral rather than in somatic pain. Indeed more than 80% of visceral primary afferent contain substance P compared with only 25% skin afferents. NKi receptors are also involved in gastrointestinal motility (Tonini et al., Gastroenterol. 120:938-945 (2001); Okano et al., J. Pharmacol. Exp. Ther. 298:559-564 (2001)). Because of this dual role in both gastrointestinal motility and in nociception, NKi antagonists are considered to have potential to ameliorate symptoms in IBS patients. Background prior art Compounds containing the l-piperidin-4-yl-piperazinyl moiety were published in WO 97/16440-A1, published May 9, 1997 by Janssen Pharmaceutica N.V. for use as substance P antagonists, in WO 02/32867, published April 25, 2002 by Glaxo Group Ltd. for their special advantages as neurokinin antagonists (more specifically were disclosed 4-piperazin-l-yl-piperidine-l-carboxylic acid amide derivatives), in WO 01/30348-A1, published May 03,2001 by Janssen Pharmaceutica N.V., for use as substance P antagonists for influencing the circadian timing system, and in WO 02/062784-A1, published August 15, 2002 by Hoffmann-La Roche AG for use as neurokinin-1 antagonists. The compounds of the present invention differ from the compounds of the prior art in the substitution of the piperazinyl moiety, being a substituted pyrrolidinyl moiety as well as in their improved ability as potent, orally and centrally active neurokinin antagonists with therapeutic value, especially for the treatment of schizophrenia, emesis, anxiety and depression, irritable bowel syndrome (IBS), circadian rhythm disturbances, visceral pain, neurogenic inflammation, asthma, micturition disorders such as urinary incontinence and nociception. Description of the Invention The present invention relates to novel substituted l-piperidin-4-yl-4-pyrrolidin-3-yl- piperazine derivatives according to the general Formula (I) (Figure Remove) N-Alk-Y-AIK-L (I) n m P q Q X each R eachR R2 Y the pharmaceutically acceptable acid or base addition salts thereof, the stereochemic^lly isomeric forms thereof, the TV-oxide form thereof and prodrags thereof, wherein : is an integer, equal to 0, 1 or 2 ; is an integer, equal to 1 or 2, provided that if m is 2, then n is 1 ; is an integer equal to 1 or 2; is an integer equal to 0 or 1 ; is O or NR3; is a covalent bond or a bivalent radical of formula -O-, -S- or -NR3-; independently from each other, is hydrogen or alkyl; independently from each other, is selected from the group of Ar1, Ar1-alkyl and di(Ar')-alkyl; is Ar2, Ar-alkyl, di(Ar2)alkyl, Het1 or Het'-alkyl; is a covalent bond or a bivalent radical of formula -C(=O)-, -SO2- >C=CH-R or >C=N-R, wherein R is H, CN or nitro ; each Alk L represents, independently from each other, a covalent bond; a bivalent straight or branched, saturated or unsaturated hydrocarbon radical having from 1 to 6 carbon atoms ; or a cyclic saturated or unsaturated hydrocarbon radical having from 3 to 6 carbon atoms ; each radical optionally substituted on one or more carbon atoms with one or more , phenyl, halo, cyano, hydroxy, formyl and amino radicals ; is selected from the group of hydrogen, alkyl, alkyloxy, alkyloxyalkyloxy, alkylcarbonyloxy, alkyloxycarbonyl, mono- and di(alkyl)amino, mono- and di(alkyloxycarbonyl)amino, mono- and di(alkylcarbonyl)amino, mono-and di(Ar3)amino, mono-and di(Ar3alkyl)ammo, mono-and di(Het2)amino, mono-and di(Het2alkyl)amino, alkylsulfanyl, adamantyl, Ar3, Ar3-oxy, Ar3carbonyl, Het2, Het-oxy and Het2carbonyl; Ar1 is phenyl, optionally substituted with 1, 2 or 3 substituents, each independently from each other, selected from the group of halo, alkyl, cyano, aminocarbonyl and alkyloxy ; Ar2 is naphthalenyl or phenyl, each optionally substituted with 1,2 or 3 substituents, each independently from each other, selected from the group of halo, nitro, amino, mono- and di(alkyl)amino, cyano, alkyl, hydroxy, alkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl and mono- and di(alkyl)aminocarbonyl; Ar3 is naphthalenyl or phenyl, optionally substituted with 1,2 or 3 substituents, each independently from each other, selected from the group of alkyloxy, Ar'carbonyloxyalkyl, Ar1 alkyloxycarbonyl, Ar'alkyloxyalkyl, alkyl, halo, hydroxy, pyridinyl, morpholinyl, pyrrolidinyl, imidazo[l,2-a]pyridinyl, morpholinylcarbonyl, pyrrolidinylcarbonyl, amino and cyano ; Het1 is a monocyclic heterocyclic radical selected from the the group of pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocyclic radical selected from the group of quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, indanyl and chromenyl; each heterocyclic radical may optionally be substituted on any atom by one or more radicals elected from the group of halo, oxo and alkyl; Het" is a monocyclic heterocyclic radical selected from the group of pyrrolidinyl, dioxolyl, imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, imidazolidinyl, tetrahydrofuranyl, 2H-pyrrolyl, pyrrolinyl, imidazolinyl, pyrazolinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, furanyl, thienyl, oxazolyl, dioxazolyl, oxazolidinyl, isoxazolyl, thiazolyl, thiadiazolyl, isotliiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl; or a bicyclic heterocyclic radical selected from the group of 2,3-dihydro-benzo[l,4]dioxine, octahydro-benzo[l,4]dioxine, benzopiperidinyl, quinolinyl, quinoxalinyl, indolyl, isoindolyl, chromanyl, benzimidazolyl, imidazo[l,2-a]pyridinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl and benzothienyl; or the tricyclic heterocyclic radical 8,9-dihydro-4//-l-oxa-3,5,7a-triaza-cyclopenta[fjazulenyl; each radical may optionally be substituted with one or more radicals selected from the group of Ar1, Ar1 alkyl, Ar'alkyloxyalkyl, halo, hydroxy, alkyl, piperidinyl, pyrrolyl, thienyl, oxo, alkyloxy, alkylcarbonyl, Ar'carbonyl, mono- and di(alkyl)aminoalkyl, alkyloxyalkyl and alkyloxycarbonyl; and alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radicals having from 3 to 6 carbon atoms ; optionally substituted on one or more carbon atoms with one or more radicals selected from the group of phenyl, halo, cyano, oxo, hydroxy, formyl and amino. More in particular, the invention relates to a compound according to the general Formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the JV-oxide form thereof and a prodrag thereof, wherein : n is an integer, equal to 1; m is an integer, equal to 1; p is an integer equal to 1 or 2; q is an integer equal to 0; Q isO X is a covalent bond; R1 isAr'-alkyl; R2 is Ar2, Ar2-alkyl, di(Ar2)alkyl or Het1; Y is a covalent bond or a bivalent radical of formula -C(=O)-, -SO2-, • >C=CH-R or >C=N-R, wherein R is CN or nitro ; each Alk represents, independently from each other, a covalent bond ; a bivalent straight or branched, saturated hydrocarbon radical having from 1 to 6 carbon atoms ; or a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms ; each radical optionally substituted on one or more carbon atoms with one or more phenyl, halo and hydroxy radicals; L is selected from the group of hydrogen, alkyl, alkyloxy, alkyloxyalkyloxy, alkylcarbonyloxy, mono- and di(alkyl)amino, mono- and di(alkyloxycarbonyl)amino, mono- and di(allcylcarbonyl)amino, mono-and di(Ar3)amino, mono-and di(Ar3alkyl)amino, mono-and di(Het2alkyl)amino, alkylsulfanyl, adamantyl, Ar3, Het2 and Het2carbonyl; Ar' is phenyl, optionally substituted with 1 or 2 halo radicals ; Ar2 is naphthalenyl or phenyl, each optionally substituted with 1, 2 or 3 substituents, each independently from each other, selected from the group of halo, alkyl and alkyloxy; Ar3 is naphthalenyl or phenyl, optionally substituted with 1,2 or 3 substituents, each independently from each other, selected from the group of alkyloxy, Ar'alkyloxycarbonyl, Ar'alkyloxyalkyl, alkyl, halo and cyano; Het' is pyridinyl or a bicyclic heterocyclic radical selected from the group of quinoxalinyl, indolyl, benzothienyl, indanyl and chromenyl; each heterocyclic radical may optionally be substituted on any atom by one or more radicals selected from the group of oxo and alkyl; Het2 is a monocyclic heterocyclic radical selected from the group of pyrrolidinyl, dioxolyL, piperidinyl, morpholinyl, pipera2inyl, tetrahydrofuranyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, dioxazolyl, oxazolidinyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocyclic radical selected from the group of 2,3-dihydro-benzo[l,4]dioxine, octahydro-benzo[l,4]dioxine, quinoxalinyl, indolyl, chromanyl, benzimidazolyl, imidazo[l,2-cr]pyridinyi, benzisoxazolyl, benzothiazolyl,benzofuranyl and benzothienyl; or the tricyclic heterocyclic radical 8,9-dihydro-4//-l-oxa-3,5,7a-triaza-cyclopenta[fjazulenyl; each radical may optionally be substituted with one or more radicals selected from the group of Ar1, Ar'alkyloxyalkyl, halo, alkyl, oxo, alkyloxy, alkylcarbonyl, Ar'carbonyl, mono- and di(alkyl)aminoalkyl, alkyloxyalkyl and alkyloxycarbonyl; and alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radicals having from 3 to 6 carbon atoms ; optionally substituted on one or more carbon atoms with one or more radicals selected from the group of phenyl, halo and hydroxy. More in particular, the invention relates to a compound according to the general Formula (1), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the TV-oxide form thereof and a prodrug thereof, wherein R1 is Ar1 methyl and attached to the 2-position or R1 is Ar1 and attached to the 3-position, as exemplified in either of the following formulas for compounds according to Formula (I) wherein m and n are equal to 1 and Ar is an unsubstituted phenyl. Preferably, Ar'methyl is a benzyl radical. (Figure Remove) More in particular, the invention relates to a compound according to the general Formula (I), the pharrnaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the TV-oxide form thereof and a prodrug thereof, wherein the R2-X-C(=Q)- moiety is 3,5-di-(trifluoromethyl) phenylcarbonyl. More in particular, the invention relates to a compound according to the general Fonnula (1), the pharrnaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the //-oxide form thereof and a prodrug thereof, wherein p is 1. More in particular, the invention relates to a compound according to the general Fonnula (I), the pharrnaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the //-oxide form thereof and a prodrug thereof, wherein Y is -C(=O)-. More in particular, the invention relates to a compound according to the general Formula (I), the pharrnaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the //-oxide form thereof and a prodrug thereof, wherein Alk is a covalent bond. More in particular, the invention relates to a compound according to the general Formula (I), the pharrnaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the //-oxide form thereof and a prodrug thereof, wherein L is Het2. More in particular, the invention relates to a compound according to the general Formula (I), the pharrnaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the W-oxide form thereof and a prodrug thereof, wherein the compound is a compound with compound number 219,270,269, 281, 408, 393, 72, 164, 253,258, 267,286, 317, 318, 313, 308, 331, 366, 31, 32,4, 71, 218, 259,287,285, 306 and 321, as mentioned in any one of Tables 1-6 further in this application. In the framework of this application, alkyl is defined as amonovalent straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms, for example methyl, ethyl, propyl, butyl, 1-methylpropyl, l,l-dimethylethyl,pentyl, hexyl; alkyl further defines a monovalent cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms, for example cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The definition of alkyl also comprises an alkyl radical that is optionally substituted on one or more carbon atoms with one or more phenyl, halo, cyano, oxo, hydroxy, formyl and amino radicals, for example hydroxyalkyl, in particular hydroxymethyl and hydroxyethyl and polyhaloalkyl, in particular difluoromethyl and trifluoromethyl. In the framework of this application, halo is generic to fluoro, chloro, bromo and iodo. In the framework of this application, with "compounds according to the invention" is meant a compound according to the general Formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the //-oxide form thereof and a prodrug thereof. In the framework of this application, especially in the moiety Alka-Y-Alkb in Formula (I), when two or more consecutive elements of said moiety denote a covalent bond, then a single covalent bond is denoted. For example, when Alk" and Y denote both a covalent bond and Alkb is -CH2-, then the moiety Alk"-Y-Alkb denotes -CH2-. Similary, if Alk°, Y and Alkb each denote a covalent bond and L denotes H, then the moiety Alka-Y-Alkb-L denotes -H. The pharmaceutically acceptable salts are defined to comprise the therapeutically active non-toxic acid addition salts forms that the compounds according to Formuk (I) are able to form. Said salts can be obtained by treating the base form of the compounds according to Formula (I) with appropriate acids, for example inorganic acids, for example hydrohalic acid, in particular hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid ; organic acids, for example acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclarnic acid,, salicylic acid, p-aminosalicylic acid and pamoic acid. The compounds according to Formula (I) containing acidic protons may also be converted into their therapeutically active non-toxic metal or amine addition salts forms by treatment with appropriate organic and inorganic bases. Appropriate base salts forms comprise, for example, the ammonium salts, the alkaline and earth alkah'ne metal salts, in particular lithium, sodium, potassium, magnesium and calcium salts, salts with organic bases, e.g. the benzathine, TV-methyl-D-glucarnine, hybramine salts, and salts with amino acids, for example arginine and lysine. Conversely, said salts forms can be converted into the free forms by treatment with an appropriate base or acid. The term addition salt as used in the framework of this application also comprises the solvates that the compounds according to Formula (I) as well as the salts thereof, are able to form. Such solvates are, for example, hydrates and alcoholates. The TV-oxide forms of the compounds according to Formula (I) are meant to comprise those compounds of Formula (I) wherein one or several nitrogen atoms are oxidized to the so-called TV-oxide, particularly those TV-oxides wherein one or more tertiary nitrogens (e.g of the piperazinyl or pyrrolidinyl radical) are TV-oxidized. Such TV-oxides can easily be obtained by a skilled person without any inventive skills and they are obvious alternatives for the compounds according to Formula (I) since these compounds are metabolites, which are formed by oxidation in the human body upon uptake . As is generally known, oxidation is normally the first step involved in drug metabolism ( Textbook of Organic Medicinal and Pharmaceutical Chemistry, 1977, pages 70- 75). As is also generally known, the metabolite form of a compound can also be administered to a human instead of the compound per se, with possibly the same effects. The compounds according to the invention possess at least 2 oxydizable nitrogens (tertiary amines moieties). It is therefore highly likely that TV-oxides will