1,3,8-TRIAZA-SPIRO'4,5!DECAN-4-ONE DERIVATIVES AS NEUROKININ RECEPTOR ANTAGONISTS

Abstract: The invention relates to compounds of the formula (I) wherein R<1> is hydrogen, lower alkyl, lower alkenyl, phenyl or the following groups -(CH2)m-non aromatic heterocyclyl, which is optionally substituted by lower alkyl, or is -(CH2)m-heteroaryl, which is optionally substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, holgen, CF3, benzyl or cyano, or is -(CH2)m-C(O)-NRR', -(CH2)m-C(O)-lower alkyl, -(CH2)m-C(O)-O-lower alkyl, -(CH2)m-O-lower alkyl, -(CH2)m-CH[C(O)-O-lower alkyl]2, -(CH2)m-CH(OH)-CH2-O-phenyl, -(CH2)m-CH(CF3)OH, -(CH2)m-OH, -(CH2)m-CN, -(CH2)m-NRR', -(CH2)m-cycloalkyl or -(CH2)m-CHF2; R<2> is hydrogen, lower alkyl, halogen or lower alkoxy; R<3> is lower alkyl, lower alkoxy, halogen or CF3; R,R' are the same or different and are hydrogen or lower alkyl; X is > N-, > C = or > CH-; X<1>/X<2> are independently from each other hydrogen, hydroxy or lower alkoxy or may be together an oxo group; Y<1>/Y<2> are independently from each other hydrogen, lower alkyl, -(CH2)m-phenyl or may be together an oxo group; Z is a bond, -CH2- or -C(O)-; m is 0, 1, 2, 3 or 4; n is 2 or 3; n' 0, 1 or 2; and pharmaceutically acceptable acid addition salts thereof. The described compounds have a good affinity to the NK1 receptor.

Description: l , 3 , 8-TRIAZA-SPIR0 λ 4 , 5 ! DECAN-4-0NE DERIVATIVES AS NEUROKININ RECEPTOR ANTAGONISTS The present invention relates to compounds of the general formula wherein R 1 is hydrogen, lower alkyl, lower alkenyl, phenyl or the following groups -(CH 2 ) m -non aromatic heterocyclyl, which is optionally substituted by lower alkyl, or is -(CH 2 ) m -heteroaryl, which is optionally substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, CF 3 , benzyl or cyano, or is -(CH 2 ) m -C(O)-NRR J , -(CH 2 ) m -C(O)-lower alkyl, -(CH 2 ) m -C(O)-O-lower alkyl, -(CH 2 ) m -O-lower alkyl, -(CH 2 ) m -CH[C(O)-O-lower alkyl] 2 , -(CH 2 ) m CH(OH)-CH 2 -O-phenyl, -(CH 2 ) m -CH(CF 3 )OH, -(CH 2 ) m -OH, -(CH 2 ) m -CN, -(CH 2 ) m -NRR\ -(CH 2 ) m -cycloalkyl or -(CH 2 ) m -CHF 2 ; R 2 is hydrogen, lower alkyl, halogen or lower alkoxy; R 3 is lower alkyl, lower alkoxy, halogen or CF 3 ; Pop/06.03.2001 R,R' are the same or different and are hydrogen or lower alkyl; X is >N-, >C= or >CH-; X X 2 are independently from each other hydrogen, hydroxy or lower alkoxy or may be together an oxo group; Y Y 2 are independently from each other hydrogen, lower alkyl, -(CH 2 ) m -phenyl or may be together an oxo group; Z is a bond, -CH 2 - or -C(O)-; m is 0, 1, 2, 3 or 4; n is 2 or 3; ri 0 , 1 or 2; and to pharmaceutically acceptable acid addition salts thereof. The compounds of formula I and their salts are characterized by valuable therapeutic properties. It has been surprisingly found that the compounds of the present invention are antagonists of the Neurokinin 1 (NK-1, substance P) receptor. Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The receptor for substance P is a member of the superfamily of G protein-coupled receptors. The neuropeptide receptor for substance P (NK-1) is widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes. The central and peripheral actions of the mammalian tachykinin substance P have been associated with numerous inflammatory conditions including migraine, rheumatoid arthritis, asthma, and inflammatory bowel disease as well as mediation of the emetic reflex and the modulation of central nervous system (CNS) disorders such as Parkinson's disease (Neurosci. Res., 1996, 7, 187-214), anxiety (Can. J. Phys., 1997, 75, 612-621) and depression (Science, 1998, 281, 1640-1645). Evidence for the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Crohn's disease, ocular injury and ocular inflammatory diseases reviewed in "Tachykinin Receptor and Tachykinin Receptor Antagonists", J. Auton. Pharmacol., 13, 23-93, 1993. The usefulness of neurokinin 1 receptor antagonists for the treatment of certain forms of urinary incontinence is further described in "Neuropeptides, 32(1), 1-49, (1998)" and "Eur. J. Pharmacol., 383(3), 297-303, (1999)". Furthermore, Neurokinin 1 receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinin, in particular substance P. Examples of conditions in which substance P has been implicated include disorders of the central nervous system such as anxiety, depression and psychosis (WO 95/16679, WO 95/18124 and WO 95/23798). The neurokinin- 1 receptor antagonists are further useful for the treatment of motion sickness and for treatment induced vomiting. In addition, in The New England Journal of Medicine, Vol. 340, No. 3 190-195, 1999 has been described the reduction of cisplatin-induced emesis by a selective neurokinin- 1- receptor antagonist. Furthermore, US 5,972,938 describes a method for treating a psychoimmunologic or a psychosomatic disorder by administration of a tachykinin receptor, such as NK-1 receptor antagonist. NK1 receptor antagonists have been reported to have also a beneficial effect in the therapy of traumatic brain injury (oral disclosure by Prof. Nimmo at the International Tachykinin Conference 2000 in La Grande Motte, France, October 17-20, 2000 with the title "Neurokinin 1 (NK-1) Receptor Antagonists Improve the Neurological Outcome Following Traumatic Brain Injury" (Authors: AJ. Nimmo, C.J. Bennett, X.Hu, I. Cernak, R. Vink)." Objects of the present invention are the compounds of formula I and pharmaceutically acceptable salts thereof, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture as well as the use of the above- mentioned compounds in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred to earlier or in the manufacture of corresponding medicaments. The compounds of formula I can also be used in form of their prodrugs. Examples are esters, N-oxides, phosphate esters, glycoamide esters, glyceride conjugates and the like. The prodrugs may add to the value of the present compounds advantages in absorption, pharmocokinetics in distribution and transport to the brain. The most preferred indications in accordance with the present invention are those, which include disorders of the central nervous system, for example the treatment or prevention of certain depressive disorders or emesis by the administration of NK-1 receptor antagonists. A major depressive episode has been defined as being a period of at least two weeks during which, for most of the day and nearly every day, there is either depressed mood or the loss of interest or pleasure in all, or nearly all activities. The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination. As used herein, the term "lower alkyl" denotes a saturated straight- or branched- chain alkyl group containing from 1-7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like. Preferred lower alkyl groups are groups with 1-4 carbon atoms. As used herein, the term "lower alkenyl" denotes a unsaturated straight- or branched-chain alkyl group containing from 2-7 carbon atoms, for example, ethenyl, propenyl, isopropenyl, n-butenyl, i-butenyl, t-butenyl and the like. Preferred lower alkyl groups are groups with 2-4 carbon atoms. The term "lower alkoxy" denotes a group wherein the alkyl residues are as defined above, and which is attached via an oxygen atom. The term "halogen" denotes chlorine, iodine, fluorine and bromine. The term "cycloalkyl" denotes a saturated carbocyclic group, containing 3-6 carbon atoms. The term "non aromatic heterocyclyl" denotes, for example, pyrrolidinyl, 5-oxo- pyrrolidinyl, 2-oxa-oxazolidinyl, piperidyl, piperazinyl, morpholinyl, imidazolidinyl or pyrazolidinyl. Preferred groups are pyrrolidinyl, 5-oxo-pyrrolidinyl, 2-oxa-oxazolidinyl, piperidyl, piperazinyl or morpholinyl. The term "heteroaryl" denotes, for example pyridinyl, 1,3,5-tτiazinyl, pyrimidinyl, quinoxalinyl, pyrazinyl, isoxazolyl, benzoimidazolyl, 1,2,4-oxadiazolyl, triazolyl, tetrazolyl, thiazolyl, thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, piperazinyl or piperidyl. Preferred groups are pyridinyl, 1,3,5-triazinyl, pyrimidinyl, quinoxalinyl, pyrazinyl, imidazolyl, thiazolyl, isoxazolyl, benzoimidazolyl, 1,2,4-oxadiazolyl, furyl and thienyl. The term "pharmaceutically acceptable acid addition salts" embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, mefhanesulfonic acid, p-toluenesulfonic acid and the like. Preferred are all compounds, wherein R is trifluoromethyl and n is 2. Exemplary preferred are compounds, in which X is >N-, X X 2 are together an oxo group and Y Y 2 are both hydrogen, for example the following compounds: 8-(3,5-Bis-trifluoromefhyl-benzoyl)-3-(4,6-dimefhoxy-[l,3,5]triazin-2-yl)-l-phenyl-l,3,8- triaza-spiro [4.5] decan-4-one, 8-(3,5-bis-trifluoromethyl-benzoyl)-l-(2-chloro-phenyl)-3-(4,6-dimethoxy-[l,3,5]triazin- 2-yl)-l,3,8-triaza-spiro[4.5]decan-4-one, 8-(3,5-,bis-trifluorometiιyl-benzoyl)-3-pyridin-3-yl-methyl-l-o-tolyl-l,3,8-triaza- spiro[4.5]decan-4-one, 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-isopropylamino-ethyl)-l-o-tolyl-l,3,8-triaza- spiro[4.5] decan-4-one, 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-pyrrolidin-l-yl-efhyl)-l-o-tolyl-l,3,8-triaza- spiro [4.5] decan-4-one, 8- (3,5-bis-trifluoromethyl-benzoyl) - 1 -phenyl-3-pyridin-4-yl- 1 ,3,8-triaza-spiro [4.5] decan- 4-one, 8-(3,5-bis-trifluoromethyl-benzoyl)-l-(2-chloro-phenyl)-3-methyl-l,3,8-triaza- spiro [4.5] decan-4-one, 8-(3,5-bis-trifluoromethyl-benzoyl)-l-(2-chloro-phenyl)-3-(3-dimethylamino-propyl)- l,3,8-triaza-spiro[4.5]decan-4-one, 8-(3,5-bis-trifluoromethyl-benzoyl)-l-(2-chloro-phenyl)-3-pyridin-4-yl-l,3,8-triaza- spiro [4.5] decan-4-one and 8-(3,5-bis-trifluoromethyl-benzoyl)-3-methyl-l-o-tolyl-l,3,8-triaza-spiro[4.5]decan-4- one. Further preferred are compounds, in which X is >N-, X X 2 are together an oxo group and one of Y 1 ^ 2 is hydrogen and the other is different from hydrogen. Examples of such compounds are: (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-l-phenyl-l,3,8-triaza- spiro [4.5] decan-4-one, (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-l-o-tolyl-l,3,8-triaza-spiro[4.5]decan- 4-one, (rac)-2-benzyl-8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-tolyl-l,3,8-triaza-spiro[4.5]decan- 4-one, (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-phenyl-l-o-tolyl-l,3,8-triaza-spiro[4.5]decan- 4-one, (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-l-phenyl-3-pyridin-3-yl-methyl-l,3,8- triaza-spiro[4.5]decan-4-one, (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2,3-dimefhyl-l-phenyl-l,3,8-triaza- spiro [4.5] decan-4-one, (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-l-phenyl-3-(2-pyrrolidin-l-yl-ethyl)- l,3,8-triaza-spiro[4.5]decan-4-one, (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-3-(3-dimethylamino-propyl)-2-methyl-l- phenyl-l,3,8-triaza-spiro[4.5]decan-4-one, (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2,3-dimethyl-l-o-tolyl-l,3,8-triaza- spiro[4.5] decan-4-one, (rac)-8-(3,5-bis-1xifluoromethyl-benzoyl)-2-methyl-3-(2-piperazin-l-yl-ethyl)-l-o-tolyl- 1,3,8-triaza-spiro [4.5] decan-4-one, (rac)-8-(3,5-bis-trifluorometiιyl-benzoyl)-2-metb.yl-3-(2-pyrrolidin-l-yl-ethyl)-l-o-tolyl- l,3,8-triaza-spiro[4.5]decan-4-one, (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-3-(2-piperidin-l-yl-ethyl)-l-o-tolyl- l,3,8-triaza-spiro[4.5]decan-4-one, (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-methoxy-ethyl)-2-methyl-l-o-tolyl-l,3,8- triaza-spiro [4.5] decan-4-one, (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-3-(2-morpholin-4-yl-ethyl)-l-o-tolyl- l,3,8-triaza-spiro[4.5]decan-4-one and (rac)-8-(3,5-dichloro-benzoyl)-2-methyl-l-o-tolyl-l,3,8-triaza-spiro[4.5]decan-4-one. Preferred are further compounds, wherein X is >N-, XVX 2 and Y Y 2 are oxo groups, for example the following compounds: 8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-tolyl-l,3,8-triaza-spiro[4.5]decane-2 ) 4-dione, 8-(3,5-bis-trifluoromethyl-benzoyl)-3-pyridin-3-yl-methyl-l-o-tolyl-l,3,8-triaza- spiro [4.5 ] decane-2,4-dione, 3-(lH-benzoimidazol-2-yl-methyl)-8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-tolyl-l,3,8- triaza-spiro[4.5]decane-2,4-dione, 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-methyl-thiazol-4-yl-methyl)-l-o-tolyl-l,3,8- triaza-spiro [4.5] decane-2,4-dione, 8-(3,5-bis-trifluoromethyl-benzoyl)-3-furan-2-yl-methyl-l-phenyl-l,3,8-triaza- spiro [4.5] decane-2,4-dione, 8-(3,5-bis-trifluoromethyl-benzoyl)-3-furan-2-yl-methyI-l-o-tolyl-l,3,8-triaza- spiro[4.5]decane-2,4-dione and 8-(3,5-bis-trifluoromethyl-benzoyl)-3-thiophen-2-yl-methyl-l-o-tolyI-l,3,8-triaza- spiro [4.5] decane-2,4-dione. Preferred are further compounds, wherein X is >C=, for example the following compounds: 8-(3,5-bis-trifluoromethyl-benzoyl)-2-(2-pyrrolidin-l-yl-ethyl)-4-o-tolyl-2,8-diaza- spiro [4.5] dec-3-en-l-one and 8-(3,5-bis-trifluoromethyl-benzoyl)-2-(3-dimethylamino-propyl)-4-o-tolyl-2,8-diaza- spiro [4.5] dec-3-en-l-one. Further preferred are compounds, wherein X is >CH-, for example the following compound: (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-o-tolyl-2,8-diaza-spiro[4.5]decan-l-one. The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which process comprises a) reacting a compound of formula with a compound of formula to a compound of formula wherein L is a leaving group, for example halogen, such as chlorine, and the other substituents have the significances given above, or b) reacting a compound of formula with a compound of formula L-R' IV in the presence of sodium hydride or in the presence of potassium carbonate and CuCl, wherein in formula IV L is a leaving group, for example chlorine, to give a compound of formula wherein the other substituents have the significances given above with the proviso that R 1 is not -(CH 2 ) m -OH and X X 2 are not hydroxy, or c) reacting a compound of formula with a compound of formula OTBDMS m-1 v to a compound of formula wherein TBDMS is a tert-butyldimethylsilyl group and the further definitions of substituents is given above, or d) reacting a compound of formula after activation as mesylate with a corresponding amine of formula RR'NH to give a compound of formula wherein the definitions of substituents are given above, or e) reacting a compound of formula 1-1 with a compound of formula < O VI to a compound of formula wherein R 4 is lower alkyl and the definitions of the other substituents are given above, or f) reacting a compound of formula with a compound of formula HO R B OH VII to a compound of formula wherein R 1 is phenyl or heteroaryl, optionally substitueted as described above and the definition of the remaining substituents is given above, or g) cyclizing a compound of formula VII! to a compound of formula 1-5 wherein the substituents are described above, or h) reacting a compound of formula with H 2 N ' to give a compound of formula I-7 wherein the substituents are described above, or i) treating a compound of formula with hydrogen on Pd/C and then with (CF 3 ) 2 C 6 H 3 COCl to obtain a compound of formula wherein the substituents are given above, or modifying one or more substituents R^R 3 within the definitions given above, and if desired, converting the compound obtained into a pharmaceutically acceptable acid addition salt. The salt formation is effected at room temperature in accordance with methods which are known per se and which are familiar to any person skilled in the art. Not only salts with inorganic acids, but also salts with organic acids come into consideration. Hydrochlorides, hydrobromides, sulphates, nitrates, citrates, acetates, maleates, succinates, methan-sulphonates, p-toluenesulphonates and the like are examples of such salts. The following schemes 1-17 describe the processes for preparation of compounds of formula I in more detail. The starting materials are known compounds and may be prepared according to methods known in the art. In the schemes the following abbreviations have been used: NMP l-methyl-2-pyrrolidinone DME ethylene glycol dimethyl ether TBDMS ter -butyldimefhylsilan DMF dimethylformamide THF tetrahydrofuran TMSCN trimethylsilyl cyanide DIBAH diisobutylaluminium hydride Sche e 1 wherein in scheme 1 L is a leaving group, for example halogen, such as chlorine, and the other substituents have the significances given above. A solution of a compound of formula II, for example 3,5-bis(trifluoromethyl)benzoyl chloride in dichloromethane, is added to a mixture of a compound of formula III, which is for example l-phenyl-l,3,8-triaza-spiro[4.5]decan-4-one and triethylamine in dichloromethane. The reaction is carried out at room temperature. Compounds of examples 1 to 3 have been prepared according to scheme 1. Scheme 2 The definition of substituents is described above. This reaction is carried out in the presence of sodium hydride and/or NMP (N-methyl-2- pyrrolidone)/l,2-dimethoxyethane. To this suspension is added a compound of formula 1-1 and then a compound of formula IV is added, which is, for example, 4-(2- chlorethyl)morpholine, 3-(chloromethyl)pyridine, 2-chloro-4,6-dimethoxy-l,3,5-triazine, l-(2-chloroethyl)piperidine, l-(2-chloroethyl)pyrrolidine, 2-bromoacetamide, 2-chloro- N,N-dimethylacetamide, methyl bromoacetate, bromomethyl methylether, dimethyl bromomalonate, phenylglycidylefher, 2,4,6-trichloropyrimidine, 2-chloro-5- (trifluoromethyl)pyridine, 3-bromo-l,l,l-trifluoro-2-propanole, 2-picolylchloride, 4- chloromethylpyridine, 2,4-dichloropyrimidine, methyliodide, l-benzyl-(2-chloromefhyl)- imidazole, 5-chloromethyl-2-oxazolidinone, l-chloro-2-dimethylaminoethane, l-(2- chloroethyl)pyrrolidine, 4-chloromethyl-2-methylthiazole, 4,6-dichloropyridine, 2,3,5- trichloropyridine, 2-chloro-4-(trifluoromethyl)-pyrimidine, 2-chloro-pyridine, 2-chloro- N,N-dimethylacetamide, 3-dimethylaminopropylchloride, 4-(chloromethyl)3,5- dimethylisoxazole or 2,4-dichloro-6-methylpyrimidine. Examples 4 to 21, 25 to 47, 70 to 82 and 86, 87 and 134 have been described in accordance with scheme 2 in more detail. Scheme 3: The definition of substituents is described above. This reaction is carried out under conditions described in scheme 2, with a compound of formula 1-1 and of formula V, which compound is, for example (3-bromopropoxy)-tert.- butyldimethylsilane. In a solution of HCl and ethanol the intermediate TBDMS-ether is cleaved. Examples 22 to 24 have been described in accordance with scheme 3. Scheme 4: The definition of substituents is given above. A solution of a compound of formula 1-2 and triethylamine in dichloromethane is added to a cooled solution of methanesuifonyl chloride in dichloromethane or DMF and then sodium bicarbonate and an amine of the formula RR'NH is added to obtain a compound of formula 1-3. Examples 48 to 58 have been described in accordance with scheme 4. Scheme 5: In scheme 5 R 4 is lower alkyl and the definition of the other substituents is given above. In accordance with this scheme to a mixture of a compound of formula I-l, cesium fluoride and tetraethoxysilane, a compound of formula VI, for example ethyl acrylate, is added. The reaction is carried out at room temperature. Examples 59 and 60 have been prepared as described in scheme 5. Scheme 6 The definition of substituents is described above. This reaction is carried out with a mixture of a compound of formula I-l in the presence of potassium carbonate, CuCl and tris[2-(2-methoxyethoxy)-efhyl] -amine, and with a solution of a compound of formula IV, which is, for example, 4,6-dichloropyrimidine in xylene. Example 61 has been described in accordance with scheme 6. Scheme 7 The definition of substituents is given above. A mixture of a compound of formula I-l, a boronic acid of formula VII, cupric acetate and triethylamine in dichloromethane is stirred at room temperature. Chromatography on silica gel yielded the desired compound of formula I. Examples 62, 83 and 84 