form in the human metabolism. The compounds of Formula (I) may be converted to the corresponding TV-oxide forms following art-known procedures for converting a bivalent nitrogen into its TV-oxide form. Said //-oxidation reaction may generally be carried out by reacting the starting material of Formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboper-oxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarbo-peroxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. tert-bnty\ 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 term "stereochemically isomeric forms" as used hereinbefore defines all the possible isomeric forms that the compounds of Formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms having that designation, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration. Compounds encompassing double bonds can have an E or Z-stereochemistry at said double bond. Stereochemically isomeric forms of the compounds of Formula (I) are obviously intended to be embraced within the scope of this invention. Following CAS nomenclature conventions, when two stereogenic centers of known absolute configuration are present in a molecule, an R or S descriptor is assigned (based on Cahn-Ingold-Prelog sequence rule) to the lowest-numbered chiral center, the reference center. R* and S* each indicate optically pure stereogenic centers with undetermined absolute configuration. If "a" and "P" are used: the position of the highest priority substituent on the asymmetric carbon atom in the ring system having the lowest ring number, is arbitrarily always in the "a" position of the mean plane determined by the ring system. The position of the highest priority substituent on the other asymmetric carbon atom in the ring system (hydrogen atom in compounds according to Formula (I)) relative to the position of the highest priority substituent on the reference atom is denominated "a", if it is on the same side of the mean plane determined by the ring system, or "P", if it is on the other side of the mean plane determined by the ring system. Compounds according to Formula (I) and some of the intermediate compounds have at least two stereogenic centers in their structure. The invention also comprises derivative compounds (usually called "pro-drugs") of the pharmacologically-active compounds according to the invention, which are degraded in vivo to yield the compounds according to the invention. Pro-drugs are usually (but not always) of lower potency at the target receptor than the compounds to which they are degraded. Pro-drugs are particularly useful when the desired compound has chemical or physical properties that make its administration difficult or inefficient. For example, the desired compound may be only poorly soluble, it may be poorly transported across the mucosal epithelium, or it may have an undesirably short plasma half-life. Further discussion on pro-drugs may be found in Stella, V. J. et al., "Prodrugs", Drug Delivery Systems, 1985, pp. 112-176, and Drugs, 1985, 29, pp. 455-473. Pro-drugs forms of the pharmacologically-active compounds according to the invention will generally be compounds according to Formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof and the JV-oxide form thereof, having an acid group which is esterified or amidated. Included in such esterified acid groups are groups of the formula — COOR*, where R" is a Chalky!, phenyl, benzyl or one of the following groups : (Figure Remove) Amidated groups include groups of the formula - CONRyRz, wherein Ry is H, C^alkyl, phenyl or benzyl and Rz is -OH, H, C|.«alkyl, phenyl or benzyl. Compounds according to the invention having an amino group may be derivatised with a ketone or an aldehyde such as formaldehyde to form a Mannich base. This base will hydrolyze with first order kinetics in aqueous solution. The compounds of Formula (I) as prepared in the processes described below may be synthesized in the form of racemic mixtures of enantiomers that can be separated from one another following art-known resolution procedures. The racemic compounds of Formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of Formula (I) involves 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 would be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials. Pharmacology Substance P and other tachykinins are involved in a variety of biological actions such as pain transmission (nociception), neurogenic inflammation, smooth muscle contraction, plasma protein extravasation, vasodilation, secretion, mast cell degranulation, and also in activation of the immune system. A number of diseases are deemed to be engendered by activation of neurokinin receptors, in particular the NKi receptor, by excessive release of substance P and other neurokinins in particular cells 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(l):5-23 (1995) and Longmore J. et al,"Neurokinin Receptors" Pharmacological Reviews 46(4):551-599 (1994)). The compounds of the present invention are potent inhibitors of neurokinin-mediated effects, in particular those mediated via the NKj, NK.2 and NK3 receptor, and may therefore be described as neurokinin antagonists, especially as substance P antagonists, as may be indicated in vitro by the antagonism of substance P-induced relaxation of pig coronary arteries. The binding affinity of the present compounds for the human, guinea-pig and gerbil neurokinin receptors may also be determined in vitro in a receptor binding test using ^H-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 neurokinin receptors, and in particular by blocking the NK], NK2 and NK3 receptor, the compounds according to the invention are useful as a medicine, in particular in the prophylactic and therapeutic treatment of tachykinin-mediated conditions. In particular are compounds according to the invention are useful as orally active, centrally penetrating medicines in the prophylactic and therapeutic treatment of tachykinin-mediated conditions. More in particular, it has been found that some compounds exhibit a combined NKi/NK.3 antagonistic activity or a combined NIQ/NKa/NKs antagonistic activity as can be seen from the Table in the experimental section. The invention therefore relates to a compound according to the general Formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the TV-oxide form thereof and prodrugs thereof, for use as a medicine. The invention also relates to the use of a compound according to any one of claims 1-3 for the manufacture of a medicament for treating, either prophylactic or therapeutic or both, tachykinin mediated conditions. The compounds according to the invention are useful in the treatment of CNS disorders, in particular schizoaffective disorders, depression, anxiety disorders, stress-related disorders, sleep disorders, cognitive disorders, personality disorders, eating disorders, neurodegenerative diseases, addiction disorders, mood disorders, sexual dysfunction, pain and other CNS-related conditions ; inflammation; allergic disorders ; emesis ; gastrointestinal disorders, in particular irritable bowel syndrome (IBS); skin disorders ; vasospastic diseases ; fibrosing and collagen diseases ; disorders related to immune enhancement or suppression and rheumatic diseases and body weight control. hi particular, the compounds according to the invention are useful in the treatment or prevention of schizoaffective disorders resulting from various causes, including schizoaffective disorders of the manic type, of the depressive type, of mixed type; paranoid, disorganized, catatonic, undifferentiated and residual schizophrenia ; schizophreniform disorder; delusional disorder ; brief psychotic disorder ; shared psychotic disorder; substance-induced psychotic disorder ; and psychotic disorder not otherwise specified. hi particular, the compounds according to the invention are useful in the treatment or prevention of depression including but not Mini ted to major depressive disorders including bipolar depression; unipolar depression ; single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, and, in the case of recurrent episodes, with or without seasonal pattern. Other mood disorders encompassed within the term "major depressive disorder" include dysthymic disorder with early or late onset and with or without atypical features, bipolar I disorder, bipolar II disorder, cyclothymic disorder, recurrent brief depressive disorder, mixed affective disorder, neurotic depression, post traumatic stress disorder and social phobia ; dementia of the Alzheimer's type with early or late onset, with depressed mood ; vascular dementia with depressed mood ; substance-induced mood disorders such as mood disorders induced by alcohol, amphetamines, cocaine, hallucinogens, inhalants, opioids, phencyclidine, sedatives, hypnotics, anxiolytics and other substances ; scbizoaffective disorder of the depressed type ; and adjustment disorder with depressed mood. Major depressive disorders may also result from a general medical condition including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion, etc. hi particular, the compounds according to the invention are useful in the treatment or prevention of anxiety disorders, including but not limited to panic attack; agoraphobia ; panic disorder without agoraphobia ; agoraphobia without history of panic disorder ; specific phobia ; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder ; acute stress disorder; generalized anxiety disorder; anxiety disorder due to a general medical condition; substance-induced anxiety disorder; and anxiety disorder not otherwise specified. hi particular, the compounds according to the invention are useful in the treatment or prevention of stress-related disorders associated with depression and/or anxiety, including but not limited to acute stress reaction ; adjustment disorders, such as brief depressive reaction, prolonged depressive reaction, mixed anxiety and depressive reaction, adjustment disorder with predominant disturbance of other emotions, adjustment disorder with predominant disturbance of conduct, adjustment disorder with mixed disturbance of emotions and conduct and adjustment disorders with other specified predominant symptoms ; and other reactions to severe stress. In particular, the compounds according to the invention are useful in the treatment or prevention of sleep disorders, including but not limited to dysomnia and/or parasomnias as primary sleep disorders ; insomnia ; sleep apnea ; narcolepsy; circadian rhythms disorders ; sleep disorders related to another mental disorder; sleep disorder due to a general medical condition ; and substance-induced sleep disorder. In particular, the compounds according to the invention are useful in the treatment or prevention of cognitive disorders, including but not limited to dementia; amnesic disorders and cognitive disorders not otherwise specified, especially dementia caused by degenerative disorders, lesions, trauma, infections, vascular disorders, toxins, anoxia, vitamin deficiency or endocrinic disorders ; dementia of the Alzheimer's type, with early or late onset, with depressed mood ; AIDS-associated dementia or amnesic disorders caused by alcohol or other causes of thiamin deficiency, bilateral temporal lobe damage due to Herpes simplex encephalitis and other limbic encephalitis, neuronal loss secondary to anoxia / hypoglycemia / severe convulsions and surgery, degenerative disorders, vascular disorders or pathology around ventricle III. Furthermore, the compounds according to the invention are also useful as memory and/or cognition enhancers in healthy humans with no cognitive and/or memory deficit. In particular, the compounds according to the invention are useful in the treatment or prevention of personality disorders, including but not limited to paranoid personality disorder ; schizoid personality disorder; schizotypical personality disorder; antisocial personality disorder ; borderline personality disorder; histrionic personality disorder ; narcissistic personality disorder ; avoidant personality disorder; dependent personality disorder ; obsessive-compulsive personality disorder and personality disorder not otherwise specified. In particular, the compounds according to the invention are also useful in the treatment or prevention of eating disorders, including anorexia nervosa; atypical anorexia nervosa; bulimia nervosa; atypical bulimia nervosa ; overeating associated with other psychological disturbances ; vomiting associated with other psychological disturbances ; and non-specified eating disorders. In particular, the compounds according to the invention are also useful in the treatment or prevention of neurodeeenerative diseases, including but not limited to Alzheimer's disease; Huntington's chorea ; Creutzfeld-Jacob disease ; Pick's disease ; demyelinating disorders, such as multiple sclerosis and ALS ; other neuropathies and neuralgia ; multiple sclerosis ; amyotropical lateral sclerosis ; stroke and head trauma. In particular, the compounds according to the invention are also useful in the treatment or prevention of addiction disorders, including but not limited to substance dependence or abuse with or without physiological dependence, particularly where the substance is alcohol, amphetamines, amphetamine-like substances, caffeine, cocaine, hallucinogens, inhalants, nicotine, opioids (such as cannabis, heroin and morphine), phencyclidine, phencyclidine-like compounds, sedative-hypnotics, benzodiazepines and/or other substances, particularly useful for treating withdrawal from the above substances and alcohol withdrawal delirium. In particular, the compounds according to the invention are also useful in the treatment or prevention of mood disorders induced particularly by alcohol, amphetamines, caffeine, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics, anxiolytics and other substances. In particular, the compounds according to the invention are also useful in the treatment or prevention of sexual dysfunction, including but not limited to sexual desire disorders ; sexual arousal disorders ; orgasmic disorders ; sexual pain disorders ; sexual dysfunction due to a general medical condition; substance-induced sexual dysfunction and sexual dysfunction not otherwise specified. In particular, the compounds according to the invention are also useful in the treatment or prevention of pain, including but not limited to 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 and phantom limb pain ; various forms of headache such as migraine, acute or chronic tension headache, temporomandibular pain, maxillary sinus pain and cluster headache ; odontalgia ; cancer pain ; visceral pain; gastrointestinal pain ; nerve entrapment pain ; sport's injury pain; dysmennorrhoea; menstrual pain; meningitis; arachnoiditis ; musculoskeletal pain; low back pain such as spinal stenosis, prolapsed disc, sciatica, angina, ankylosing spondyolitis ; gout; burns ; scar pain ; itch; and thalamic pain such as post stroke thalamic pain. In particular, the compounds according to the invention are also useful in the treatment or prevention of the following other CNS-related conditions : akinesia, akinetic-rigid syndromes, dyskinesia and medication-induced parkinsonism, Gilles de la Tourette syndrome and its symptoms, tremor, chorea, myoclonus, tics and dystonia, attention-deficit / hyperactivity disorder (ADHD), Parkinson's disease, drug-induced Parkinsonism, post-encephalitic Parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonism-ALS dementia complex and basal ganglia calcification, behavioral disturbances and conduct disorders in dementia and the mentally retarded, including restlessness and agitation, extra-pyramidal movement disorders, Down's syndrome and Akathisia. In particular, the compounds according to the invention are also useful in the treatment or prevention of inflammation, including but not limited to inflammatory conditions in asthma, influenza, chronic bronchitis and rheumatoid arthritis ; inflammatory conditions in the gastrointestinal tract such as, but not limited to Crohn's disease, ulcerative colitis, inflammatory bowel disease and non-steroidal anti-inflammatory drug induced damage ; inflammatory conditions of the skin such as herpes and eczema ; inflammatory conditions of the bladder such as cystitis and urge incontinence ; eye and dental inflammation and pancreatitis, in particular chronic and acute pancreatitis. In particular, the compounds according to the invention are also useful in the treatment or prevention of allergic disorders, including but not limited to allergic disorders of the skin such as but not limited to urticaria ; and allergic disorders of the airways such as but not limited to rhinitis. In particular, the compounds according to the invention are also useful in the treatment or prevention of emesis. i.e. nausea, retching and vomiting, including but not limited to acute emesis, delayed emesis and anticipatory emesis ; emesis induced by drugs such as cancer chemotherapeutic agents such as alkylating agents, for example cyclophosphamide, carmustme, lomustine and chlorambucil; cytotoxic antibiotics, for example dactinomycin, doxorabicin, mitomycin-C and bleomycin; anti-metabolites, for example cytarabine, methotrexate and 5-fluorouracil; vinca alkaloids, for example etoposide, vinblastine and vincristine ; and other drugs such as cisplatin, dacarbazine, procarbazine and hydroxyurea; and combinations thereof; radiation sickness ; radiation therapy, such as in the treatment of cancer ; poisons ; toxins such as toxins caused by metabolic disorders or by infection, such as gastritis, or released during bacterial or viral gastrointestinal infection; pregnancy ; vestibular disorders, such as motion sickness, vertigo, dizziness and Meniere's disease ; post-operative sickness ; gastrointestinal obstruction ; reduced gastrointestinal motility; visceral pain, such as myocardial infarction or peritonitis ; migraine ; increased intracranial pressure ; decreased intracranial pressure (such as altitude sickness); opioid analgesics, such as morphine ; 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. In particular, the compounds according to the invention are also useful in the treatment or prevention of gastrointestinal disorders, including but not limited to irritable bowel syndrome (IBS), 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 ; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis ; disorders related to immune enhancement or suppression such as systemic lupus erythematosus and rheumatic diseases such as fibrositis ; cough; and body weight control, including obesity. The present invention also relates to a method for the treatment and/or prophylaxis of tachykinin-mediated diseases, in particular for the treatment and/or prophylaxis of schizophrenia, depression, anxiety disorders, emesis and irritable bowel syndrome (IBS) comprising administering to a human in need of such administration an effective amount of a compound according to the invention, in particular according to Formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the A'-oxide form thereof, as well as the pro-drugs thereof. The invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound according to the invention, in particular a compound according to Formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the A'-oxide form thereof and a prodrug thereof The compounds according to the invention, in particular the compounds according to Formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the A'-oxide form thereof and the prodrugs thereof, or any subgroup or combination thereof may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an 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 carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, in particular, for administration orally, rectally, percutaneously, by parenteral injection or by inhalation. 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, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect 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, as an ointment. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used 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 unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof. Since the compounds according to the invention are potent orally, mainly centrally active NK], NK|/NK3 and NKi/NK2/NK3 antagonists, pharmaceutical compositions comprising said compounds for administration orally are especially advantageous. Synthesis The compounds according to the invention can generally be prepared by a succession of steps, each of which is known to the skilled person. The final compounds of Formula (I) are conveniently prepared by reductively Af-alkylating an intermediate compound of Formula (II) with an intermediate compound of Formula (III) . Said reductive A^-alkylation may be performed in a reaction-inert solvent such as, for example, dichloromethane, ethanol or 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 cyanoborohydride 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(IV)isopropylate as described in J. Org. diem, 1990, 55, 2552-2554. Using said complex-forming agent may also result in an improved cisi'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 hydrogen is used as reducing agent, it may be advantageous to add a dehydrating agent to the reaction mixture such as, for example, aluminium fer/-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. (Figure Remove) hi this and the following preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, trituration and chromatography. Especially advantageous is the preparation of a final compound according to Formula (1) according to the previously mentioned reaction scheme in which the Alk-Y-Alk-L-moiety is benzyl, thus giving rise to a compound according to Formula (I) in which the Alk-Y-Alk-L-moiety is benzyl. Said final compound is pharmacologically active and can be converted into a final compound according to the invention in which the Alk-Y-Alk-L-moiety is hydrogen by reductive hydrogenation using e.g. hydrogen as a reducing agent in combination with a suitable catalyst such as, for example, palladium-on-charcoal or platinum-on-charcoal. The resulting final compound according to the invention can then be converted into other compounds according to Formula (I) by art-known transformations, e.g. acylation and alkylation. In particular, the final compounds of Formula (T) can be prepared by reacting a final compound of Formula (I1) with an intermediate compound of Formula (V) 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. The reaction can be performed in a reaction-inert solvent such as, for example, a chlorinated hydrocarbon, e.g. dichloromethane or a ketone, e.g. methyl isobutylketone, and in the presence of a suitable base such as, for example, sodium carbonate, sodium hydrogen carbonate or triethylamine. Stirring may enhance the rate of the reaction. The reaction may conveniently be carried out at a temperature ranging between room temperature and reflux temperature. (Figure Remove) Alternatively, the final compounds of Formula (I") can also be prepared by reacting a final compound of Formula (I1) with a carboxylic acid of Formula (VI). The reaction can be performed in a reaction-inert solvent such as, for example, a chlorinated hydrocarbon, e.g. dichloromethane, in the presence of a suitable base such as, for example, sodium carbonate, sodium hydrogen carbonate or triethylamine and in the presence of an activator, such as e.g. DCC (dicyclohexylcarbodiimide), CDI (carbonyldiimidazole) and EDCI (l-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl). Stirring may enhance the rate of the reaction. The reaction may conveniently be carried out at a temperature ranging between room temperature and reflux temperature. (Figure Remove) In particular, the final compounds of Formula (Ib) can be prepared by reacting a final compound of Formula (I1) with a compound of Formula (VII) 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. 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 isobutylketone, and in the presence of a suitable base such as, for example, sodium carbonate, sodium hydrogen carbonate or triethylamine. Stirring may enhance the rate of the reaction. The reaction may conveniently be carried out at a temperature ranging between room temperature and reflux temperature. (Figure Remove) The final compounds of Formula (Ic) and Formula (I*1) can be prepared either by alkylation or reductive amination of a final compound of Formula (I1) with either a compound of Formula (VIII) or (IX) wherein W^ in Formula (VIII) 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 and wherein Alk in Formula (Id) is defined as -CH2-Alk. 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 isobutylketone, and in the presence of a suitable base such as, for example, sodium carbonate, sodium hydrogen carbonate or triethylamine. Stirring may enhance the rate of the reaction. The reaction may conveniently be carried out at a temperature ranging between room temperature and reflux temperature. (Figure Remove) 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, intermediate compounds of Formula (II) may be prepared by reductively Af-alkylating an intermediate compound of Formula (XI) with an intermediate compound of Formula (XII) in which W4 is a benzyl radical, after which the resulting compound is subsequently reduced to yield an intermediate compound according to Formula (II). Said reductive W-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 cyanoborohydride 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(IV)iso-propylate 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 hydrogen is used as reducing agent, it may be advantageous to add a dehydrating agent to the reaction mixture such as, for example, aluminium terf-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. (Figure Remove) The preparation of intermediate compounds (XI) and (XII) and other intermediates is described in WO 97/16440-A1, published May 9,1997 by Janssen Pharmaceutica N. V, which is disclosed herein by reference as well as in other publications mentioned in WO 97/16440-A1, such as , e.g. EP-0,532,456-A. The following examples are intended to illustrate but not to limit the scope of the present invention. Experimental Part Hereinafter "RT" means room temperature, "THF" means tetrahydrofuran, "DIPE" means diisopropylether and "DMF" means //,Af-dimethylformamide. A. Preparation of the intermediate compounds (Figure Remove) Example Al a. Preparation of intermediate compound Et3N (0.55 mol) was added to a stirring mixture of 7-(phenylmethyl)-l,4-dioxa-8-azaspiro[4.5]decane (0.5 mol) hi toluene (1500 ml). 3,5-Bis(trifluoromethyl)benzoyl chloride (0.5 mol) was added over a 1-hour period (exothermic reaction). The mixture was stirred at room temperature for 2 hours, allowed to stand for the weekend and washed three times with water (500 ml, 2x250 ml). The organic layer was separated, dried, filtered and the solvent was evaporated. Yield: 245 g (100%). Part of this fraction was crystallized from petroleum ether. The precipitate was filtered off and dried. Yield: 1.06 g of intermediate compound 1. (Figure Remove) bl. Preparation of intermediate compound 2 HC1 cp (300 ml) was added to a mixture of intermediate compound 1 (0.5 mol) in ethanol (300 ml) and H2O (300 ml). The reaction mixture was stirred at 60 °C for 20 hours. The precipitate was filtered off, ground, stirred in H2O, filtered off, washed with petroleum ether and dried. Yield: 192 g of intermediate compound 2 ((+-)-l-[3,5~ bis(trifluoromethyl)benzoyl]-2-(phenylmediyl)-4-piperidinone) (89.4%) (mixture of R and S enantiomers). Intermediate compound 2 was separated into its optical isomers by chiral column chromatography over Chiralpak (CHIRALPAK AS 1000 A 20 mm (DAICEL); eluent: hexane/2-propanol 70/30). Two product fractions were collected and each solvent was evaporated. Yield Fraction 1: 32.6 g of intermediate compound 10 (R), and Fraction 2: 30.4 g of intermediate compound 11 (S). (Figure Remove) c. Preparation of intermediate compound 3 A mixture of intermediate compound 10 (0.046 mol), 1 -(phenylmethyl)piperazine (0.051 mol) and Ti-isopropoxide (0.056 mol) was stirred for 2 hours at 40 °C. The reaction mixture was cooled to room temperature. Ethanol, p.a. (350 ml) was added. NaBH4 (0.138 mol) was added. The resulting reaction mixture was stirred for one hour at room temperature and for one hour at 50 °C. More NaBHt (5.2 g) was added and the reaction mixture was stirred for 2 hours at 50 °C. Again, NaBiLt was added and the reaction mixture was stirred overnight at room temperature and for 2 hours at 50 °C. Water (10 ml) was added. The mixture was stirred for 15 min. CHoCk (200 ml) was added and the mixture was stirred for 15 min. The organic phase was separated, dried (MgSO*), dicalite was added, the mixture was filtered over dicalite, and the filtrate was evaporated. This fraction was separated into (CIS) and (TRANS) by column chromatography over silica gel. The desired (TRANS)-fractions were collected and the solvent was evaporated, giving 14.8 g of residue ((I), 1.06% (CIS)) and 4.9 g of residue ((II), 6% (CIS)). Resolution and purification of those (TRANS)-fractions (± 20 g in total) was obtained by chromatography over stationary phase Chiralcel OD (1900Gr) in Prochrom LCI 10 35 bar (eluent: hexane/ethanol 90/10). The desired fractions were collected and the solvent was evaporated. Yield: 9.5 g of intermediate compound 3 (2R-trans)-l-[3,5-bis(rrifluoromethyl)ben2oyl]-2-(phenylmemyl)^-[4-(phenylmethyl)-l-piperazinyljpiperidine. It is without saying that the same reaction can be carried out on compound 11 for obtaining the S-isomer, as well as on any mixture of them. It is also without saying that also the cis-isomer can be used in all reactions in this application exemplified for the trans-isomer or for a mixture of cis and trans-isomers. (Figure Remove) d. Preparation of intermediate compound 4 A mixture of intermediate compound 3 (0.288 mol) in methanol (700 ml) was hydrogenated at 40 °C with Pd/C, 10% (5 g) as a catalyst. After uptake of H2 (1 eq.), the catalyst was filtered off and the filtrate was evaporated. Yield: 141.2 g of intermediate compound 4 (+)-(2R-trans)-l-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-( 1 -piperazinyl)piperidine. Example A2 a. Preparation of intermediate compound 5 (Figure Remove) A mixture of final compound 1 (prepared according to Bla) (0.03 mol) in z'PrOH (150 ml) and KOH (0.3 mol) was stirred and refluxed for 18 hours. The solvent was evaporated and the residue