describe the process of scheme 7 in more detail. Scheme 8 The definition of substituents is described above. A mixture of a compound of formula VIII, formic acid and acetic anhydride is stirred at room temperature to give the intermediate N-formyl derivative, which is treated with formic acid and acetic acid to give the intermediate amide. The amide is dissolved in triefhyl orthoformate and boiled. After evaporation the solid is dissolved in methanol and sodium borohydride at room temperature is added. The desired product is obtained by chromatography on silica gel. Examples 63 to 68 and 85 describe the processes in accordance with scheme 8 in more detail. Scheme 9 1-7 The definition of substituents is described above. An ethylenediamine-trimethylaluminium complex is added to a solution of a compound of formula 1-6 in toluene. The reaction is carried out at about 120 °. Examples 69 has been described in accordance with scheme 9. Scheme 10 (intermediates) The definition of substituents is described above. A solution of a compound of formula IX in dichloromethane is added with cooling to a solution of 4-piperidone trifluoroacetate and triethylamine. The reaction is carried out at room temperature. Example A describes this process in more detail. Scheme 11 (intermediates) ( The definition of substituents is described above. To a solution of a compound of formula XI in acetic acid is added with cooling a compound of formula XII, for example 3-chloroaniline, and TMSCN. Examples B, C, D, E, F, G and H are prepared in accordance with scheme 11. Scheme 12 The definition of substituents is described above. In accordance with scheme 12 to a solution of l-benzyl-piperidin-4-one (XI- 1) in acetic acid is added a compound of the formula (R 2 ) n '-C 6 H 4 -Z-NH 2 , for example aniline, and TMSCN. To a solution of the intermediate amino nitrile in formic acid is added with cooling acetic anhydride and the obtained foam is dissolved in formic acid and acetic acid. The intermediate is cyclized by boiling in triethylorthoformate and subsequently treated with a Grignard reagent, for example with methylmagnesium bromide. The intermediate is treated with hydrogen and palladium on charcoal in methanol. The last step is the treatment of the obtained solution with 3,5-bis-trifluoromethylbenzoylchloride to obtain a compound of formula 1-8. Examples 91 to 109, 112, 114 to 120 and 132 describe the processes in accordance with scheme 12 in more detail. Scheme 13 1) (R 2 )n'-C 6 H 4 -Z-NH 2 , TMSCN, AcOH XI-1 5) (CF 3 ) 2 C 6 H 3 COCI, Eta , CH 2 CI 2 I-9 The definition of substituents is described above. To a solution of the compound of formula XI- 1 in acetic acid a compound of formula (R 2 ) n' -C 6 H 4 -Z-NH 2 , for example aniline, and TMSCN are added. Then, to a solution of the intermediate amino nitrile, chlorosulfonyl isocyanate is added. The solid is suspended in hydrochloric acid and refluxed. The intermediate is treated with hydrogen and palladium on charcoal. The last step is the treatment with (CF 3 ) 2 C 6 H 3 COCl to give a compound of formula 1-9. Examples 110, 111 and 113 are described in more detail in accordance with scheme 13. Scheme 14 -10 The definition of substituents is described above. To a solution of l-benzyl-piperidin-4-one (XI- 1) in acetic acid is added a compound of formula (R 2 ) n >-C 6 H 4 -Z-NH 2 , for example aniline, and TMSCN. To a solution of the obtained intermediate amino nitrile in dichloromethane is added chlorosulfonyl isocyanate. The obtained white solid is suspended in HCl and refluxed. The reduction is then performed with diisobutyl aluminium hydride. The intermediate n-benzyl protected spiropiperidine is treated with hydrogen and palladium on charcoal. After stirring in a hydrogen atmosphere at room temperature (CF 3 ) 2 C 6 H 3 COCl is added to give a compound of formula I- 10. Examples 129 and 130 are described in accordance with scheme 14. Scheme 15 The definition of substituents is described above. To a solution of l-benzyl-piperidin-4-one (XI- 1) in acetic acid is added a compound of formula (R 2 ) n >-C 6 H 4 -Z-NH 2 , for example o-toluidine, and TMSCN. The solution of the obtained intermediate amino nitrile is dissolved in acetic acid PtO 2 , and the reaction mixture is hydrogenated at room temperature. To the solution of the obtained intermediate in dichloromethane and triethylamine is added trichloromethyl chloroformat at about -20°C. The obtained intermediate N-benzyl protected spiropiperidine is treated with hydrogen and palladium on charcoal. After stirring in a hydrogen atmosphere at room temperature (CF 3 ) 2 C6H 3 COCl is added to give a compound of formula 1-11. Example 131 is prepared in accordance with scheme 15. Scheme 16 The definition of substituents is described above. To a solution sodium ethoxide is added benzyl cyanide and N-benzyl-4-piperidone (XI- 1) and the reaction is run at 85 °C for 3 h. Workup with concentrated hydrochloric gives the intermediate (l-benzyl-piperidin-4-ylidene)-phenyl-acetonitrile which is treated with potassium cyanide. The obtained intermediate N-benzyl protected spiropiperidine is treated with hydrogen and palladium on charcoal. After stirring in a hydrogen atmosphere at room temperature (CF 3 ) 2 C 6 H 3 COCl is added to give a compound of formula 1-12. Example 156 is prepared in accordance with scheme 16. Scheme 17 6) (CF 3 ) 2 C 6 H 3 COCI, Et 3 N, CH 2 CI 2 1-13 The definition of substituents is described above. To a solution sodium ethoxide is added benzyl cyanide and N-benzyl-4-piperidone (XI-1) and the reaction is run at 85 °C for 3 h. Workup with concentrated hydrochloric gives the intermediate (l-benzyl-piperidin-4-yl-idene)-phenyl-acetonitrile which is treated with potassium cyanide. Reduction of one carbonyl group is performed with an excess of diisobutylaluminium hydride and elimination is performed with acetic acid. The obtained intermediate N-benzyl protected spiropiperidine is treated with hydrogen and palladium on charcoal. After stirring in a hydrogen atmosphere at room temperature (CF 3 ) 2 C 6 H 3 COCl is added to give a compound of formula 1-13. Example 161 is prepared in accordance with scheme 17. As mentioned earlier, the compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. It has been found that the compounds of the present invention are antagonists of the Neurokinin 1 (NK-1, substance P) receptor. The compounds were investigated in accordance with the tests given hereinafter. The affinity of test compounds for the NKi receptor was evaluated at human Ki receptors in CHO cells infected with the human NKi receptor (using the Semliki virus expression system) and radiolabelled with [ 3 H] substance P (final concentration 0.6 nM). Binding assays were performed in HEPES buffer (50 mM, pH 7.4) containing BSA (0.04 %) leupeptin (8 μg / ml), MnCl (3mM) and phosphoramidon (2 μM). Binding assays consisted of 250 μl of membrane suspension (1.25xl0 5 cells / assay tube), 0.125 μl of buffer of displacing agent and 125 μl of [ 3 H] substance P. Displacement curves were determined With at least seven concentrations of the compound. The assay tubes were incubated for 60 min at room temperature after which time the tube contents were rapidly filtered under vacuum through GF/C filters presoaked for 60 min with PEI (0.3%) with 2 x 2 ml washes of HEPES buffer (50 mM, pH 7.4). The radioactivity retained on the filters was measured by scintillation counting. All assays were performed in triplicate in at least 2 separate experiments. The affinity to the NK-1 receptor, given as pKi, is in the range of 6.5-8.8 for the exemplified compounds. Examples of such compounds are The compounds of formula I as well as their pharmaceutically usable acid addition salts can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions. The compounds of formula I and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc can be used as such excipients e.g. for tablets, dragees and hard gelatine capsules. Suitable excipients for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semi- solid and liquid polyols etc. Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc. Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc. Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc. Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances. The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 10 to 1000 mg per person of a compound of general formula I should be appropriate, although the above upper limit can also be exceeded when necessary. The following Examples illustrate the present invention without Umiting it. All temperatures are given in degrees Celsius. Example 1 8- (3,5-Bis-trifluoromethyl-benzoyl)- 1 -phenyl- 1 ,3,8-triaza-spiro [4.5] decan-4-one A solution of 3,5-bis(trifluoromethyl)benzoyl chloride (2.3 mL, 13 mmol) in dichloromethane (50 mL) was added with stirring to a mixture of 1 -phenyl- 1,3,8-triaza- spiro[4.5]decan-4-one (2.9 g, 13mmol) and triethylamine (3.5 mL, 25 mmol) in dichloromethane (250 mL) at room temperature. Stirring was continued for 2 h. Water (150 mL) was added, the phases were separated and the water phase was extracted twice with dichloromethane (100 mL). Organic phases were pooled, washed with brine (200 mL), dried with Na 2 SO and the solvent was evaporated. Chromatography on silica gel (ethylacetate/n-hexane 1:1) yielded the desired product (5.3 g, 89 %) m.p. 251 °C and MS: m/e = 472.1 (M+H + ). Example 2 l-Phenyl-8- (3,4,5-trimethoxy-benzoyl)- 1 ,3,8-triaza-spiro [4.5] decan-4-one The title compound, MS: m/e = 426.4 (M+H + ), was prepared in accordance with the general method of example 1 from 3,4,5-trimethoxybenzoyl chloride and l-phenyl-1,3,8- triaza-spiro[4.5] decan-4-one. Example 3 8-(3-Fluoro-5-trifluoromethyl-benzoyl)- 1-phenyl- 1 ,3,8-triaza-spiro [4.5] decan-4-one The title compound, MS: m/e = 422.3 (M+H + ), was prepared in accordance with the general method of example 1 from 