was taken up in CHjCb/HaO. The layers were separated. The organic layer was dried and filtered. The solvent was evaporated and the residue purified by column chromatography over silica gel (gradient eluent: CH2Cl2/(MeOH/NH3) 95/5 to 90/10). The product fractions were collected and the solvent evaporated. Yield: 12 g of intermediate compound 5. b. Preparation of intermediate compound 6 (Figure Remove) A mixture of intermediate compound 5 (0.029 mol) in bis(l,l-dimethylethyl)-dicarbonic acid ester (0.035 mol) was stirred 18 hours at room temperature. The solvent was evaporated for 30 minutes at 50-60 °C. The residue was taken up in CH2C12/H2O and NaOH. The organic layer was separated, washed with water, dried and the solvent evaporated. The residue was suspended in toluene and the solvent was evaporated. Yield : 15.5 g of intermediate compound 6. (Figure Remove) c. Preparation of intermediate compound 7 A mixture of intermediate compound 6 (0.03 mol), Pd/C, 10% (2 g), H2 (1 eq) in methanol (250 ml) was stirred. After uptake of Hz (1 eq.), the catalyst was filtered off and the filtrate was evaporated The residue was purified by column chromatography over silica gel (gradient eluent: CH2Cl2/(MeOH/NH3) 90/10 to 85/15). The product fractions were collected and suspended in petroleum ether, filtered and dried Yield: 1 1 .6 g of intermediate compound 7. (Figure Remove) d. Preparation of intermediate compound 8 A mixture of 3-furancarboxylic acid (0.033 mol) in CH2C12 (100 ml) and 1,1'-carbonylbis- l//-imidazole (0.033 mol) was stirred for 3 hours at room temperature. Intermediate compound 7 (0.027 mol) in CH2C12 (100 ml) was added and stirred overnight at room temperature. The reaction mixture was washed with aqueous NaOH, with H2O, dried and the solvent was evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CH2Cl2/MeOH) 98/2 to 90/10). The product fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE. The solid was dried. Yield : 7.83 g of intermediate compound (Figure Remove) Preparation of intermediate compound 9 iPrOH.HCl (3 ml) was added to a mixture of intermediate compound 8 (1 g) in /'PrOH (30 ml). The mixture was stirred at 65 °C for 90 minutes. The solvent was evaporated. The residue was suspended in DIPE. The precipitate was filtered and washed with DIPE. Yield : 0.93 g of intermediate compound 9 (.HC1). (Figure Remove) Example A3 a. Preparation of intermediate compound 12 A mixture of 6,7,8,9-tetrahydro-5-ftr-imidazo[l,2-a]azepine (0.02 mol) and Et3N (0.035 mol) in CHsCN (50 ml) was stirred at room temperature and under Nz flow. Chloro-oxo acetic acid ethyl ester (0.03 mol) was added dropwise at b. Preparation of T/^~~~intermediate compound 13 1 / •cr A mixture of intermediate compound 12 (0.0084 mol) in 2-propanone (30 ml) was stirred, while cooling on an ice-bath. Excess Jones'reagent (prepared according to the method below) was added dropwise at room temperature. The reaction mixture was stirred for a while. Water (50 ml) was added and this mixture was alkalized with K2C03. This mixture was evaporated. The residue was stirred in CHjOH. The salts were removed by filtration over dicalite. The filtrate was evaporated. The residue was stirred in CH2Cl2. The organic layer was decanted, dried (MgSO^), filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CHjCyCHsOH 95/5). The pure fractions were collected and the solvent was evaporated. The residue (0.56 g) was stirred in DIPE , filtered off and dried Yield: 0.32 g of intermediate compound 13 (25%). Preparation of Jones' reagent: CrO3 (26.72 g) was dissolved in H2O (50 ml). H2SO4 (98%;23 ml) was added dropwise, while cooling. Water was added until a total volume of 100 ml was obtained. (Figure Remove) c. Preparation of intermediate compound 14 A mixture of intermediate compound 13 (0.0176 mol) in H2O (10 ml) and HOAc (3 ml) was stirred at 50 °C. NaNO2 (1.35 g) was added portionwise over a 5 min. period and the mixture was stirred at 50 °C for 1 h. The mixture was cooled on an ice bath and filtered off. The precipitate was washed with icewater and dried in an desiccator. Yield : 1.25 g of intermediate compound 14 (35.8 %). (Figure Remove) d. Preparation of intermediate compound 15 A mixture of intermediate compound 14 (0.045 mol) in HOAc (90 ml) and acetic acid anhydride (9 ml) was stirred on an oil bath at 85 °C. Acetylchloride (13.7 ml) was added dropwise over a 30 min. period and the mixture was stirred at 85 °C for 1 hour. The mixture was cooled, poured into ice/K2CC>3 and extracted with CHCls. The organic layer was dried and evaporated. The residue was boiled up in CH3CN and cooled. The precipitate was filtered off and dried. Yield : 14.32 g of intermediate compound 15 (47.3 (Figure Remove) Example A4 a. Preparation of intermediate compound 16 NaH (0,086 mol) was added portionwise to a solution of 3-thiophene ethanol (0.078 mol) in THF at 5 °C. The mixture was stirred for 1 hour at 5°C. BiLiNI (0.001 mol) and (bromomethyl)benzene (0.080 mol) were added. The mixture was stirred at room temperature for 3 hours, taken up in H20 and extracted with AcOEt. The organic layer was separated, dried (MgSO^) and solvent was evaporated. The concentrate 1 (18 g) was purified by column chromatography over silica gel (gradient eluent: Cyclohexane/AcOEt 100/0 to 80/20). The pure fractions were collected and the solvent was evaporated. Yield: 9.9 g intermediate compound 16 (58 %). (Figure Remove) b. Preparation of intermediate compound 17 To a solution of intermediate compound 16 (0.023 mol) in THF (50 ml) at -50 °C, BuLi[1.6M] (0.025 mol) was added portionwise under N2. The temperature was raised slowly to 0°C. The mixture was stirred at 0 °C for 1 hour and cooled to -40°C. A solution of SO2C12 (0.046 mol) in pentane (50 ml) was added at-40°C. The mixture was stirred at -40°C for 1 hour. The concentrate was hydrolyzed, extracted with AcOEt, washed with a saturated solution of NaCl, dried over MgSO^ and concentrated, providing 9 g. The concentrate was purified by column chromatography over silica gel (gradient eluent: Cyclohexane/AcOEt 100/0 to 80/20). Yield 1.2 g of intermediate compound 17(16%). (Figure Remove) Example A5 a. Preparation of intermediate compound 18 NaH (60 % in oil) (0.086 mol, 3.4 g) was added portionwise to a solution of 2-(2-thienyl)ethanol (0.078 mol, 10 g) in THF (150 ml) under N2 flow at 5 °C. The mixture was stirred at 5 °C during 1 hour..Tetrabutylammonium iodide (0.001 mol, 0.3 g) and (bromomethyl)benzene (0.080 mol, 9.5 ml) were added consecutively to the solution. The mixture was stirred at room temperature during 3 hours poured into water, extracted with ethyl acetate, dried over MgSCXt and concentrated. The crude product (18 g) was purified by column chromatography over silica gel (gradient eluent: CHaCyCyclohexane 0/100 to 20/80) and the product fractions were concentrated. Yield: 11.4 g (66 %) of intermediate compound 18. (Figure Remove) b. Preparation of intermediate compound 19 n-BuLi (1.6 M) (0.015 mol, 9.45 ml) was added slowly to a solution of intermediate compound 18 (0.014 mol, 3 g) in THF (30 ml) under N2 flow at -40 °C. The reaction was allowed to warm up slowly to 0°C and cooled to -70°C. Dry ice (~ 2 g) was added. The temperature was slowly allowed to rise to room temperature. NaOH (1 mol per liter, 30 ml) was added, the mixture was washed with diethyl ether. The aqueous layer was acidified with HC1 (IN) and extracted with CH^Ck. The organic layer was dried over MgSC>4 and concentrated to yield 2.6 g (71%) of intermediate compound 19. (Figure Remove) Example A6 a. Preparation of intermediate compound 20 A mixture of 2-[(3,4-dichlorophenyl)methyl]-4-oxo-l-piperidinecarboxyUc acid ethyl ester (0.3 mol), 1,2-ethanediol (1.5 mol) and 4-methylbenzenesulfonic acid (2 g) in toluene (750 ml) was stirred and refluxed for 68 hours using a water separator. The solvent was evaporated. The residue was partitioned between water and toluene. The organic layer was separated, washed with water, dried, filtered and the solvent evaporated. Yield: 113.5 g of intermediate compound 20. (Figure Remove) b. Preparation of intermediate compound 21 A mixture of intermediate compound 20 (0.1 mol) and K.OH (0.9 mol) in 2-propanol (500 ml) was stirred and refluxed overnight. The solvent was evaporated. The residue was dissolved in CHaClj and washed with a small amount of HaO. The organic layer was dried, filtered and the solvent was evaporated. Yield: 33 g of intermediate compound 21. (Figure Remove) c. Preparation of intermediate compound 22 Intermediate compound 21 (0.139 mol) was dissolved in CHjClj (420 ml) . 3,5-bis(trifluoromethyl)benzoylchloride (0.15 mol) was added dropwise (exothermic). (30 ml) was added. The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was washed with a basic NaOH solution, dried, filtered and the solvent evaporated. The residue was purified over silica gel on a glass filter (gradient eluent: CH2C12/CH3OH from 100/0 to 95/5). The product fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE, filtered off and dried. Yield: 56.3 g of fraction 1 . The filtrate was evaporated. The residue was suspended in petroleum ether, filtered off and dried. Yield: 9 g of fraction 2. The total yield (65.3 g) of these fractions was separated and purified by chiral column chromatography (AD-packing, eluent: heptane/ethanol 95/5). Two product fraction groups were collected and their solvent was evaporated. Each residue was crystallized from DIPE, filtered off and dried. Yield: 23.9 g of intermediate compound 22 (optically pure). (Figure Remove) d. Preparation of intermediate compound 23 A mixture of intermediate compound 22 (0.0424 mol) in HC1 (6N) (230 ml) was stirred and refluxed for 4 hours. The reaction mixture was stirred overnight and extracted with CH2C12- The organic layer was separated, washed with water, dried and the solvent was evaporated. Yield: 20 g of intermediate compound 23 (S-isomer). (Figure Remove) Example A7 a. Preparation of intermediate compound 24, 25 and 26 A mixture of 1,1-dimethylethyl-l-pyrrolidinecarboxylic acid ester (0.2 mol) and 1-(phenylmethyl)piperazine (0.2 mol) in methanol (250 ml) was stirred and hydrogenated at 50°C with Pd/C, 10% (3 g) as a catalyst in the presence of thiophene solution (3 ml). After uptake of H2 (1 eq), the catalyst was filtered off and the filtrate was evaporated. Yield: intermediate compound 24 (racemic mixture). This 'fraction was separated and purified by column chromatography (DAICELjAD-packing, 2000 g, 750 ml/min; eluent: heptane/ethanol/methanol 90/5/5). Two product fraction groups were collected and their solvent was evaporated. Yield: 30 g of intermediate compound 25 (S-isomer) (ee: > 99%), and 26 g of intermediate compound 26 (R-isomer) (ee: > 99%). b. Preparation of intermediate compound 27 ^-^N~^" A mixture of intermediate compound 26 (0.078 mol) in methanol (250 ml) was hydrogenated at room temperature with Pd/C 10% (2 g) as a catalyst. After uptake of H2 (1 eq.), the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in CH2C12 and washed with H2O. The organic layer was separated, dried (MgSO4), filtered off and the solvent was evaporated. Yield: 16.3 g of intermediate compound 27 (82 %) (R-isomer). (Figure Remove) c. Preparation of intermediate compound 28 A solution of intermediate compound 27 (0.02 mol) in a small amount of CH2C12 was added to 3-phenyl-l-(phenylmethyl)-4-piperidinone (0.02 mol) and the mixture was stirred, toluene was added and the reaction mixture was evaporated. Titanium, tetrakis(2-propanolato) (0.025 mol) was added to the residual oil and the mixture was stirred for 3 hours at 50°C, EtOH, p.a. (30 ml) was added and the resulting mixture was stirred for 15 min. at room temperature. Finally NaBHsCN (0.04 mol) was added and the reaction mixture was stirred for 20 hours at room temperature. The mixture was washed with a basic NaOH solution and CH2C12 was added. The resulting mixture was stirred for 15 min. and after addition of dicalite the mixture was filtered over dicalite. The organic layer was separated, dried (MgSO4), filtered off and the solvent was evaporated. The residue was purified over silica gel on a glass filter (gradient eluent: CH2Cl2/CH3OH 100/0 -> 90/10). The product fractions were collected and the solvent was evaporated. Yield: 6.4 g of intermediate 28. (Figure Remove) d. Preparation of intermediate compound 29 A mixture of intermediate compound 28 (0.013 mol) in CHbOH (150 ml) was hydrogenated at 50CC with Pd/C 10% (2 g) as a catalyst. After uptake of H2 (1 eq.), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CH2C12/(CH3OH/NH3) 100/0 -> 80/20). The product fractions were collected and the solvent was evaporated. Yield: 2 g of intermediate compound 29. Example AS Preparation of intermediate Hl^^| ft compound 30 S-isomer The intermediate compound 30 was obtained by the same method as described in A7.b, but instead of intermediate compound 26 intermediate compound 25 was used. B. Preparation of the final compounds (Figure Remove) Example Bl a) Preparation of final compound 1 A mixture of (2R-trans) l-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-(l-piperazinyl)piperidine [intermediate compound 3] (0.05 mol) and 1 -(phenylmethyl)-3-pyrrolidinone (0.05 mol) in methanol (250ml) was hydrogenated at 50 °C with Pd/C 10% (3 g) as a catalyst in the presence of a thiophene solution (2 ml). After uptake of H2 (1 eq.), the catalyst was filtered off and the solvent was evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CfLCVMeOH 100/0;99/1 ;98/2;96/4). The desired fractions were collected and the solvent was evaporated. This fraction was recrystallized from DIPE. The precipitate was filtered off, washed with DIPE and dried (vacuum ; 50 °C). Yield : 16.8 g (49 %) of final compound 1. (Figure Remove) b~) Preparation of final compound 2 Final compound 1 (0.022 mol) in methanol (250ml) was hydrogenated with Pd/C 10 % (2 g) as a catalyst. After uptake of Kb (1 eq.), the catalyst was filtered off and the solvent was evaporated. This fraction was triturated under DIPE. The precipitate was filtered off, washed with DIPE and dried (vacuum ; 50 °C; 3 days). Yield : 11.58 g (92 %) of final compound 2. (Figure Remove) Example B2 Preparation of final compound 3 A mixture of final compound 2 (0.0016 mol), benzoylchloride (0.0018 mol) and Et3N (0.0018 mol) in CH2C12 (50 ml) was stirred at room temperature for 3 hours. The reaction mixture was washed with aq. diluted NaOH solution. The separated organic layer was dried (MgSO4), filtered and the solvent was evaporated. This fraction was purified by column chromatography over silica gel (gradient eluent: CH2Q2/MeOH 100/0 to 90/10). The desired fractions were collected and the solvent was evaporated. The residue was dried (vacuum ; 50 °C). Yield : 0.410 g of final compound 3. (Figure Remove) Example B3 Preparation of final compound 80 A mixture of final compound 2 (0.0017 mol), methyl acrykte (0.0019 mol) in methanol (50 ml) was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by column chromatography over silica gel (gradient eluent: CH2Cl2/MeOH 100/0 to 90/10). The desired fractions were collected and the solvent was evaporated. The residue was dried (vacuum, 50 °C). Yield : 0.266 g of final compound 80. (Figure Remove) Example B4 Preparation of final compound 5 A mixture of final compound 2 (0.003 mol), 2-chloropyrimidine (0.0033 mol) and Na2CO3 (0.004 mol) in ethanol p.a. (50 ml) was stirred and refluxed for 8 hours. The solvent was evaporated and the residue was taken up in H2O/CH2C12. The layers were separated, the aqueous layer was extracted with CH2C12 and the organic layer was washed with H2O, dried (MgSO/i) and filtered. The solvent was evaporated and the . residue was purified by column chromatography over silica gel (gradient eluent: CH2C12/CH3OH from 100/0 to 90/10). The product fractions were collected and the solvent was evaporated. Yield: 1.378 g of final compound 5. CH, (Figure Remove) Example B5 Preparation of final compound 79 A mixture of final compound 2 (0.002 mol), 3,5-dimethylisoxazole-4-sulfonylchloride (0.002 mol),Na2CO3 (0.005 mol) and CH2C12 (50 ml) was stirred at room temperature overnight. The reaction mixture was purified by column chromatography over silicagel (eluent CH2Cl2/MeOH 95/5). The desired fractions were collected and the solvent evaporated. The residu was dried at 50 °C. Yield : 0.98 g of final compound 79. (Figure Remove) Example B6 Preparation of final compound 81 A mixture of intermediate compound 9 (prepared according to A2e) (0.0005 mol) in CH2C12 (25 ml), 3,4,5-trimethoxybenzoylchloride (0.0006 mol) and Et3N (1 ml) was stirred for 3 hours. The reaction mixture was washed with diluted NaOH during 30 minutes, washed with H2O, dried and the solvent was evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CHbCla/MeOH 98/2; 90/10). The desired fractions were collected and the solvent evaporated. Yield: 0.114 g of final compound 81. (Figure Remove) Example B7 Preparation of final compound 104 Final compound 2 was dissolved in QH^Clo (100 ml). Alpha-chlorobenzeneacetyl chloride (0.01 mol) was added and the mixture was stirred for 18 hours at room temperature. The reaction mixture was washed with aqueous NaaCOa. The organic layer was separated, dried and the solvent evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CI^CWMeOH 100/0 to 90/10). The desired fractions were collected and the solvent evaporated. Yield : 6 g of final compound 104. (Figure Remove) Example B8 Preparation of final compound 108 A mixture of final compound 104 (prepared according to B7) (0.001 mol) and pyrrolidine (0.5g) was stirred overnight at a bath temperature of 85°C. The excess pyrrolidine was evaporated. The residue was purified by column chroma^ography over silica gel (gradient eluent: CH2Cl2/MeOH 100/0 to 80/20). The desired fractions were collected and the solvent evaporated. Yield : 0.194g of final compound 108. (Figure Remove) Example B9 Preparation of final compound 109 Final compound 104 (prepared according to B7) (0.001 mol) was dissolved in methanol (5 ml). NaOCHa (0.002 mol) was added and the mixture was stirred and refluxed for 48 hours. After 24 hours of stirring and refluxing once more NaOCHs (0.002 mol) was added. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CH2Cl2/MeOH 100/0 to 90/10). The desired fractions were collected and the solvent evaporated. Yield : 0.310 g of final compound 109. (Figure Remove) Example BIO Preparation of final compound 110 NaH (0.002 mol) was added to 2-methylimidazole (0.002 mol) in DMF (10 ml). To the mixture final compound 104 (prepared according to B7) (0.001 mol) diluted in DMF (5 ml) was added and stirred at room temperature for 1 hour. The mixture was stirred for 18 hours at a temperature of 100 °C. The solvent was evaporated. The residue was taken up in HaO/CHiCfe. The organic layer was separated, dried and evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CH2Cl2/MeOH 100/0 to 80/20). The desired fractions were collected and the solvent evaporated. The residue was suspended in petroleum ether, filtered off and dried. Yield : 0.190 g of final compound 110. (Figure Remove) Example Bll a. Preparation of final compound 230 Chloroacetyl chloride (0.01 mol) was added to a solution of final compound 2 (prepared according to Bl.b) (0.01 mol) in CH2C12 (75 ml), Et3N (3 ml) was added and the reaction mixture was stirred for 4 hours at room temperature. The mixture was washed with a basic NaOH solution, dried and the solvent was evaporated ( (Figure Remove) b. Preparation of final compound 196 Final compound 230 (prepared according to Bl l.a) (0.001 mol) was taken up in pyrrolidine (1 ml) and the reaction mixture was stirred for 2 hours at 60 °C , the solvent was evaporated and the residue was purified by column chromatography (gradient eluent: C^Ck^CHjOH/NHs) 100/0 - 90/10). The product fractions were collected and the solvent was evaporated. Yield: 0.257 g of final compound 196. (Figure Remove) Example B12 Preparation of final cornpcmpd 209 NaH (0.001 mol) was added to a solution of 2-methylimidazole (0.001 mol) in DMF (20 ml) and the resulting mixture was stirred for 1 hour and warmed to 40 °C. Final compound 230 (prepared according to Bl l.a) (0.001 mol) was added and the reaction mixture was stirred for 18 hours at 50 °C. The solvent was evaporated till dryness and the residue was taken up in CH2C12/H2O. The organic layer was separated, dried (MgSO (Figure Remove) Example Bl 3 Preparation of final compound 207 Final compound 230 (prepared according to Bll.a) (0.001 mol) and Na2CO3 (0.5 g) were added to a mixture of 2-aminobenzenemethanol (0.001 mol) in DMF (20 ml) and the reaction mixture was stirred for 18 hours at 50 °C. The solvent was evaporated till dryness and the residue was taken up in CEbClj/HiO. The organic layer was separated, dried (MgSO^), filtered off and the solvent was evaporated. The residue was purified by column chromatography (gradient eluent: CH2C12/CH3OH 100/0 - 85/15). The desired product fractions were collected and the solvent was evaporated. Yield: 0.043 g of final compound 207. (Figure Remove) Example B14 a. Preparation of final compound 206 l-Hydroxy-l//-benzotriazole (0.004 mol) and Et3N (0.004 mol) were added to a solution of l-(l,l-dunetiiylemyl)-l,2-piperidinedicarboxyric acid ester (0.004 mol) in CH2C12, p.a. (50 ml) and the mixture was stirred at room temperature, Ar-(emylcarbonirmdoyI)-//,Ar-dimemyH,3-propanediamine (0.004 mol) was added and the reaction mixture was stirred for 10 min. at room temperature. A mixture of final compound 2 (prepared according to Bl.b) (0.003 mol) in CH2C12, p.a. (20 ml) was added and the reaction mixture was stirred overnight at room temperature. The mixture was washed with H2O/NaHCO3 and with H2O. The organic layer was separated, dried ), filtered off and the solvent was evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CHiCVCHjOH 100/0 - 80/20). The product fractions were collected and the solvent was evaporated. Yield: 1.3 g of final compound 206. (Figure Remove) b. Preparation of final compound 294 (Figure Remove) 2-propanol/HCl (3 ml) was added to a solution of final compound 206 (prepared according to B14.a) (0.0017 mol) in 2-propanol (30 ml) and the reaction mixture was stirred and refluxed for 2 hours. The solvent was evaporated and the residue was • suspended in DIPE. The resulting precipitate was filtered off, taken up in H2O and washed with DIPE. The aqueous layer was alkalised and extracted with CH2C12. The organic layer was separated, dried (MgSO^), filtered off and the solvent, was evaporated till dryness. Yield: 1.0 g of final compound 294. c. Preparation of final compound 295 2-Chlorobenzoyl chloride (0.0004 mol) was added to a solution of final compound 294 (prepared according to B14.b) (0.0004 mol) in CH2C12, p.a. (15 ml), Na2CO3 (0.3 g) was added and the reaction mixture was stirred overnight. The crude mixture was filtered over silica gel (gradient eluent: CH2Cl2/CH3OH 100/0 - 90/10). The product fractions were collected and the solvent was evaporated and the residue was dried. Yield: 0.250 g of final compound 295. (Figure Remove) Example B15 Preparation of final compound 167 2,2-Dimethylpropanoyl chloride (0.001 mol) and Na2CO3 (0.5 g) were added to a solution of final compound 2 (prepared according to Bl.b) (0.001 mol) in CH2C12 (25 ml) and the reaction mixture was stirred for 2 hours. The mixture was filtered over a glass filter (gradient eluent: CH2Cl2/CH3OH 100/0 - 90/10). The product fractions were collected and the solvent was evaporated and the residue was dried. Yield: 0.448 g of final compound 167. (Figure Remove) Example B16 a. Preparation of final compound 216 CH2C12 (50 ml) was added to tetrahydro-3-furancarboxylic acid (0.0012 rnol) and 1,1 '-carbonylbis-l//-imidazole (0.0012 mol) was added. The mixture was stirred for 45 min. at 40 °C and stirred for 3 hours at room temperature. Final compound 2 (0.001 mol) was added and the reaction mixture was stirred overnight at room temperature. The mixture was washed with a basic NaOH solution, the organic layer was separated, washed with H20, dried (MgSO4), filtered off and the solvent was evaporated. The residue was purified by column chromatography (gradient eluent: CH2C12/CH3OH 100/0 - 80/20). The product fractions were collected and the solvent was evaporated and the residue was dried. Yield: 0.480 g of final compound 216. (Figure Remove)b. Preparation of final compound 195 2-Cyanobenzoic acid (0.001 mol) was taken up in CH2C12 (30 ml) and 1,1 '-carbonylbis-l#-imidazole (0.001 mol) was added. The resulting mixture was stirred for 2 hours at 40 °C and was cooled to room temperature. Final compound 2 (prepared according to Bl.b) (0.001 mol) was added and the reaction mixture was stirred overnight at room temperature and was left to stand over the weekend. The mixture was washed with a basic NaOH solution, the organic layer was separated, dried (MgSO^, filtered off and the solvent was evaporated. The residue was filtered over silica gel (gradient eluent: CH2C12/CH3OH 100/0 - 90/10). The product fractions were collected and the solvent was evaporated and the residue was dried. Yield: 0.272 g of final compound 195. Example B17 Preparation of final compound 203 Trifluoromethanecarbonic acid anhydride (0.001 mol) and Na2CC>3 (0.5 g) were added to a solution of final compound 2 (prepared according to Bl.b) (0.001 mol) in CI^Clj (15 ml) and the reaction mixture was stirred for 2 hours. The mixture was filtered on a glass filter over silica gel (gradient eluent: CH2C12/CH3OH 100/0 - 90/10). The product fractions were collected and the solvent was evaporated and the residue was dried. Yield: 0.276 g of final compound 203. (Figure Remove) compound 166 A mixture of 4-[(acetyloxy)methyl]-l,2,3-thiadiazole-5-carboxylic acid methyl ester (0.002 mol) and final compound 2 (prepared according to Bl.b) (0.004 mol) in CH3OH (25 ml) was stirred over the weekend at room temperature and the reaction mixture was filtered over silica gel (gradient eluent: CH2C12/CH3OH 100/0 - 90/10). The product fractions were collected and the solvent was evaporated and the residue was dried. Yield: 0.600 g of final compound 166. (Figure Remove) Example Bl9 Preparation of final compound 375 A mixture of final compound 2 (prepared according to Bl.b) (0.001 mol), intermediate compound 15 (prepared according to A3.d) (0.001 mol) and titanium, tetrakis(2-propanolato) (1 ml) in CH3OH (50 ml) was hydrogenated at 50 °C with Pd/C 10 % (0.1 g) as a catalyst in the presence of thiophene soln. (0.1 ml). After uptake of H2 (1 eq.), the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in HzO/CHjCk, dicalite was added and the resulting mixture was filtered over dicalite. The organic layer was separated, dried (MgSO4), filtered off and the solvent was evaporated. The residue was purified by column chromatography (gradient eluent: CH2C13/(CH3OH/NH3) 99/1 - 80/20). The product fractions were collected and the solvent was evaporated and the residue was dried. Yield: 0.017 g of final compound 375. (Figure Remove) Example B20 a. Preparation of final compound 205 l-Hydroxy-l#-benzotriazole (0.004 mol) and Et3N (0.004 mol) were added to a solution of Ar-[(l,l-dimethylethoxy)carbonyl]-2-methylalanine (0.004 mol) in CH2Q2 (50 ml) and the mixture was stirred at room temperature, A^-(ethylcarbommidoyl)-Af,7V-dimethyl-l,3-propanediamine (0.004 mol) was added and the reaction mixture was stirred for 10 min. at room temperature. A mixture of final compound 2 (prepared according to Bl.b) (0.003 mol) in CH2C12 (20 ml) was added and the reaction mixture was stirred overnight at room temperature. The mixture was washed with IfcO/NaHCOa and with H2O. The organic layer was separated, dried (MgSO4), filtered off and the solvent was evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CH2C12/CH3OH 100/0 - 80/20). The product fractions were collected and the solvent was evaporated. Yield: 0.414 g of final compound 205. (Figure Remove) b. Preparation of final compound 304 50% NaH (0.0015 mol) was added to a solution of final compound 205 (prepared according to B20.a) (0.0013 mol) in DMF p.a. (25 ml) and the resulting mixture was slowly (35 min.) heated to 45 °C. CH3I (0.0015 mol) was added and the reaction mixture was stirred for 4 hours at 50 °C and stirred overnight at room temperature. The solvent was evaporated and the residue was taken up in H2O and the mixture was extracted with CHjCk. The organic layer was separated, dried (over MgSO4), filtered off and the solvent was evaporated. The residue was purified by column chromatography (gradient eluent: CH2Cl2/CH3OH 100/0 - 90/10). The product fractions were collected and the solvent was evaporated and the residue was dried. Yield: 0.47 g of final compound 304. (Figure Remove) c. Preparation of final compound 309 2-Propanol/HCl (2 ml) was added to a solution of final compound 304 (prepared according to B20.b) (0.00061 mol) in 2-propanol (20 ml) and the reaction mixture was stirred and refluxed for 90 min. The solvent was evaporated and the residue was taken up in H^O and washed with DIPE. The aqueous layer was alkalised and extracted with CH2C12. The organic layer was separated, dried (MgSO4), filtered off and the solvent was evaporated. Yield: 0.320 g of final compound 309. (Figure Remove) d. Preparation of final compound 11Q Cyclopropanecarbonyl chloride (0.0005 mol) was added to a solution of final compound 309 (prepared according to B20.c) (0.00048 mol) in CH2C12 (20 ml), Na2CO3 (0.5 g) was added and the reaction mixture was stirred for 2 hours at room temperature. The crude mixture was purified by column chromatography over silica gel (gradient eluent: CH2C12/CH3OH 100/0 - 90/10). The desired product fractions were collected and the solvent was evaporated and the residue was dried. Yield: 0.080 g of final compound 310. Example B21 Preparation of final compound 147 CHaGb (10 ml) was added to intermediate compound 9 (prepared according to A2.e) (0.000177 mol) and the mixture was stirred to give solution (I). Solution (I) (10 ml) was added to (RS) 2,3-dihydro-l#-indene-l-carboxylic acid (0.000266 mol), (Novabiochem 01-64-0211)(0.000531 mol; 1.90mmol/g) and 1-hydroxy-1/^-benzotriazole (0.000407 mol) and the reaction mixture was stirred for 16 hours at room temperature. HCO, (Novabiochem 01-64-0419) (0.001221 SS-C1 mol; 5.80 mmol/g) and ° (PS-TsCl) (0.000266 mol; 1.97 mmol/g) were added and the mixture was stirred for 16 hours at room temperature. The scavengers were filtered off and the filtrate was evaporated. Yielding final compound 147. (Figure Remove) Example B22 a. Preparation of final compound p.a. A