3-fluoro-5-(trifluoromethyl)benzoyl chloride and 1- phenyI-l,3,8-triaza-spiro[4.5]decan-4-one. Example 4 8-(3,5-Bis- fluoromethyl-benzoyl)-3-(2-morpholin-4-yl-ethyl)-l-phenyl-l,3,8-triaza- spiro [4.5] decan-4-one Sodium hydride (34 mg, 60 %) was suspended in N-methyl-2-pyrrolidone (2 mL) and 8- (3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8-triaza-spiro[4.5]decan-4-one (200 mg) was added with stirring. After 5 minutes stirring at room temperature 4- (2- chlorethyl)morpholine hydrochloride (79 mg) was added. The mixture was heated to 100 °C with stirring and kept for 1 h at that temperature. After cooling, saturated sodium bicarbonate solution was added and the mixture was extracted with ethylacetate. Organic phases were pooled, dried with Na 2 SO and the solvent was evaporated. Chromatography on silica gel (ethylacetate) yielded the desired product (180 mg, 73%), MS: m/e = 585.1 (M+H + ). Example 5 8-(3,5-Bis-trifluoromethyl-benzoyl)-l-phenyl-3-ρyridin-3-yl-methyl-l,3,8-triaza- spiro [4.5] decan-4-one The title compound, MS: m/e = 563.3 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza-spiro[4.5]decan-4-one and 3-(chloromethyl)pyridine hydrochloride in 1,2- dimethoxyethane as solvent. Example 6 8-(3,5-Bis-trifluoromethyl-benzoyl)-3-(4,6-dimethoxy-[l,3,5]triazin-2-yl)-l-phenyl-l,3,8- triaza-spiro[4.5]decan-4-one The title compound, MS: m/e = 611.0 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza-spiro[4.5]decan-4-one and 2-chloro-4,6-dimethoxy-l,3,5-triazine in 1,2- dimethoxyethane as solvent. Example 7 8-(3,5-Bis-trifluorome1-hyl-benzoyl)-l-phenyl-3-(2-piperidin-l-yl-efhyl)-l ) 3,8-triaza- spiro [4.5] decan-4-one The title compound, MS: m/e = 583.2 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza-spiro[4.5]decan-4-one and l-(2-chloroethyl)piperidine hydrochloride. Example 8 8-(3,5-Bis-trifluoromethyl-benzoyl)-l-phenyl-3-(2-pyrroKdm-l-yl-efhyl)-l,3,8-triaza- spiro [4.5] decan-4-one The title compound, MS: m/e = 569.2 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza-spiro[4.5]decan-4-one and l-(2-chloroethyl)ρyrrolidine hydrochloride. Example 9 2- [8-(3,5-Bis-trifluoromefhyl-benzoyl)-4-oxo- 1-phenyl- 1 ,3,8-triaza-spiro [4.5] dec-3-yl] - acetamide The title compound, MS: m/e = 529.2 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza-spiro[4.5]decan-4-one and 2-bromoacetamide in 1,2-dimethoxyethane as solvent. Example 10 2- [8- (3,5-Bis-trifluoromethyl-benzoyl)-4-oxo- 1-phenyl- 1 ,3,8-triaza-spiro [4.5] dec-3-yl] - N,N-dimethyl~acetamide The title compound, MS: m/e = 557.2 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl~benzoyI)-l-phenyl-l,3,8- triaza-spiro[4.5]decan-4-one and 2-chlor-N,N-dimefhyacetamide in 1,2-dimethoxyethane as solvent. Example 11 [8-(3,5-Bis-trifluoromethyl-benzoyl)-4-oxo-l-phenyl-l,3,8-triaza-spiro[4.5]dec-3-yl]- acetic acid methyl ester The title compound, MS: m/e = 544.2 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza-spiro[4.5]decan-4-one and methyl bromoacetate in 1,2-dimethoxyethane as solvent. Example 12 8-(3,5-Bis-1 ifluorome yl-benzoyl)-3-methoxymethyl-l-phenyl-l,3,8-triaza- spiro [4.5] decan-4-one The title compound, MS: m/e = 516.2 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza-spiro [4.5] decan-4-one and bromomethyl methylether in 1,2-dimethoxyethane as solvent. Example 13 2- [8- (3,5-Bis-trifluoromethyl-benzoyl)-4-oxo- 1-phenyl- 1 ,3,8-triaza-spiro [4.5] dec-3-yI]- malonic acid dimethyl ester The title compound, MS: m/e = 602.0 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza- spiro [4.5] decan-4-one and dimethyl bromomalonate in 1,2-dimefhoxyethane as solvent. Example 14 (R,S)-8-(3,5-Bis-trifluoromethyl-benzoyl)-3-(2-hydroxy-3-phenoxy-propyl)-l-phenyl- l,3,8-triaza-spiro[4.5]decan-4-one The title compound, MS: m/e = 622.1 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromefhyl-benzoyl)-l-phenyl- 1,3,8- triaza-spiro [4.5] decan-4-one and phenylglycidylether in 1,2-dimethoxyethane as solvent. Example 15 8-(3,5-Bis-trifluorometJ yl-benzoyl)-3-(4,6-d cUoro-pyrimidin-2-yl)-l-phenyl-l,3,8- triaza-spiro [4.5] decan-4-one The title compound, MS: m/e = 618.0 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza-spiro[4.5]decan-4-one and 2,4,6-trichlorpyrimidine in 1,2-dimethoxyethane as solvent. Example 16 8-(3,5-Bis-trifluoromethyl-benzoyl)-l-phenyl-3-(5-trifluorometiιyl-pyridin-2-yl)-l,3,8- triaza-spiro [4.5] decan-4-one The title compound, MS: m/e = 617.1 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza-spiro[4.5]decan-4-one and 2-chloro-5-(trifluoromefhyl)pyridine in 1,2- dimethoxyethane as solvent. Example 17 (R,S)-8-(3,5-Bis-trifluoromethyl-benzoyl)-l-phenyl-3-(3,3,3-trifluoro-2-hydroxy-ρropyl)- 1,3,8-triaza-spiro [4.5]decan-4-one The title compound, MS: m/e = 584.0 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza-spiro[4.5]decan-4-one and 3-bromo-l,l,l-trifluoro-2-propanole. Example 18 8-(3,5-Bis-tjrifluoromethyl-benzoyl)-l-phenyl-3-pyridin-2-yl-methyl-l,3,8-triaza- spiro [4.5] decan-4-one The title compound, MS: m/e = 563.3 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza-spiro[4.5]decan-4-one and 2-picolylchloride hydrochloride in 1,2-dimethoxyethane as solvent. Example 19 8-(3,5-Bis-trifluoromethyl-benzoyl)-l-phenyl-3-pyridin-4-yl-methyl-l,3,8-triaza- spiro [4.5] decan-4-one The title compound, MS: m/e = 563.3 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza-spiro[4.5]decan-4-one and 4-chloromethylpyridine hydrochloride in 1,2- dimethoxyethane as solvent. Example 20 8-(3,5-Bis-trifluorome yl-benzoyl)-3-(4-cMoro-pyrimidin-2-yl)-l-phenyl-l,3,8-triaza- spiro [4.5] decan-4-one The title compound, MS: m/e = 584.1 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza-spiro [4.5] decan-4-one and 2,4-dichloropyrimidine in 1,2-dimethoxyethane as solvent. Example 21 8- ( 3 ,5-Bis-trifluoromethyl-benzoyl) -3- (4-cUoro-6-methyl-pyrimidin-2-yl)- 1 -phenyl- 1 ,3,8-triaza-spiro [4.5] decan-4-one The title compound, MS: m/e = 598.0 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza-spiro[4.5]decan-4-one and 2,4-dichloro-6-methylpyrimidinein 1,2- dimethoxyethane as solvent. Example 22 8-(3,5-Bis-trifluoromet yl-benzoyl)-3-(3-hydroxy-propyl)-l-phenyl-l,3,8-triaza- spiro [4.5] decan-4-one The title compound, MS: m/e = 530.2 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza-spiro[4.5]decan-4-one and (3-bromopropoxy)-tert.-butyldimethylsilane in 1,2- dimethoxyethane as solvent. HCl in ethanol (3% cone.) cleaved the intermediate TBDMS- ether. Example 23 8-(3,5-Bis-trifluoromethyl-benzoyl)-3-(2-hydroxy-ethyl)-l-o-tolyl-l,3,8-triaza- spiro [4.5] decan-4-one The title compound, MS: m/e = 530.2 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-tolyl-l,3,8- triaza-spiro[4.5]decan-4-one and (3-bromoethoxy)-tert.-butyldimethylsilane. HCl in ethanol (3% cone.) cleaved the intermediate TBDMS-ether. Example 24 8-(3,5-Bis-txifluoromethyl-benzoyl)-3-(2-hydroxy-ethyl)-l-phenyl-l,3,8-triaza- spiro [4.5 ] decan-4-one The title compound, MS: m/e = 516.2 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza-spiro[4.5]decan-4-one and 2-chloroethoxytrimethylsilane in 1,2-dimethoxyethane as solvent. Silicagel chromatography cleaved the intermediate TMS-efher. Example 25 8- (3,5-Bis-txifluoromethyl-benzoyl)- l-phenyl-3-pyrimidin-2-yl- 1 ,3,8-triaza- spiro [4.5] decan-4-one The title compound, MS: m/e = 550.1 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza-spiro[4.5]decan-4-one and 2-chloropyrimidine. Example 26 8-(3,5-Bis-tτifluoromet yl-benzoyl)-3-(3,5-dicMoro-pyridin-2-yl)-l-phenyl-l,3,8-triaza- spiro [4.5] decan-4-one The title compound, MS: m/e = 617.0 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza-spiro[4.5]decan-4-one and 2,3,5-trichloropyridine in 1,2-dimethoxyethane as solvent. Example 27 2-[8-(3,5-Bis-trifluoromethyl-benzoyl)-4-oxp-l-phenyl-l,3,8-triaza-spiro[4.5]dec-3-yl]-6- methyl-nicotinonitrile The title compound, MS: m/e = 588.2 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza-spiro[4.5]decan-4-one and 2-chloro-3-cyanopyridine in 1,2-dimethoxyethane as solvent. Example 28 8-(3,5-Bis-1xifluoromemyl-benzoyl)-3-(3-cHoro-5-trifluoromethyl-pyridin-2-yl)-l- phenyl- 1 ,3,8-triaza-spiro [4.5 ] decan-4-one The title compound, MS: m/e = 651.0 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyI-benzoyl)-l-phenyl-l,3,8- triaza-spiro[4.5]decan-4-one and 2,3-dichloro-5-(trifluoromefhyl)pyridine in 1,2- dimethoxyethane as solvent. Example 29 8- (3 ,5-Bis-trifluoromethyl-benzoyl) -3- ( 5-ethyl-pyrimidin-2-yι)- 1 -phenyl- 1 ,3,8-triaza- spiro [4.5] decan-4-one The title compound, MS: m/e = 578.0 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza-spiro[4.5]decan-4-one and 2-chloro-5-ethylpyrimidine in 1,2-dimethoxyethane as solvent. Example 30 8- (3,5-Bis-trifluoromefhyl-benzoyl)- l-phenyl-3- (4-trifluorometuyl-pyrimidin-2-yl)- 1,3,8- triaza-spiro [4.5] decan-4-one The title compound, MS: m/e = 618.1 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza-spiro[4.5]decan-4-one and 2-chloro-4-(trifluoromefhyl)pyrimidine in 1,2- dimethoxyethane as solvent. Example 31 8-(3,5-Bis-1xifluoromethyl-benzoyl)-3-(3-chloro-pyrazin-2-yl)-l-phenyl-l,3,8-triaza- spiro [4.5] decan-4-one The title compound, MS: m/e = 584.1 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza-spiro[4.5]decan-4-one and 2,3-dichloropyrazine in 1,2-dimefhoxyethane as solvent. Example 32 [8-(3,5-Bis-trifluoromethyl-benzoyl)-4-oxo-l-phenyl-l,3,8-triaza-spiro[4.5]dec-3-yl]- acetic acid ethyl ester The title compound, MS: m/e = 558.2 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza-spiro[4.5]decan-4-one and ethyl bromoacetate in 1,2-dimethoxyethane as solvent. Example 33 8-(3,5-Bis-trifluoromethyl-benzoyl)-3-(3-chloro-quinoxalin-2-yl)-l-phenyl-l,3,8-triaza- spiro [4.5] decan-4-one The title compound, MS: m/e = 634.0 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza-spiro [4.5] decan-4-one and 2,3-dichloroquinoxaline in 1,2-dimefhoxyethane as solvent. Example 34 8-(3,5-Bis-trifluoromethyl-benzoyl)-3-(6-chloro-pyrazin-2-yl)-l-phenyl-l,3,8-triaza- spiro[4.5] decan-4-one The title compound, MS: m/e = 584.1 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl- 1,3,8- triaza-spiro[4.5]decan-4-one and 2,6-dichloropyrazine in 1,2-dimethoxyethane as solvent. Example 35 8-(3,5-Bis-trifluoromethyl-benzoyl)-l-phenyl-3-pyrazin-2-yl-l,3,8-triaza- spiro [4.5] decan-4-one The title compound, MS: m/e = 550.1 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza-spiro[4.5]decan-4-one and 2-chloropyrazine in 1,2-dimefhoxyethane as solvent. Example 36 [8-(3,5-Bis-trifluoromethyl-benzoyl)-4-oxo-l-phenyl-l,3,8-triaza-spiro[4.5]dec-3-yl]- acetonitrile The title compound, MS: m/e = 510.1 (M + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8-triaza- spiro [4.5] decan-4-one and bromoacetonitrile in 1,2-dimethoxyethane as solvent. Example 37 8-(3,5-Bis-trifluoromethyl-benzoyl)-3-(4,6-ώ^ethoxy-pyrimidin-2-yl)-l-phenyl-l,3,8- triaza-spiro [4.5] decan-4-one The title compound, MS: m/e = 610.0 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza-spiro[4.5]decan-4-one and 2-chloro-4,6-dimethoxypyrimidine. Example 38 (S)-8-(3,5-Bis-trifluoromethyl-benzoyl)-l-phenyl-3-(4,4,4-trifluoro-3-hydroxy-butyl)- 1 ,3,8-triaza-spiro [4.5] decan-4-one The title compound, MS: m/e = 598.0 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza-spiro[4.5]decan-4-one and toluene-4-sulfonic acid (S)-4,4,4-trifluoro-3-hydroxy- butyl ester in 1,2-dimethoxyefhane as solvent. Example 39 8- (3,5-Bis-trifluoromethyl-benzoyl)- 1- (3,4-dichloro-phenyl)-3- (4,6-dimethoxy- [ 1 ,3,5] triazin-2-yl)- 1 ,3,8-triaza-spiro [4.5] decan-4-one The title compound, MS: m/e = 679.0 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-(3,4-dichloro- phenyl)-l,3,8-triaza-spiro[4.5]decan-4-one and 2-chloro-4,6-dimethoxy-l,3,5-triazine in 1,2-dimethoxyethane as solvent. Example 40 8-(3,5-Bis-tτifluoromethyl-benzoyl)-l-(3-cUoro-phenyl)-3-(4,6-dimethoxy-[l,3,5]triazin- 2-yl)-l,3,8-triaza-spiro[4.5]decan-4-one The title compound, MS: m/e = 645.1 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-(3-chloro- phenyl)-l,3,8-triaza-spiro[4.5]decan-4-one and 2-chloro-4,6-dimethoxy-l,3,5-triazine in 1,2-dimethoxyethane as solvent. Example 41 8- (3,5-Bis-trifluoromethyl-benzoyl)-3- (4,6-dimethoxy- [ 1 ,3,5] triazin-2-yl)-l-o-tolyl- 1 ,3,8- triaza-spiro [4.5] decan-4-one The title compound, MS: m/e = 625.1 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-tolyl-l,3,8- triaza-spiro [4.5] decan-4-one and 2-chloro-4,6-dimethoxy-l,3,5-triazine in 1,2- dimethoxyethane as solvent. Example 42 8-(3,5-Bis-1xifluoromemyl-benzoyl)-l-(2-cUoro-ρhenyl)-3-(4,6-dimethoxy-[l,3,5]triazin- 2-yl)- 1 ,3,8-triaza-spiro [4.5] decan-4-one The title compound, MS: m/e = 645.0 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-(2-chloro- phenyl)-l,3,8-triaza-spiro[4.5]decan-4-one and 2-chloro-4,6-dimethoxy-l,3,5-triazine in 1,2-dimethoxyethane as solvent. Example 43 8-(3,5-Bis-trifluoromemyl-benzoyl)-l-(4-cUoro-ρhenyl)-3-(4,6-dimeώoxy-[l,3,5]txiazin- 2-yl)- 1 ,3,8-triaza-spiro [4.5] decan-4-one The title compound, MS: m/e = 645.1 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-(4-chloro- phenyl)-l,3,8-triaza-spiro[4.5]decan-4-one and 2-chloro-4,6-dimethoxy-l,3,5-triazine in 1,2-dimethoxyefhane as solvent. Example 44 8- (3,5-Bis-trifluoromethyl-benzoyl)- 1- (2-chloro-phenyl)-3-pyridin-3-yl-methyl- 1 ,3,8- triaza-spiro [4.5] decan-4-one The title compound, MS: m/e = 597.0 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-(2-chloro- phenyl)-l,3,8-triaza-spiro[4.5]decan-4-one and 3-(chloromethyl)pyridine hydrochloride in 1,2-dimethoxyethane as solvent. Example 45 8- (3,5-Bis-trifluorome1hyl-benzoyl)-3-pyridin-3-yl-methyl- 1-o-tolyl- 1,3,8-triaza- spiro [4.5] decan-4-one The title compound, MS: m/e = 577.0 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-tolyl-l,3,8- triaza-spiro[4.5]decan-4-one and 3-(chloromethyl)pyridine hydrochloride in 1,2- dimethoxyethane as solvent. Example 46 8-(3,5-Bis-trifluorome yl-benzoyl)-l-(2-methoxy-phenyl)-3-pyridm-3-yl-methyl-l,3,8- triaza-spiro [4.5] decan-4-one The title compound, MS: m/e = 592.1 (M + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-(2-methoxy-phenyl)- 1, 3,8-triaza -spiro [4.5] decan-4-one and 3-(chloromethyl)pyridine hydrochloride in 1,2- dimethoxyethane as solvent. Example 47 8- (3,5-Bis-trifluoromefhyl-benzoyl)-3- (4,6-dimethoxy- [ 1 ,3,5] triazin-2-yl)- 1- (2-methoxy- phenyl)- 1 ,3,8-triaza-spiro [4.5] decan-4-one The title compound, MS: m/e = 640.2 (M + ), was prepared in accordance with the general method of example 4 from 8- (3,5-bis-trifluoromethyl -benzoyl) - 1 - (2-methoxy-phenyl) - l,3,8-triaza-spiro[4.5]decan-4-one and 2-chloro-4,6-dimethoxy-l,3,5-triazine in 1,2- dimethoxyethane as solvent. Example 48 8-(3,5-Bis-trifluoromethyl-benzoyl)-3-(3-imidazol-l-yl-propyl)-l-phenyl-l,3,8-triaza- spiro [4.5] decan-4-one A solution of 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(3-hydroxy-propyl)-l-phenyl-l,3,8- triaza-spiro[4.5]decan-4-one (128 mg, 0.25 mmol) and triethylamine (35 μL, 0.27 mmol) in dichloromethane (2 mL) was cooled to 0 °C. A solution of methanesulfonyl chloride (19 μL, 0.25 mmol) in dichloromethane (0.5 mL) was added and the mixture was stirred for 4h at 0 °C. Sodium bicarbonate (saturated solution, 2.5 mL) was added, the phases were separated, the organic phase was dried with Na 2 SO and the solvent was evaporated. Chromatography on silica gel (efhylacetate/n-hexane 1:1) yielded the intermediate mesylate. The mesylate was dissolved in dimethylformamide (6 mL), sodium bicarbonate (70 mg, 0.74 mmol) and imidazole (26 mg, 0.37 mmol) was added and the mixture stirred for 2 d at 80 °C. Filtration and evaporation of the solvent yielded a residue which was purified by chromatography on silica gel (CH 2 Cl 2 /MeOH 9:1) to yield the desired product (23 mg, 16 %), MS: m/e = 580.1 (M+H + ). Example 49 8-(3,5-Bis-tτifluoromethyl-benzoyl)-3-(3-isopropylamino-propyl)-l-phenyl-l,3,8-triaza- spiro [4.5] decan-4-one The title compound, MS: m/e = 571.1 (M+H + ), was prepared in accordance with the general method of example 48 from 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(3-hydroxy- propyl)-l-phenyl-l,3,8-triaza-spiro[4.5]decan-4-one and isopropylamine. Example 50 8- (3,5-Bis-trifluoromethyl-benzoyl)-3- [3- (4-methyl-piperazin- l-yl)-propyl] - 1-phenyl- l,3,8-triaza-spiro[4.5]decan-4-one The title compound, MS: m/e = 612.2 (M+H + ), was prepared in accordance with the general method of example 48 from 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(3-hydroxy- propyl)-l-phenyl-l,3,8-triaza-spiro[4.5]decan-4-one and 1-methylpiperazine. Example 51 8-(3,5-Bis-txifluoromemyl-benzoyl)-3-(3-dimemylarn o-propyl)-l-phenyl-l,3,8-triaza- spiro [4.5 ] decan-4-one The title compound, MS: m/e = 557.2 (M+H + ), was prepared in accordance with the general method of example 48 from 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(3-hydroxy- propyl) - 1 -phenyl- 1 ,3,8-triaza-spiro [4.5 ] decan-4-one and dimethylamine. Example 52 8- (3,5-Bis-trifluoromethyl-benzoyl)-3- (2-imidazol- 1-yl-ethyl)- 1-phenyl- 1,3,8- triaza- spiro [4.5 ] decan-4-one The title compound, MS: m/e = 566.2 (M+H + ), was prepared in accordance with the general method of example 49 from 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-hydroxy- ethyl)-l-phenyl-l,3,8-triaza-spiro[4.5]decan-4-one and imidazole. Example 53 8-(3,5-Bis-trifluoromemyl-benzoyl)-3-(2-isopropylamino-ethyl)-l-phenyl-l,3,8-triaza- spiro [4.5] decan-4-one The title compound, MS: m/e = 557.2 (M+H + ), was prepared in accordance with the general method of example 48 from 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-hydroxy- ethyl)-l-phenyl-l,3,8-triaza-spiro[4.5]decan-4-one and isopropylamine. Example 54 8-(3,5-Bis-trifluorome1iιyl-benzoyl)-3-[2-(4-methyl-piperazin-l-yl)-ethyl]-l-phenyl- 1 ,3,8-triaza-spiro [4.5] decan-4-one The title compound, MS: m/e = 598.1 (M+H + ), was prepared in accordance with the general method of example 48 from 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-hydroxy- ethyl) - 1 -phenyl- 1,3,8-triaza-spiro [4.5] decan-4-one and 1 -methylpiperazine. Example 55 8-(3,5-Bis-txifluoromethyl-benzoyl)-3-(2-dimethylamino-ethyl)-l-phenyl-l,3,8- triaza- spiro [4.5 ] decan-4-one The title compound, MS: m/e = 543.2 (M+H + ), was prepared in accordance with the general method of example 48 from 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-hydroxy- ethyl)-l-phenyl-l,3,8-triaza-spiro[4.5]decan-4-one and dimethylamine. Example 56 8- (3,5-Bis-trifluoromethyl-benzoyl)-3- (2-dimethylamino-ethyl)- 1-o-tolyl- 1 ,3,8-triaza- spiro [4.5] decan-4-one The title compound, MS: m/e = 557.2 (M+H + ), was prepared in accordance with the general method of example 48 from 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-hydroxy- ethyl)-l-o-tolyl-l,3,8-triaza-spiro[4.5] decan-4-one and dimethylamine. Example 57 8-(3,5-Bis-trifluoromemyl-benzoyl)-3-(2-isopropylammo-ethyl)-l-o-tolyl-l,3,8-triaza- spiro [4.5 ]decan-4-one The title compound, MS: m/e = 571.1 (M+H + ), was prepared in accordance with the general method of example 48 from 8-(3,5-bis-trifluoromefhyl-benzoyl)-3-(2-hydroxy- ethyl)-l-o-tolyl-l,3,8-triaza-spiro[4.5] decan-4-one and isopropylamine. Example 58 8- (3,5-Bis-trifluoromethyl-benzoyl)-3- (2-pyrrolidin- 1-yl-ethyl)- 1-o-tolyl- 1 ,3,8-triaza- spiro [4.5] decan-4-one The title compound, MS: m/e = 583.2 (M+H + ), was prepared in accordance with the general method of example 48 from 8-(3,5-bis-trifluoromefhyl-benzoyl)-3-(2-hydroxy- ethyl)-l-o-tolyl-l,3,8-triaza-spiro[4.5]decan-4-one and pyrrolidine. Example 59 3-[8-(3,5-Bis-trifluorome yl-benzoyl)-4-oxo-l-phenyl-l,3,8-triaza-spiro[4.5]dec-3-yl]- propionic acid ethyl ester To a mixture of 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8-triaza- spiro[4.5]decan-4-one (1.0 g, 2.1 mmol), cesium