mixture of final compound 2 (prepared according to Bl.b) (0.002 mol) in (50 ml) was stirred at room temperature. A solution of bis( 1,1-dimethylethyl)dicarbonic acid ester (0.002 mol) in CH2C12 was added dropwise and the reaction mixture was stirred for 1 hour at room temperature. The solvent was evaporated and the residue was purified by column chromatography over silica gel (gradient eluent: CH2C12/CH3OH from 100/0 to 90/10). The product fractions were collected and the solvent was evaporated. Yield: 1.039 g of final compound 130 (78 (Figure Remove) b. Preparation of final compound 150 and 151 A mixture of intermediate compound 4 (prepared according to Al .d) (0.15 mol) and 1,1-dimethylethyl-l-pyrrolidinecarboxylic acid ester (0.165 mol) in CHaOH (500 ml) was hydrogenated overnight at 50°C with Pd/C 10% (5 g) as a catalyst in the presence of thiophene (4 ml). After uptake of H2 (1 equiv.), the catalyst was filtered off and the filtrate was evaporated. The residue was crystallised from DIPE, the resulting precipitate was filtered off, giving solid S and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CUCyCHbOH from 100/0 to 95/5) The product fractions were collected and the solvent was evaporated. This residue and solid S were combined. This fraction was separated into its enantiomers by Chiral separation (AD, eluent: Hexane/2-propanol 90/10). Two product fractions were collected and the solvent was evaporated. Yield fraction 1:46 g of final compound 150 ([2R-[2a,4p(S*)]]) (46 %) and yield fraction 2: 39 g of final compound 151 ([2R-[2a,4p(R*)]]) (39 %) (Figure Remove) Example B23 Preparation of final compound 349 A mixture of final compound 2 (prepared according to Bl.b) (0.001 mol, 0.5 g), 1,4-dioxane-2,5-diol (0.001 mol, 0.113 g) and 3-thiophene boronic acid (0.001 mol, 0.106 g) in ethanol (5 ml) was stirred at room temperature for 18 hours . This was followed by addition of solution of K^COa (10 %) and extracted with ethyl acetate. The combined organic layers were dried (MgSO^), filtered and concentrated under vacuum. The residue (0.6 g) was purified by column chromatography over silica gel (eluent: CHzCk/MeOH/NHUOH 93/07/0.5) and the product fractions were concentrated. Yield: 0.075 g (12 %) of final compound 349. (Figure Remove) Example B24 a. Preparation of final compound 335 Intermediate compound 17 (prepared according to A4.b) (0.002 mol, 0.67 g) was added portionwise to a solution of final compound 2 (prepared according to Bl.b) (0.002 mol, 1.0 g) in CH2Cl2 at room temperature. The mixture was stirred at room temperature during 18 hours , washed wrthK2CO3 (10 %), dried over MgSO4 and concentrated. The crude product (1.5 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/MeOH 98/2) and the product fractions were concentrated. Yield : 1.1 g (73 %) of final compound 335. (Figure Remove) b. Preparation of final compound 342 BBr3 (1M in CH2C12) (0.004 mol, 3.6 ml) was slowly added to a mixture of final compound 335 (prepared according to B24.a) (0.001 mol, 0.6 g) in CH2C12 (6 ml) at -70 °C under N2 flow. The reaction was allowed to warm up slowly to -50 °C and stirred at -50 °C during 1 hour. The mixture was hydrolyzed with K2COj (10 %), extracted with CHjCk, dried over MgSC>4 and concentrated. The crude product (0.65 g) was purified by column chromatography over silica gel (gradient eluent: CH2Cl2/MeOH/NH4OH 96/4/0.1 to 92/8/0.5) and the product fractions were .concentrated. Yield: 0.113 g of final compound 342 (21 %). (Figure Remove) Example B25 a. Preparation of final compound 356 l-(3-Dimetylammopropyl)-3-ethylcarbodiimide.hydrochloride (0.002 mol, 0.33g) was added portionwise to a solution of final compound 2 (prepared according to Bl.b) (0.002 mol, Ig), intermediate compound 19 (prepared according to AS.b) (0.002 mol, 0.56g), 1-hydroxybenzotriazole (0.002 mol, 0.29g) and triethylamine (0.003 mol, 0.37 ml) in CHiCL (10 ml) at room temperature. The mixture was stirred at room temperature during 18 hours, washed with K^COs 10%, dried over MgSC>4 and concentrated. The crude product (1.65g) was purified by column chromatography over silica gel (eluent: CH^CyMeOH/NHiOH 96/4/0.5) and the product fractions were concentrated. Yield: 0.62 g (43%) of final compound 356. (Figure Remove) b. Preparation of final compound 159 The same procedure as described in Example B24.b but instead of the use of final compound 334 (prepared according to B24.a), final compound 356 (prepared according to B25.a) was used. (Figure Remove) Example B26 Preparation of final compound 344 A mixture of dimethyl-A'-cyanodithioiminocarbonate (Ig; 6.8 mmol) and isopropylamine (0.6 ml; 6.8 mmol) in acetonitrile (10 ml) was heated under reflux for 5 hours. After cooling the solution to -10 °C, final compound 2 (prepared according to Bl.b) (3.87 g; 6.8 rnmol) and 3N sodium hydroxide solution (2.3 ml; 6.8 mmol) were added. The mixture was stirred for 5 minutes and a solution of silver nitrate (1.16 g; 6.8 mmol) in acetonitrile (5 ml) was added dropwise. The reaction mixture was stirred at 0°C for 2 hours and at room temperature for 2 hours. The reaction mixture was filtered and the residue washed with acetonitrile. The solvent was evaporated and the residue was purified by column chromatography over silica gel (15-40 mm, eluent: CHaC^/MeOH/NHUOH 95/5/0.5). The pure fractions were collected and evaporated. Yield: 1.9 g of of final compound 344 (41 %). (Figure Remove) Example B27 Preparation affinal compound 301 Dimemyl-A'-cyanodithioiminocarbonate (0.001 mol) was added to a mixture of final compound 2 (prepared according to Bl.b) (0.0009 mol) in /PrOH (25ml). The mixture was stirred and refluxed for 20 hours. H2O was added. The mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO,]), filtered, and the solvent was evaporated. The residue (0.52g) was purified by column chromatography over silica gel (eluent: CH^CVCHaOH/NtLtOH 97/3/0.1). The pure fractions were collected and the solvent was evaporated. Yield: 0.27g of final compound 301. (Figure Remove) Example B28 Preparation of final compound 354 A mixture of l,l-bis(methylthio)-2-nitroethylene (0.15 g; 0.9 mmol) and isopropylamine (0.08 ml; 0.9 mmol) in acetonitrile (5 ml) was heated under reflux overnight. After cooling the solution to -10 °C, final compound 2 (prepared according to Bl.b) (0.512 g; 0.9 mmol) and 3N NaOH solution (0.9 ml; 0.9 mmol) were added. The mixture was stirred for 5 minutes and a solution of silver nitrate (0.16 g; 0.9 mmol) in acetonitrile (5 ml) was added dropwise. The reaction mixture was stirred for 2 hours at 0 °C, and stirred overnight at room temperature. The solution was filtered and the residue washed with acetonitrile. The solvent was evaporated and the residue was purified by column chromatography over silica gel (Kromasil 10 mm, eluent: CHiCyMeOH/NHLiOH 96/4/0.1). The pure fractions were collected and evaporated. Yield: 0.267 g of final compound 354 (43 %). (Figure Remove) Example B29 a. Preparation of final compound 383 A mixture of final compound 2 (prepared according to Bl.b) (2 g; 3.5 mmol) and 2-chloromethyloxirane (0.70 ml; 8.9 mmol) in methanol (20 ml) was stirred at room temperature overnight. The solvent was evaporated and the residue was taken up in methylene chloride. The solvent was evaporated and the residue was purified by column chromatography over silica gel (15-40 mm, eluent: CH2Cl2/MeOH/NIi,OH 92/8/0.5). The pure fractions were collected and evaporated. Yield: 0.23 g of final compound 383 (10%). (Figure Remove) b. Preparation of final compound 384 A mixture of final compound 383 (0.230 g; 0.35 mmol), isopropylamine (0.033 ml; 0.38 mmol) and potassium carbonate (0.072 g; 0.52 mmol) in acetonitrile (5 ml) were heated under reflux overnight. The reaction mixture was filtered and the solvent was evaporated. Yield: 0.225 g of final compound 384 (95 %). (Figure Remove) c. Preparation of final compound 385 A mixture of final compound 384 (0.220 g; 0.29 mmol) and l.l'-carbonyldiimidazole (0.071 g; 0.44 mmol) in CH2C12 (10 ml) was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by column chromatography over silica gel (Kromasil 10 mm, eluent: CH2Cl2/MeOH/NH|OH 95/5/0.5). The pure fractions were collected and evaporated. Yield: 0.118 g of final compound 385 (52 %). (Figure Remove) Example B30 Preparation of final compound 343 A mixture of final compound 2 (prepared according to Bl .b) (1.0 g; 1.76 mmol) and 3-methoxyphenyl isocyanate (0.25 ml; 1.93 mmol) in THF (10 ml) was stirred at room temperature overnight. The reaction mixture was poured onto ice-water and extracted with CH2Cl2. The organic layers were dried over MgSCXt, filtered and evaporated. The residue was purified by column chromatography over silica gel (40 mm, eluent: CH2Cl2/MeOH/NH4OH 97/3/0.5). The pure fractions were collected and evaporated. Yield: 1.3 g of final compound 343 (100 %). (Figure Remove) Example B31 a) Preparation of final compound 243 F F F A mixture of intermediate compound 23 (prepared according to A6.d) (0.02 mol), intermediate compound 30 (prepared according to A8) (0.02 mol) and Pt/C 5% (3 g) in thiophene solution (2 ml) and CH3OH (250 ml) was stirred at 50°C under H2 (gas), titanium, tetrakis(2-propanolato) (15 g) was added and the reaction mixture was filtered. The filtrate was evaporated and the residue was taken up in CEfeGb/HaO. The biphasic mixture was stirred for 15 min. and filtered through dicalite. The organic filtrate was separated, dried and the solvent was evaporated. The residue was. separated by column chromatography over silica gel (gradient eluent: CH2C12/CH3OH 100/0 -> 90/10). The product fractions were collected and the solvent was evaporated. The purification was repeated, two product fractions were collected and the solvent was evaporated. The desired fraction was crystallised from petroleum ether and the resulting solids were collected. Yield: 1.8 g of final compound 243. (Figure Remove) HCl/2-propanol (5 ml) was added to a solution of final compound 243 (0.0046 mol) in 2-propanol (50 ml) and the reaction mixture was stirred and refluxed for 2 hours. The resulting precipitate was filtered off and washed with DIPE/2-propanol. The solids were taken up in HjO. The mixture was alkalised and extracted with CtfeCk. The organic layer was separated, dried and the solvent was evaporated. Yield: 2.1 g of final compound 244 (72%). (Figure Remove) c^ Preparation of final compound 393 A mixture of final compound 298 (prepared according to B31.a) (1.47 g) in a 5 to 6N HCl/isopropanol solution (40 ml) and THF (5 ml) was stirred at room temperature for 4 hours. The reaction mixture was concentrated, poured onto a 10% sodium carbonate solution and extracted with CHjCfe. The organic layers were dried over MgSCU, filtered and evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/MeOH/NH4OH 85/15/1). The pure fractions were collected and evaporated. The residue was taken up with diisopropylether, filtered and dried. Yield: 0.273 g of final compound 393 (19%). (Figure Remove) Example B32 a) Preparation of final compound 405 3,5-bis(trifluoromethyl)benzoylchloride (0.005 mol) was added to a solution of intermediate compound 29 (prepared according to A7.d) (0.0048 mol) in CH2C12 (20 ml) and the mixture was briefly stirred, Et3N (1 ml) was added and the reaction mixture was stirred for 18 hours. The mixture was washed with a diluted NaOH solution and with H2O, dried and the solvent was evaporated. Yield: 2.8 g of final compound 405. (Figure Remove) b) Preparation of final compound 406 Final compound 405 (0.0043 mol) was taken up in HCl/2-propanol (5 ml) and 2-propanol (50 ml) was added (precipitation occurred), the reaction mixture was stirred and refluxed for 2 hours. The mixture was cooled and the resulting precipitate was filtered off. The precipitate was taken up in H2O, alkalised with a basic NaOH solution and extracted with CH2C12. The organic layer was separated, washed with H2O, dried (MgSO^), filtered off and the solvent was evaporated. The residue was purified over silica gel on a glass filter (gradient eluent: CH2C12/(CH3OH/NH3) 99/1 -> 90/10). The product fractions were collected and the solvent was evaporated. Yield: 1.5 g of final compound 406. (Figure Remove) Example B33 Preparation of final compound 204 A mixture of final compound 2 (prepared according to Bl.b) (0.0014 mol), 3-chloro-1,2-benzoisoxazole (0.0015 mol), Na2CO3 (0.0014 mol) and KI (0.0014 mol) in 4- methylpentanone (20 ml, p.a.) was stirred under N2 in autoclave at 160°C over the weekend. The reaction mixture was cooled and the solvent was evaporated. The residue was partitioned between H2O/CH2C12 and the aqueous layer was extracted with CH2C12. The organic layer was dried (MgSO4), filtered off and the solvent was evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CH2CyCH3OH from 100/0 to 90/10). The product fractions were collected and the solvent was evaporated. Yield: 0.783 g of final compound 204 (82 %). (Figure Remove) Example B34 Preparation of final compound 185 p i P A mixture of final compound 144 (prepared according to B14.b) (0.00096 mol), 2-chloro-JV,A'"-dimethylethanamme (0.00098 mol) and Na2CO3 (0.0029 mol) in 2-butanol (5 ml) was stirred under microwave irradiation (45 min. at 175°C). The mixture was evaporated under vacuum and the residue was suspended in CH2C12) then isocyanate-resin (0.125 g, scavenger) was added and the reaction mixture was stirred for 5 hours at room temperature. The mixture was filtered off, the filter residue was washed with CH2C12 and the solvent was evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CH2C12/(CH3OH/NH3) (7N) from 100/0 to 80/20). The product fractions were collected, the solvent was evaporated and the residue was dried (vac., 50°C) for 48 hours. Yield: 0.056 g of final compound 185 (8%). (Table Remove) cb=covalent bond C. Analytical data For a number of compounds, either melting points, LCMS data or optical rotations were recorded. 1. Melting points If possible, melting points (or ranges) were obtained with a Leica VMHB Koffler bank. The melting points are unconnected. Table 7 : Melting points for selected compounds. (Table Remove) 2. LCMS conditions Method A The HPLC gradient was supplied by a Waters Alliance HT 2790 system (Waters, Milford, MA) with a columnheater set at 40°C. Flow from the column was split to a Waters 996 photodiode array (PDA) detector and a Waters-Micromass ZQ mass , spectrometer with an electrospray ionization source operated in positive and negative ionization mode. Reversed phase HPLC was carried out on a Xterra MS CIS column (3.5 mm, 4.6 x 100 mm) with a flow rate of 1.6 ml/min. Three mobile phases (mobile phase A : 95% 25.mM ammoniumacetate + 5% acetonitrile; mobile phase B : acetonitrile ; mobile phase C : methanol) were employed to run a gradient condition from 100 % A to 50% B and 50% C in 6.5 min., to 100 % B in 1 min, 100% B for 1 min. and re-equilibrate with 100 % A for 1.5 min. An injection volume of 10 |J.L was used. Mass spectra were acquired by scanning from 100 to 1000 in 1 s using a dwell time of 0.1 s. The capillary needle voltage was 3kV and the source temperature was maintained at 140°C . Nitrogen was used a the nebulizer gas. Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode. Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system. Table 8 : LCMS parent peak and retention time for selected compounds. (Table Remove) Method B The HPLC gradient was supplied by a Waters Alliance HT 2790 system (Waters, Milford, MA) with a columnheater set at 40°C. Flow from the column was split to a Waters 996 photodiode array (PDA) detector and a Waters-Micromass ZQ mass spectrometer with an electrospray ionization source operated in positive and negative ionization mode. Reversed phase HPLC was carried out on a Xterra MS CIS column (5 mm, 3.9 x 150 mm) with a flow rate of 1 ml/min. Two mobile phases (mobile phase A: 85% 6.5mM ammonium acetate + 15% acetonitrile ; mobile phase B : 20% 6.5 mM ammonium acetate + 80% acetonitrile) were employed to run a gradient condition from 100 % A for 3 min to 100% B in 5 min., 100% B for 6 min to 100 % A in 3 min, and re-equilibrate with 100 % A for 3 min). Mass spectra were acquired as in Method A. Table .9 : LCMS parent peak and retention time for selected compounds. (Table Remove) Optical rotations Optical rotations were recorded on a polarimeter (Perkin Elmer) at 20°C in methanol, using a cell pathlength = 1 dm, a volume = 5 ml at a concentration = 0.5 mg/ml. Table 10 : Optical rotation data for selected compounds. (Table Remove) D. Pharmacological example Example D.I : Binding experiment for h-NKj. h-NK? and h-NK? receptors The compounds according to the invention were investigated for interaction with various neurotransmitter receptors, ion channels and transporter binding sites using the radioligand binding technique. Membranes from tissue homogenates or from cells, expressing the receptor or transporter of interests, were incubated with a radioactively labelled substance ([3H]- or [125I] ligand) to label a particular receptor. Specific receptor binding of the radioligand was distinguished from the non-specific membrane labelling by selectively inhibiting the receptor labelling with an unlabelled drug (the blank), known to compete with the radioligand for binding to the receptor sites. Following incubation, labelled membranes were harvested and rinsed with excessive cold buffer to remove non-bound radioactivity by rapid filtration under suction. Membrane beomd radioactivity was counted in a scintillation counter and results were expressed in counts per minute (cpm). The compounds were dissolved in DMSO and tested at 10 concentrations ranging from l(r10tol(r5M. The ability of the compounds according to the invention to displace [3H]-Substance P from cloned human h-NKi receptors expressed in CHO cells, to displace [3H]-SR-48968 from cloned human h-NK2 receptors expressed in Sf9 cells, and to displace [3H]-SR-142801 from cloned human h-NK3 receptors expressed in CHO cells was evaluated. The receptor binding values (pICso) for the h-NKi ranges for all compounds according to the invention between 10 and 6. Example D.2 : Signal transduction (ST) This test evaluates in vitro functional NKi antagonistic activity. For the measurements of intracellular Ca4"1" concentrations the cells were grown on 96-well (black wall/transparent bottom) plates from Costar for 2 days until they reached confluence. The cells were loaded with 2 fiM Fluo3 in DMEM containing 0.1% BSA and 2.5 mM probenecid for 1 h at 37°C. They were washed 3x with a Krebs buffer (140 mM NaCl, 1 mM MgCl2x6H20, 5 mM KC1, 10 mM glucose, 5 mM HEPES; 1.25 mM CaCl2; pH 7.4) containing 2.5 mM probenecid and 0.1 % BSA (Ca^-buffer). The cells were preincubated with a concentration range of antagonists for 20 min at RT and Ca44-signals after addition of the agonists were measured in a Fluorescence Image Plate Reader (FL1PR from Molecular Devices, Crawley, England). The peak of the Ca*- transient was considered as the relevant signal and the mean values of corresponding wells were analysed as described below. The sigmoidal dose response curves were analysed by computerised curve-fitting, using the GraphPad Program. The ECso-value of a compound is the effective dose showing 50 % of maximal effect. For mean curves the response to the agonist with the highest potency was normalised to 100 %. For antagonist responses the IC50-value was calculated using non-linear regression. The pIC5o data for the signal transduction testing for a representative selection of compounds are presented in Table 11. The last colums indicates - without being limited thereto - for which action the compounds might be most suitable. Ofcourse, since for some neurokinin receptors no data was determined, it is obvious that these compounds might be attributed to another suitable use. Table 11 : Pharmacological data for the signal transduction for selected compounds. (n.d.= not determined) (Table Remove) E. Coropogitiori examples "Active ingredient" (A.I.) as used throughout these examples relates to a compound of Formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the TV-oxide form thereof and prodrugs thereof. Example E.I : ORAL DROPS 500 Grams of the A.I. was dissolved in 0.5 lof 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.I. The resulting solution was filled into suitable containers. Example E.2 : ORAL SOLUTION 9 Grams of methyl 4-hydroxybenzoate and 1 gram of propyl 4-hydroxybenzoate 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 12 11,2,3-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 E.3 : FILM-COATED TABLETS &r?paratiQn.of.tab.lef.cQ.re 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 micro crystalline 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 solution 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 homogenated. The tablet cores were coated with the thus obtained mixture in a coating apparatus. Example E.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 to room temperature and supplemented with water for injection q.s. ad 11, giving a solution comprising 4 rag/ml of A.I.. The solution was sterilized by filtration and filled in sterile containers. CLAIMS 1. A compound according to the general Formula (I) (Figure Remove) the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the W-oxide form thereof and prodrugs thereof, wherein : n is an integer, equal to 0, 1 or 2 ; m is an integer, equal to 1 or 2, provided that if m is 2, then n is 1 ; p is an integer equal to 1 or 2; q is an integer equal to 0 or 1 ; Q isOorNR3; X is a covalent bond or a bivalent radical of formula -0-, -S- or -NR3-; each R3 independently from each other, is hydrogen or alkyl; each R1 independently from each other, is selected from the group of Ar1, Ar'-alkyl and diCAr^-alkyl; R2 is Ar2, Ar2-alkyl, di(Ar2)alkyl, Met1 or Het'-alkyl; Y is a covalent bond or a bivalent radical of formula -C(=O)-, -SO2- >C=CH- R or >C=N-R, wherein R is H , CN or nitro ; each Alk represents, independently from each other, a covalent bond ; a bivalent straight or branched, saturated or unsaturated hydrocarbon radical having from 1 to 6 carbon atoms ; or a cyclic saturated or unsaturated hydrocarbon radical having from 3 to 6 carbon atoms ; each radical optionally substituted on one or more carbon atoms with one or more , phenyl, halo, cyano, hydroxy, formyl and amino radicals ; L is selected from the group of hydrogen, alkyl, alkyloxy, alkyloxyalkyloxy, alkylcarbonyloxy, alkyloxycarbonyl, mono- and di(alkyl)amino, mono- and di(alkyloxycarbonyl)amino, mono- and di(alkylcarbonyl)amino, mono-and di(Ar3)amino, mono-and di(Ar3alkyl)amino, mono-and di(Het2)amino, mono-and di(Het2aLkyl)amino, alkylsulfanyl, adamantyl, Ar3, Ar3-oxy, Ar3carbonyl, Het2, Het-oxy and Het2carbonyl; Ar1 is phenyl, optionally substituted with 1, 2 or 3 substituents, each independently from each other, selected from the group of halo, alkyl, cyano, aminocarbonyl and alkyloxy; Ar2 is naphthalenyl or phenyl, each optionally substituted with 1, 2 or 3 substituerits, each independently from each other, selected from the group of halo, nirro, amino, mono- and di(alkyl)amino, cyano, alkyl, hydroxy, alkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl and mono- and di(alkyl)aminocarbonyl; Ar3 is naphthalenyl or phenyl, optionally substituted with 1, 2 or 3 substituents, each independently from each other, selected from the group of alkyloxy, Ar'carbonyloxyalkyl, Ar1 alkyloxycarbonyl, Ar'alkyloxyalkyl, alkyl, halo, hydroxy, pyridinyl, morpholinyl, pyrrolidinyl, imidazo[l,2- Het' is a monocyclic heterocyclic radical selected from the the group of pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocyclic radical selected from the group of quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, indanyl and chromenyl; each heterocyclic radical may optionally be substituted on any atom by one or more radicals elected from the group of halo, oxo and alkyl; Het2 is a monocyclic heterocyclic radical selected from the group of pyrrolidinyl, dioxolyl, imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, imidazolidinyl, tetrahydrofuranyl, 2H-pyrrolyl, pyrrolinyl, imidazolinyl, pyrazolinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, furanyl, thienyl, oxazolyl, dioxazolyl, oxazolidinyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl; or a bicyclic heterocyclic radical selected from the group of 2,3-dihydro-benzo[l,4]dioxine, octahydro-benzo[l,4]dioxine, benzopiperidinyl, quinolinyl, quinoxalinyl, indolyl, isoindolyl, chromanyl, benzimidazolyl, imidazo[l,2-o]pyriduiyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl or benzothienyl; or the tricyclic heterocyclic radical 8,9-dihydro-4#-l-oxa-3,5,7a-triaza-cyclopenta[fjazulenyl; each radical may optionally be substituted with one or more radicals selected from the group of Ar1, Ar1 alkyl, Ar'alkyloxyalkyl, halo, hydroxy, alkyl, piperidinyl, pyrrolyl, thienyl, oxo, alkyloxy, alkylcarbonyl, Ar'carbonyl, mono- and di(alkyl)aminoalkyl, alkyloxyalkyl and alkyloxycarbonyl; and alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radicals having from 3 to 6 carbon atoms ; optionally substituted on one or more carbon atoms with one or more radicals selected from the group of phenyl, halo, cyano, oxo, hydroxy, formyl and amino. 2. A compound according to claim 1 wherein : n is an integer, equal to 1; m is an integer, equal to 1; p is an integer equal to 1 or 2; q is an integer equal to 0; Q isO X is a covalent bond; R' is Ar'-alkyl; R2 is Ar2, Ar2-alkyl, di(Ar2)alkyl or Het'; Y is a covalent bond or a bivalent radical of formula -C(=O)-, ~SO2-, >C=CH-R or >C=N-R, wherein R is CN or nitro ; each Alk represents, independently from each other, a covalent bond ; a bivalent straight or branched, saturated hydrocarbon radical having from 1 to 6 carbon atoms ; or a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms ; each radical optionally substituted on one or more carbon atoms with one or more phenyl, halo and hydroxy radicals; L is selected from the group of hydrogen, alkyl, alkyloxy, alkyloxyalkyloxy, alkylcarbonyloxy, mono- and di(alkyl)amino, mono- and di(alkyloxycarbonyl)amino, mono- and di(alkylcarbonyl)amino, mono-and di(Ar3)amino, mono-and di(Ar3alkyl)amino, mono-and di(Het2alkyl)amino, alkylsulfanyl, adamantyl, Ar3, Het2 and Het2carbonyl; Ar1 is phenyl, optionally substituted with 1 or 2 halo radicals ; Ar2 is naphthalenyl or phenyl, each optionally substituted with 1, 2 or 3 substituents, each independently from each other, selected from the group of halo, alkyl and alkyloxy; Ar3 is naphthalenyl or phenyl, optionally substituted with 1, 2 or 3 substituents, each independently from each other, selected from the group of alkyloxy, Ar1 alkyloxycarbonyl, Ar'alkyloxyalkyl, alkyl, halo and cyano; Het1 is pyridinyl or a bicyclic heterocyclic radical selected from the group of quinoxalinyl, indolyl, benzothienyl, indanyl and chromenyl; each heterocyclic radical may optionally be substituted on any atom by one or more radicals selected from the group of oxo and alkyl; Het2 is a monocyclic heterocyclic radical selected from the group of pyrrolidinyl, dioxolyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuranyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, dioxazolyl, oxazolidinyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocyclic radical selected from the group of 2,3-dihydro-benzo[l,4]dioxine, octahydro-benzo[l,4]dioxine, quinoxalinyl, indolyl, chromanyl, benzimidazolyl, imidazo[l,2-a]pyridinyl, benzisoxazolyl, benzothiazolyl,benzofuranyl and benzothienyl; or the tricyclic heterocyclic radical 8,9-dihydro-4#-l-oxa-3,5,7a-triaza-cyclopenta[f]azulenyl; each radical may optionally be substituted with one or more radicals selected from the group of Ar1, Ar'alkyloxyalkyl, halo, alkyl, oxo, alkyloxy, alkylcarbonyl, Ar'carbonyl, mono- and di(alkyl)aminoalkyl, alkyloxyalkyl and alkyloxycarbonyl; and alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radicals having from 3 to 6 carbon atoms ; optionally substituted on one or more carbon atoms with one or more radicals selected from the group of phenyl, halo and hydroxy. 3. A compound according to any of claims 1-2, characterized in that R1 is Ar'methyl and attached to the 2-position or R1 is Ar1 and attached to the 3-position . 4. A compound according to any of claims 1-3, characterized in that the R2-X-C(=Q)- moiety is 3,5-di-(trifluoromethyl) phenylcarbonyl. 5. A compound according to any of claims 1-4, characterized in that p is 1. 6. A compound according to any of claims 1-5, characterized in that Y is -C(=O)-. 7. A compound according to any of claims 1-6, characterized in that Alk is a covalent bond. 8. A compound according to any of claims 1-3, characterized in that L is Het2. 9. A compound select from the group of compounds with compound number 219, 70, 269, 281, 408, 393, 72, 164, 253, 258, 267, 286, 317, 318, 313, 308, 331, 366, 31, 32, 4, 71, 218, 259, 287, 285, 306 and 321, as mentioned in anyone of Tables 1-6. 10. A compound according to any one of claims 1 -9 for use as a medicine. 11. A compound according to any one of claims 1-10 for use as an orally active, central penetrating medicine. 12. The use of a compound according to any one of claims 1 1 for the manufacture of a medicament for treating tachykinin mediated conditions. 13. The use of a compound according to claim 1-11 for the manufacture of a medicament for treating schizophrenia, emesis, anxiety, depression, irritable bowel syndrome (IBS), circadian rhythm disturbances, pain, neurogenic inflammation, asthma, micturition disorders such as urinary incontinence and nociception. 14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound according to any one of claims 1-9. 15. A process for preparing a pharmaceutical composition as claimed in claim 14, characterized in mat a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound as claimed in any one of claims 1-9. 16. A process for the preparation of a compound of Formula (I") in which an intermediate compound of Formula (II) is reacted with an intermediate compound of Formula (III), wherein the radicals R2, X, Q, R1, m, n, p and q are as defined in claim 1 . (Figure Remove) 17. A process for the preparation of a compound of Formula (I) in which a final compound of Formula (I") is reductively hydrogenated, wherein the radicals R2, X, Q, R1, m, n, p and q are as defined in claim 1. (Figure Remove) 18. A process for the preparation of a compound according to Formula (I1) comprising the consecutive steps of 1) obtaining a compound of Formula (I") according to claim 16 ; 2) obtaining a compound of Formula (I1) according to claim 17.