fluoride (32 mg, 0.21 mmol) and tetraethoxysilane (475 μL, 2.1 mmol) in THF (10 mL) was added ethyl acrylate (254 μL, 2.3 mmol). The mixture was stirred for 1 d at room temperature. Evaporation of the solvent yielded a residue which was purified by chromatography on silica gel (ethyl acetate/n- hexane 1:2) to yield the desired product (0.9 g, 75 %), MS: m/e = 572.1 (M+H + ). Example 60 3- [ 8- (3,5-Bis-trifluoromethyl-benzoyl)-4-oxo- 1 -phenyl- 1,3,8-triaza-spiro [4.5] dec-3-yl] - propionic acid methyl ester The title compound, MS: m/e = 558.2 (M+H + ), was prepared in accordance with the general method of example 59 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza-spiro [4.5] decan-4-one and methyl acrylate. Example 61 8-(3,5-Bis-trifluoromethyl-benzoyl)-3-(6-cUoro-pyrimidin-4-yl)-l-phenyl-l,3,8-triaza- spiro [4.5] decan-4-one A mixture of 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8-triaza-spiro[4.5]decan-4- one (0.1 g, 0.21 mmol), potassium carbonate (59 mg, 0.42 mmol), CuCl (2 mg, 0.021 mmol), tris[2-(2-methoxyethoxy)-ethyl]-amine (1.5 μL) and 4,6-dichloropyrimidine (32 mg, 0.21 mmol) in xylene (5 mL) was stirred and boiled for 18 h. The mixture was cooled, washed with water, ammonia in water ( 10 %) and water again. Evaporation of the solvent yielded a residue which was purified by chromatography on silica gel (ethyl acetate/n- hexane 1:2) to yield the desired product (29 mg, 24 %), m.p. 212-214 °C and MS: m/e = 584.1 (M+H + ). Example 62 8-(3,5-Bis-trifluoromeώyl-benzoyl)-l-phenyl-3-pyridin-4-yl-l,3,8-triaza- spiro [4.5] decan-4-one A mixture of 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8-triaza-spiro[4.5]decan-4- one (0.1 g, 0.21 mmol), 4-pyridylboronic acid (52 mg, 0.42 mmol), cupric acetate (58 mg, 0.32 mmol) and triethylamine (60 μL, 0.42 mmol) in dichloromethane (2 mL) was stirred for 2 d at room temperature. Chromatography on silica gel (ethyl acetate) yielded the desired product (26 mg, 21 %), MS: m/e = 549.1 (M+H + ). Example 63 8- (3,5-Bis-trifluoromethyl-benzoyl)- 1- (3-chloro-phenyl)- 1 ,3,8-triaza-spiro [4.5] decan-4- one To a solution of l-(3,5-bis-trifluoromethyl-benzoyl)-4-(3-chloro-phenylamino)- piperidine-4-carbonitrile (6.2 g, 13 mmol) in formic acid (80 mL) was added with cooling acetic anhydride (80 mL). Stirring continued for 2 h at room temperature. Evaporation of the solvent yielded 7.2 g white foam, which was used without further purification in the next step. The solid was dissolved in formic acid (74 L) and acetic acid was added (7.4 mL). The solution was stirred at room temperature over night. The solvents were evaporated, saturated sodium bicarbonate solution (150 mL) was added and the mixture was extracted with ethylacetate. The organic phases were pooled, dried with Na 2 SO and the solvent was evaporated. The residue was a white foam (7.5 g), which was used without further purification in the next step. The solid was dissolved in triethyl orthoformate (320 mL) and boiled for a week. After cooling the solvent was evaporated to yield 8.5 g brownish foam which was used without further purification in the next step. The solid was dissolved in methanol (300 mL), sodium borohydride (1.03 g, 27 mmol) was added to the solution and the mixture was stirred for 1 h at room temperature and for 1 h at 60 °C. After cooling the solvent was evaporated, the residue was dissolved in dichloromethane (250 mL) and washed with ice cold ammonia (12%). The phases were separated, the water phase was extracted with dichloromethane, and organic phases were pooled and dried with MgSO . Evaporation yielded 8.1 g light brown residue. Chromatography on silica gel (dichloromethane/methanol 50:1) yielded the desired product (2.7 g, 41 %), m.p. 235-236 °C and MS: m/e = 506.2 (M+H + ). Example 64 8-(3,5-Bis-txifluoromethyl-benzoyl)-l-(4-chloro-ρhenyl)-l,3,8-triaza-spiro[4.5]decan-4- one The title compound, m.p. 233-235 °C and MS: m/e = 506.2 (M+H + ), was prepared in accordance with the general method of example 63 from 1 -(3,5-bis-μifluoromethyl- benzoyl)-4-(4-chloro-phenylamino)-piperidine-4-carbonitrile. Example 65 8- (3,5-Bis-tτifluoromethyl-benzoyl)- 1- (3,4-dichloro-phenyl)- 1,3,8-triaza-spiro [4.5] decan- 4-one The title compound, m.p. 220-222 °C and MS: m/e = 540.1 (M+H + ), was prepared in accordance with the general method of example 63 from l-(3,5-bis-trifluoromethyl- benzoyl)-4-(3,4-dichloro-phenylamino)-piperidine-4-carbonitrile. Example 66 8-(3,5-Bis-trifluoromethyl-benzoyl)-l-o-tolyl-l,3,8-triaza-spiro[4.5]decan-4-one The title compound, m.p. 164-168 °C and MS: m/e = 486.3 (M+H + ), was prepared in accordance with the general method of example 63 from l-(3,5-bis-trifluoromethyl- benzoyl)-4-o-tolylamino-piperidine-4-carbonitrile. Example 67 8- (3,5-Bis-trifluoromethyl-benzoyl)- 1- (2-chloro-phenyl)- 1,3,8-triaza-spiro [4.5] decan-4- one The tide compound, m.p. 157-159 °C and MS: m/e = 506.2 (M+H + ), was prepared in accordance with the general method of example 63 from l-(3,5-bis-trifluoromethyl- benzoyl)-4-(2-chloro-phenylamino)-piperidine-4-carbonitrile. Example 68 8-(3,5-Bis-trifluoromethyl-benzoyl)-l-(2-methoxy-phenyl)-l,3,8-triaza-spiro[4.5]decan- 4-one The title compound, MS: m/e = 502.2 (M+H + ), was prepared in accordance with the general method of example 63 from l-(3,5-bis-trifluoromethyl-benzoyl)-4-(2-methoxy- phenylamino)-piperidine-4-carbonitrile. Example 69 8-(3,5-Bis-trifluoromethyl-benzoyl)-3-(4,5-dihydro-lH-imidazol-2-yl-methyl)-l-phenyl- l,3,8-triaza-spiro[4.5]decan-4-one Ethylenediamine-trimethylaluminium complex (0.8 mmol) was added to a solution of [8- (3,5-bis-trifluoromethyl-benzoyl)-4-oxo-l-phenyl-l,3,8-triaza-spiro[4.5]dec-3-yl]- acetonitrile (0.2 g, 0.4 mmol) in toluene (1.5 mL) and heated tol20 °C for 18 h. Chromatography on silica gel (dichloromethane/methanol 9:1) yielded the desired product (14 mg, 6 %), MS: m/e = 554.2 (M+H + ). Example 70 8- (3,5-Bis-trifluoromethyl-benzoyl)- 1- (2-chloro-phenyl)-3-methyl- 1 ,3,8-triaza- spiro [4.5] decan-4-one 8-(3,5-Bis-trifluoromethyl-benzoyl)-l-(2-chloro-phenyl)-l,3,8-triaza-spiro[4.5]decan-4- one (253 mg) was suspended in 1,2-dimethoxyethane (3 mL) and sodium hydride (24 mg, 60 %) was added with stirring at room temperature. After 15 minutes methyliodide (78 mg) was added and stirring was continued overnight at room temperature. Water was added and the mixture was extracted with ethylacetate. Organic phases were pooled, dried with Na 2 SO 4 and the solvent was evaporated. Chromatography on silica gel (hexane/ ethylacetate=l:l) yielded the desired product (152 mg, 59%), MS: m/e = 520.1 (M+H + ). Example 71 3-(l-Benzyl-lH-imidazol-2-y]meΛyl)-8-(3,5-bis-trifluoromethyl-benzoyl)-l-(2-chloro- phenyl)- 1 ,3,8-triaza-spiro [4.5] decan-4-one 8- (3,5-Bis-trifluoromethyl-benzoyl) - 1- (2-chloro-phenyl) - 1 ,3,8-triaza-spiro [4.5] decan-4- one (253 mg) was suspended in 1,2-dimethoxyethane (3 mL) and sodium hydride (24 mg, 60 %) was added with stirring at room temperature. After 15 minutes l-benzyl-(2- chloromethyl)-imidazole ( 121 mg) was added and stirring was continued overnight at 80°C. After cooling down to room temperature water was added and the mixture was extracted with ethylacetate. Organic phases were pooled, dried with Na 2 SO 4 and the solvent was evaporated. Chromatography on silica gel (hexane/ ethylacetate=l:l) yielded the desired product (215 mg, 64%), MS: m/e = 676.0 (M+H + ). Example 72 8-(3,5-Bis-txifluoromemyl-benzoyl)-l-(2-chloro-phenyl)-3-(2-oxo-oxazolidin-5- ylmethyl)- 1 ,3,8-triaza-spiro [4.5] decan-4-one The title compound, MS: m/e = 604.9 (M+H + ), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-(2-chloro- phenyl)-l,3,8-triaza-spiro[4.5]decan-4-one and 5-chloromethyl-2-oxazolidinone. Example 73 8-(3,5-Bis-txifluoromethyl-benzoyl)-l-(2-chloro-phenyl)-3-(2-dimethylammo-e1-hyl)- 1 ,3,8-triaza-spiro [4.5] decan-4-one The tide compound, MS: m/e = 577.0 (M+H + ), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-(2-chloro- phenyl)-l,3,8-triaza-spiro[4.5]decan-4-one and l-chloro-2-dimethylaminoethane hydrochloride. Example 74 8-(3,5-Bis-trifluoromethyl-benzoyl)-l-(2-cUoro-phenyl)-3-(2-pyrroHdin-l-yl-efhyl)- 1,3,8- triaza-spiro [4.5] decan-4-one The tide compound, MS: m/e = 603.0 (M+H + ), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-(2-chloro- phenyl)-l,3,8-triaza-spiro[4.5]decan-4-one and l-(2-chloroethyl)-pyrrolidine hydrochloride. Example 75 8-(3,5-Bis-trifluoromemyl-benzoyl)-l-(2-chloro-phenyl)-3-(2-me yl-thiazol-4- ylmethyl)- 1 ,3,8-triaza-spiro [4.5] decan-4-one The title compound, MS: m/e = 617.0 (M+H + ), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-(2-chloro- phenyl)-l,3,8-triaza-spiro[4.5]decan-4-one and 4-chloromethyl-2-methylthiazole hydrochloride. Example 76 8-(3,5-Bis-trifluorome yl-benzoyl)-l-(2-chloro-phenyl)-3-(6-chloro-pyrimidin-4-yl)- 1,3,8-triaza-spiro [4.5] decan-4-one The tide compound, MS: m/e = 618.0 (100, M+H + ), 620.0 (80, M+H + ), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl- benzoyl)- 1 - ( 2-chloro-phenyl) - 1,3,8-triaza-spiro [4.5] decan-4-one and 4,6- dichloropyrimidine. Example 77 8-(3,5-Bis-txifluorome yl-benzoyl)-l-(2-chloro-phenyl)-3-(3,5-dicUoro-pyridin-2-yl)- 1 ,3 ,8-triaza-spiro [4.5 ] decan-4-one The tide compound, MS: m/e = 652.9 (100, M+H + ), 654.9 (100, M+H + ), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl- benzoyl)-l-(2-chloro-phenyl)-l,3,8-triaza-spiro[4.5]decan-4-one and 2,3,5- trichloropyridine. Example 78 8- (3,5-Bis-ttifluoromethyl-benzoyl)- 1- (2-chloro-phenyl)-3- (4-trifluoromethyl-pyrirnidin- 2-yl)- 1 ,3,8-triaza-spiro [4.5] decan-4-one The tide compound, MS: m/e = 651.9 (M+H + ), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-(2-chloro- phenyl)-l,3,8-triaza-spiro[4.5]decan-4-one and 2-chloro-4-(trifluoromefhyl)-pyrimidine. Example 79 8-(3,5-Bis-tτifluoromemyl-benzoyl)-l-(2-cbdoro-ph^ spiro [4.5 ] decan-4-one The tide compound, MS: m/e = 584.0 (M+H + ), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-(2-chloro- phenyl)-l,3,8-triaza-spiro[4.5]decan-4-one and 2-chloro-pyrimidine. Example 80 2- [8- (3,5-Bis-trifluoromethyl-benzoyl)- 1- (2-chloro-phenyl)-4-oxo-l ,3,8-triaza- spiro [4.5] dec-3-yl] -N,N-dimethyl-acetamide The tide compound, MS: m/e = 591.0 (M+H + ), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-(2-chloro- phenyl)-l,3,8-triaza-spiro[4.5]decan-4-one and 2-chloro-N,N-dimethylacetamide. Example 81 8-(3,5-Bis-txifluoromethyl-benzoyl)-l-(2-^ 1 ,3,8-triaza-spiro [4.5] decan-4-one The tide compound, MS: m/e = 591.1 (M+H + ), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromefhyl-benzoyl)-l-(2-chloro- phenyl)-l,3,8-triaza-spiro[4.5]decan-4-one and 3-dimethylaminopropylchloride hydrochloride. Example 82 8- (3,5-Bis-trifluoromethyl-benzoyl)- 1- (2-chloro-phenyl)-3- (3,5-dimethyl-isoxazol-4-yl- methyl)- 1 ,3,8-triaza-spiro [4.5] decan-4-one The title compound, MS: m/e = 615.1 (M+H + ), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-(2-chloro- phenyl)-l,3,8-triaza-spiro[4.5]decan-4-one and 4-(chloromethyl)-3,5-dimethylisoxazole. Example 83 8-(3,5-Bis-trifluoromethyl-benzoyl)-l-(2-chloro-phenyl)-3-pyridin-3-yl-l,3,8-triaza- spiro [4.5] decan-4-one 8-(3,5-Bis-1xifluoromethyl-benzoyl)-l-(2-chloro-phenyl)-l,3,8-triaza-spiro[4.5]decan-4- one (253 mg) was dissolved in dichloromethane (5 mL), 3-pyridineboronic acid (246mg), triethylamine (101 mg) and copper(II)-acetate (136 mg) were added. The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by chromatography on silica gel (hexane/ ethylacetate=2:l) to yield the desired product (120 mg, 41%), MS: m/e = 583.0 (M+H + ). Example 84 8-(3,5-Bis-trifluorome yl-benzoyl)-l-(2-cUoro-phenyl)-3-pyridin-4-yl-l,3,8-triaza- spiro [4.5] decan-4-one The tide compound, MS: m/e = 583.0 (M+H + ), was prepared in accordance with the general method of example 83 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-(2-chloro- phenyl)-l,3,8-triaza-spiro[4.5]decan-4-one and 4-pyridineboronic acid. Example 85 l-Benzyl-8-(3,5-bis-trifluoromethyl-benzoyl)-l,3,8-triaza-spiro[4.5]decan-4-one The tide compound, MS: m/e = 486.3 (M+H + ), was prepared in accordance with the general method of example 63 from 4-benzylamino-l-(3,5-bis-trifluoromethyl-benzoyl)- piperidine-4-carbonitrile. Example 86 l-Benzyl-8-(3,5-bis-trifluoromethyl-benzoyl)-3-methyl-l,3,8-triaza-spiro[4.5]decan-4- one The tide compound, MS: m/e = 500.3 (M+H + ), was prepared in accordance with the general method of example 71 from l-benzyl-8-(3,5-bis-trifluoromethyl-benzoyl)-l,3,8- triaza-spiro[4.5]decan-4-one and methyliodide. Example 87 l-Benzyl-8-(3,5-bis-1xifluoromethyl-benzoyl)-3-(2-pyrroUdin-l-yl-ethyI)-l,3,8- triaza- spiro [4.5] decan-4-one hydrochloride The tide compound, MS: m/e = 583.2 (M+H + ), was prepared in accordance with the general method of example 71 from l-benzyl-8-(3,5-bis-trifluoromethyl-benzoyl)-l,3,8- triaza-spiro[4.5]decan-4-one and l-(2-chloroethyl)-pyrrolidine. Example 88 8-(3,5-Bis-trifluoromethyl-benzoyl)-l-(2-chloro-benzyl)-l,3,8-μiaza-spiro[4.5]decan-4- one l-Benzyl-8-(3,5-bis-trifluoromethyl-benzoyl)-l,3,8-triaza-spiro[4.5]decan-4-one (292 mg) was dissolved in methanol (5 mL) and palladium on charcoal (10%, 78 mg) was added. After stirring in a hydrogen atmosphere ( 1 bar) at room temperature for 30 min the mixture was filtered over celite and the solvent was evaporated. The residue was dissolved in 1,2-dichloroethane (5 ml), 2-chlorobenzaldehyde (71 mg), acetic acid (300 mg) and sodium triacetoxyborohydride (148 mg) were added. The reaction mixture was stirred overnight at room temperature. Water was added, the organic layer was separated and dried. The solvent was evaporated and the residue was purified by chromatography on silica gel (ethylacetate) to yield the desired product (160 mg, 62%), MS: m/e = 520.1 (M+H + ). Example 89 8-(3,5-Bis-txifluoromemyl-benzoyl)-l-(3-chloro-berizyl)-3-methyl-l,3,8-triaza- spiro [4.5 ] decan-4-one The tide compound, MS: m/e = 534.2 (M+H + ), was prepared in accordance with the general method of example 88 from l-benzyl-8-(3,5-bis-trifluoromethyl-benzoyl)-3- methyl- 1 ,3,8-triaza-spiro [4.5] decan-4-one and 3-cblorobenzaldehyde. Example 90 l-Benzoyl-8-(3,5-bis-trifluoromethyl-benzoyl)-l,3,8-triaza-spiro[4.5]decan-4-one l-Benzyl-8-(3,5-bis-trifluoromethyl-benzoyl)-l,3,8-triaza-spiro[4.5]decan-4-one (50 mg) was dissolved in methanol (2 mL) and palladium on charcoal (10%, 13 mg) was added. After stirring in a hydrogen atmosphere ( 1 bar) at room temperature for 30 min the mixture was filtered over celite and the solvent was evaporated. The residue was dissolved in dichloromethane (2 ml), triethylamine (22 mg) was added and the mixture was cooled to 0°C. Benzoylchloride (14 mg) was added and the mixture was stirred for 1 h at this temperature. Water was added, the organic layer was separated and dried. The solvent was evaporated and the residue was purified by chromatography on silica gel (ethylacetate) to yield the desired product (30 mg, 60%), MS: m/e = 500.2 (M+H + ). Example 91 (rac)-8-(3,5-Bis-trifluoromethyl-benzoyl)-2-methyl-l-phenyl-l,3,8-triaza- spiro [4.5] decan-4-one To a solution of l-benzyl-piperidin-4-one (18.9 g, 100 mmol) in acetic acid (150 mL) were added at 0°C aniline (10.2 g, 110 mmol) and trimethylsilylcyanide (12.5 mL, 100 mmol). The suspension was stirred for 22 h at room temperature. The reaction mixture was than added to ice- ater (350 mL) and ammonia was added until pH 9. After that the mixture was extracted with dichloromethane, the organic phases were pooled, washed with brine and dried with MgSO 4 . The solvent was evaporated and the residue crystallized from diethylether to yield the intermediate amino nitrile (19.2 g, 66 %). To a solution of the intermediate amino nitrile (16.0 g, 55 mmol) in formic acid (210 mL) was added with cooling acetic anhydride (210 mL). Stirring continued for 2.5 h at room temperature. Evaporation of the solvent yielded a white foam, which was used without further purification in the next step. The foam was dissolved in formic acid (210 mL) and acetic acid was added (21 mL). The solution was stirred at room temperature over night. The solvents were evaporated, saturated sodium bicarbonate solution (300 mL) was added and the mixture was extracted with dichloromethane. The organic phases were pooled, dried with Na 2 SO 4 and the solvent was evaporated. The residue was a white foam (18.2 g), which was used without further purification in the next step. The solid was dissolved in triethyl orthoformate (500 mL) and boiled for a week. After cooling the solvent was evaporated to yield 18.5 g brownish foam which was used without further purification in the next step. The brown foam (7.68 g, 24 mmol) was dissolved in THF (80 mL) and was slowly added at room temperature to methylmagnesium bromide (24 mL 3M in diethylether, 72 mmol) and stirred at room temperature overnight. The reaction mixture was quenched with saturated ammonium chloride (100 mL) and extracted with ethyl acetate. Organic phases were pooled and dried with MgSO 4 . Evaporation yielded 7.64 g light brown residue. Chromatography on silica gel (hexane, ethyl acetate, triethyl amine 40:20:1) yielded the intermediate n-benzyl protected piperidine(3.7 g, 46 %). The intermediate (3.7 g, 11 mmol) was dissolved in methanol (125 mL) and palladium on charcoal (10%, 1.25 g) was added. After stirring in a hydrogen atmosphere (1 bar) at room temperature overnight the mixture was filtered and the solvent was evaporated. The residue was dissolved in dichloromethane (200 ml), triethyl amine (2.1 mL, 15 mmol) and 3,5-bistrifluoromethyl benzoylchloride (1.8 L, 10 mmol) were added and the mixture was stirred at room temperature overnight. Water was added, the organic layer was separated and dried. The solvent was evaporated and the residue was purified by chromatography on silica gel (hexane, ethyl acetate, triethyl amine 20:10:1) to yield the desired product (4.17 g, 86%), MS: m/e = 486.3 (M+H + ). Example 92 (rac)-8-(3,5-Bis-trifluoromethyl-benzoyl)-2-phenethyl-l-phenyl-l,3,8-triaza- spiro [4.5 ] decan-4-one The tide compound, MS: m/e = 576.0 (M+H + ), was prepared in accordance with the general method of example 91 from l-benzyl-piperidin-4-one, aniline andphenethyl magnesium chloride. Example 93 (rac)- 8-(3,5-Bis-trifluoromethyl-benzoyl)-2-isopropyl-l-phenyl-l,3,8-triaza- spiro [4.5] decan-4-one The tide compound, MS: m/e = 514.3 (M+H + ), was prepared in accordance with the general method of example 91 from l-benzyl-piperidin-4-one, aniline and isopropyl magnesium chloride. Example 94 (rac)-2-Benzyl-8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8-triaza- spiro [4.5] decan-4-one The tide compound, MS: m/e = 562.2 (M+H + ), was prepared in accordance with the general method of example 91 from l-benzyl-piperidin-4-one, aniline and benzyl magnesium chloride. Example 95 (rac)-8-(3,5-Bis-trifluoromethyl-benzoyl)-l,2-diphenyl-l,3,8-triaza-spiro[4.5]decan-4- one The tide compound, MS: m/e = 548.1 (M+H + ), was prepared in accordance with the general method of example 91 from l-benzyl-piperidin-4-one, aniline and phenyl magnesium chloride. Example 96 (rac)-8-(3,5-Bis-μifluoromethyl-benzoyl)-2-methyl-l-o-tolyl-l,3,8-triaza- spiro[4.5]decan-4-one The tide compound, MS: m/e = 500.2 (M+H + ), was prepared in accordance with the general method of example 91 from l-benzyl-piperidin-4-one, 1-methyl aniline and methyl magnesium bromide. Example 97 (rac)-2-Benzyl-8-(3,5-bis-trifluoromefhyl-benzoyl)- 1-o-tolyl- 1 ,3,8-triaza-spiro [4.5] decan- 4-one The tide compound, MS: m/e = 576.0 (M+H + ), was prepared in accordance with the general method of example 91 from l-benzyl-piperidin-4-one, 1-methyl aniline and benzyl magnesium chloride. Example 98 (rac)-8-(3,5-Bis-trifluoromethyl-benzoyl)-2-phenyl-l-o-tolyl-l,3,8-triaza- spiro [4.5] decan-4-one The tide compound, MS: m/e = 