Documents:

2725-DELNP-2005-Abstract(1-1-2008).pdf

2725-delnp-2005-abstract-15-04-2008.pdf

2725-delnp-2005-abstract.pdf

2725-DELNP-2005-Claims(1-1-2008).pdf

2725-delnp-2005-claims-15-04-2008.pdf

2725-delnp-2005-claims.pdf

2725-DELNP-2005-Correspondence-Others(1-1-2008).pdf

2725-delnp-2005-correspondence-others-15-04-2008.pdf

2725-delnp-2005-correspondence-others.pdf

2725-DELNP-2005-Description (Complete)(1-1-2008).pdf

2725-delnp-2005-description (complete).pdf

2725-DELNP-2005-Form-1(1-1-2008).pdf

2725-delnp-2005-form-1.pdf

2725-delnp-2005-form-18.pdf

2725-DELNP-2005-Form-2(1-1-2008).pdf

2725-delnp-2005-form-2.pdf

2725-DELNP-2005-Form-3(1-1-2008).pdf

2725-delnp-2005-form-3.pdf

2725-delnp-2005-form-5.pdf

2725-DELNP-2005-GPA(1-1-2008).pdf

2725-delnp-2005-gpa.pdf

2725-delnp-2005-pct-304.pdf

2725-delnp-2005-pct-409.pdf

2725-delnp-2005-pct-416.pdf

2725-delnp-2005-pct-search report.pdf

2725-DELNP-2005-Petition-137(1-1-2008).pdf

2725-DELNP-2005-Petition-138(1-1-2008).pdf

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