562.3 (M+H + ), was prepared in accordance with the general method of example 91 from l-benzyl-piperidin-4-one, 1-methyl aniline and phenyl magnesium chloride. Example 99 (rac)-8-(3,5-Bis-trifluoromeΛyl-benzoyl)-2-meώyl-l-phenyl-3-pyri<un-3-yl-mefhyl- l,3,8-triaza-spiro[4.5]decan-4-one (rac)-8-(3,5-Bis-trifluoromethyl-benzoyl)-2-methyl-l-ρhenyl-l,3,8-triaza- spiro[4.5]decan-4-one (200 mg, 0.41 mmol) was dissolved in dimethyl formamide (10 mL) and sodium hydride (40 mg, 60% in mineral oil, 1 mmol) and 3-chloromethyl pyridinium chloride (82 mg, .5 mmol) were added and stirred at room temperature overnight. Water (30 mL) was added and the reaction mixture extacted with ethyl actetate. The organic phases were pooled, dried with MgSO 4 and the solvent was evaporated. The residue was purified by chromatography on silica gel (ethyl acetate) to yield the desired product (219 mg, 93%), MS: m/e = 577.0 (M+H + ). Example 100 (rac)-8-(3,5-Bis-txifluoromethyl-benzoyI)-2,3-dimethyl-l-phenyl-l,3,8-triaza- spiro [4.5] decan-4-one The tide compound, MS: m/e = 500.2 (M+H + ), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-l- phenyl-l,3,8-triaza-spiro[4.5]decan-4-one l-benzyl-piperidin-4-one and methyl iodide. Example 101 (rac)-8-(3,5-Bis-txifluoromelhyl-benzoyl)-2-methyl-l-phenyl-3-(2-pyrroUd n-l-yl-ethyl)- 1 ,3,8-triaza-spiro [4.5] decan-4-one The tide compound, MS: m/e = 583.2 (M+H + ), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-l- phenyl-l,3,8-triaza-spiro[4.5]decan-4-one l-benzyl-piperidin-4-one and l-(2- chloroethyl)pyrrolidine. Example 102 (rac)-8-(3,5-Bis-txifluoromethyl-benzoyl)-2-memyl-3-(2-methyl-thiazol-4-yl-methyl)-l- phenyl- 1 ,3,8-triaza-spiro [4.5] decan-4-one The tide compound, MS: m/e = 597.0 (M+H + ), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-l- phenyl-l,3,8-triaza-spiro[4.5]decan-4-one l-benzyl-piperidin-4-one and 4-chloromethyl- 2-methylthiazole. Example 103 (rac)-8-(3,5-Bis-trifluorome yl-benzoyl)-3-cyclopropylmethyl-2-methyl-l-phenyl-l,3,8- triaza-spiro [4.5] decan-4-one The tide compound, MS: m/e = 540.3 (M+H + ), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-l- phenyl-l,3,8-triaza-spiro[4.5]decan-4-one l-benzyl-piperidin-4-one and cyclopropyl methyl bromide. Example 104 (rac)-8-(3,5-Bis-trifluoromethyl-benzoyl)-3-(3-dimethylamino-propyl)-2-methyl-l- phenyl- 1 ,3,8- triaza-spiro [4.5] decan-4-one The tide compound, MS: m/e = 571.1 (M+H + ), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-l- phenyl-l,3,8-triaza-spiro[4.5]decan-4-one l-benzyl-piperidin-4-one and 3- dimethylaminol-propyl chloride. Example 105 (rac)-8-(3,5-Bis-1xifluoromethyl-benzoyl)-2,3-dimethyl-l-o-tolyl-l,3,8-triaza- spiro [4.5] decan-4-one The tide compound, MS: m/e = 571.1 (M+H + ), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-l- o-tolyl-l,3,8-triaza-spiro[4.5]decan-4-one and methyl iodide. Example 106 (rac)-8-(3,5-Bis-trifluoromemyl-benzoyl)-2-methyl-3-(2-pyrroUdin-l-yl-ethyl)-l-o-tolyl- 1 ,3,8-triaza-spiro [4.5] decan-4-one The tide compound, MS: m/e = 597.1 (M+H + ), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-l- o-tolyl-l,3,8-triaza-spiro[4.5]decan-4-one and l-(2-chloroethyl)-pyrrolidine. Example 107 (rac)-8-(3,5-Bis-trifluoromethyl-benzoyl)-2-methyl-3-(2-piperidin-l-yl-ethyl)-l-o-tolyl- 1 ,3,8-triaza-spiro [4.5] decan-4-one The tide compound, MS: m/e = 610.3 (M+H + ), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-l- o-tolyl-l,3,8-triaza-spiro[4.5]decan-4-one and l-(2-chloroethyl)-piperidine. Example 108 (rac)-8-(3,5-Bis-trifluoromethyl-benzoyl)-2-methyl-3-(2-piperazin-l-yl-ethyl)-l-o-tolyl- l,3,8-triaza-spiro[4.5]decan-4-one The tide compound, MS: m/e = 626.1 (M+H + ), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-l- o-tolyl-l,3,8-triaza-spiro[4.5] decan-4-one and l-(2-chloroethyl)-piperazine. Example 109 (rac)-8-(3,5-Bis-trifluoromethyl-benzoyl)-2-methyl-l-phenyl-3-pyridin-4-yl-l,3,8-triaza- spiro [4.5] decan-4-one The tide compound, MS: m/e = 563.2 (M+H + ), was prepared in accordance with the general method of example 63 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-l- phenyl-l,3,8-triaza-spiro[4.5]decan-4-one and pyridine-4-boronic acid. Example 110 8-(3,5-Bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8-triaza-spiro[4.5]decane-2,4-dione To a solution of l-benzyl-piperidin-4-one (18.9 g, 100 mmol) in acetic acid (150 mL) were added at 0°C aniline (10.2 g, 110 mmol) and trimethylsilylcyanide (12.5 mL, 100 mmol). The suspension was stirred for 22 h at room temperature. The reaction mixture was than added to ice-water (350 mL) and ammonia was added until pH 9. After that the mixture was extracted with dichloromethane, the organic phases were pooled, washed with brine and dried with MgSO 4 . The solvent was evaporated and the residue crystallized from diethylether to yield the intermediate amino nitrile (19.2 g, 66 %). To a solution of the intermediate amino nitrile (5.0 g, 17.2 mmol) in dichloromethane(50 mL) was added chlorosulfonyl isocyanate (1.65 mL, 19 mmol). Stirring continued for 1 h at room temperature. Evaporation of the solvent yielded a white solid, which was used without further purification in the next step. The white solid was suspended in IN hydrochloric acid (50 mL) and refluxed for 2 h. The pH was adjusted to exactiy 7 by adding 15% sodium hydroxide solution and the mixture was than extracted with dichloromethane. Organic phases were pooled and dried with MgSO 4 . Evaporation yielded 5.4 g of a solid residue. Chromatography on silica gel (hexane, ethyl acetate 1:1) yielded the intermediate n-benzyl protected spiropiperidine(2.6 g, 45 %). The intermediate (500 mg, 1.5 mmol) was dissolved in methanol (30 mL) and palladium on charcoal (10%, 100 mg) and 5 drops of concentrated hydrochloric acid were added. After stirring in a hydrogen atmosphere (1 bar) at room temperature overnight the mixture was filtered and the solvent was evaporated. The residue was dissolved in dichloromethane (20 ml), triethyl amine (0.63 mL, 4.5 mmol) and 3,5-bistrifluoromethyl benzoylchloride (0.27 mL, 1.5 mmol) were added and the mixture was stirred at room temperature overnight. Water was added, the organic layer was separated and dried. The solvent was evaporated and the residue was purified by chromatography on silica gel (hexane, ethyl acetate 1:1) to yield the desired product (414 mg, 57%), MS: m/e = 486.3 (M+H + ). Example 111 8- (3,5-Bis-trifluoromethyl-benzoyl)- 1-o-tolyl- 1,3,8-triaza-spiro [4.5] decane-2,4-dione The tide compound, MS: m/e = 498.3 (M-H + ), was prepared in accordance with the general method of example 110 from l-benzyl-piperidin-4-one and o-toluidine. Example 112 8- (3,5-Bis-trifluoromethyl-benzoyl)- l-phenyI-3-pyridin-3-yl-methyl- 1 ,3,8-triaza- spiro [4.5] decane-2,4-dione The tide compound, MS: m/e = 577.0 (M+H + ), was prepared in accordance with the general method of example 121 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8- triaza-spiro [4.5] decane-2,4-dione and 3-(hydroxymethyl)-pyridine. Example 113 8-(3,5-Bis-trifluoromethyl-benzoyl)-l,3-diphenyl-l,3,8-triaza-spiro[4.5]decane-2,4- dione The tide compound, MS: m/e = 562.2 (M+H + ), was prepared in accordance with the general method of example 110 from l-benzyl-piperidin-4-one, aniline and phenyl isocyanate. Example 114 8- (3,5-Bis-txifluoromethyl-benzoyl)-3-pyridin-3-yl-methyl- 1 -o-tolyl- 1 ,3,8-triaza- spiro [4.5] decane-2,4-dione The tide compound, MS: m/e = 591.1 (M+H + ), was prepared in accordance with the general method of example 121 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-tolyl-l,3,8- triaza-spiro[4.5]decane-2,4-dione and 3- (hydroxymethyl) -pyridine. Example 115 8-(3,5-Bis-trifluoromethyl-benzoyl)-3-(2-pyrrohdin-l-yl-ethyl)-l-o-tolyl-l,3,8-triaza- spiro [4.5] decane-2,4-dione The tide compound, MS: m/e = 597.1 (M+H + ), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-tolyl-l,3,8- triaza-spiro [4.5] decane-2,4-dione and l-(2-chloroethyl)-pyrrolidine. Example 116 8-(3,5-Bis-trifluoromethyl-benzoyl)-3-(3,5-dimethyl-isoxazol-4-yl-methyl)-l-o-tolyl- 1 ,3,8-triaza- spiro [4.5] decane-2,4-dione The tide compound, MS: m/e = 609.0 (M+H + ), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-tolyl-l,3,8- triaza-spiro [4.5] decane-2,4-dione and 4-(chloromethyl)-3,5-dimethylisoxazole. Example 117 3- ( lH-Benzoimidazol-2-yl-methyl)-8- (3,5-bis-trifluoromethyl-benzoyl)- 1-o-tolyl- 1 ,3,8- triaza-spiro [4.5] decane-2,4-dione The tide compound, MS: m/e = 630.0 (M+H + ), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-tolyl-l,3,8- triaza-spiro [4.5] decane-2,4-dione and 2-(chloromethyl)-benzimidazole. Example 118 8- (3,5-Bis-trifluoromethyl-benzoyl)-3- (2-methyl-thiazol-4-yl-methyl)- 1-o-tolyl- 1 ,3,8- triaza-spiro [4.5] decane-2,4-dione The tide compound, MS: m/e = 611.0 (M+H + ), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-toιyl-l,3,8- triaza-spiro [4.5] decane-2,4-dione and 4-chloromethyl-2-methylthiazole. Example 119 8-(3,5-Bis-trifluoromethyI-benzoyl)-3-[l,2,4]oxadiazol-3-yI-methyl-l-o-tolyl-l,3,8-triaza- spiro [4.5] decane-2,4-dione The tide compound, MS: m/e = 581.2 (M + ), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-tolyl-l,3,8-triaza- spiro[4.5]decane-2,4-dione and 3-(chloromethyl)-l,2,4-oxadiazole. Example 120 8- (3,5-Bis-trifluoromethyl-benzoyl)-3- (2-oxo-oxazolidin-5-yl-methyl)- 1-o-tolyl- 1,3,8- triaza-spiro [4.5 ] decane-2,4-dione The tide compound, MS: m/e = 599.0 (M + ), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-tolyl-l,3,8-triaza- spiro [4.5] decane-2,4-dione and 5-chloromefhyl-2-oxazolidinone. Example 121 8-(3,5-Bis-trifluoromethyl-benzoyl)-3-furan-2-yl-methyl-l-phenyl-l,3,8-triaza- spiro [4.5] decane-2,4-dione 8-(3,5-Bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8-triaza-spiro[4.5]decane-2,4-dione (200 mg, 0.41 mmol) was dissolved in dry dioxane ( 10 mL) and triphenylphosphin ( 145 mg, 0.54 mmol), furfuryl alcohol (53.1 mg, 0.54 mmol) and diethylazodicarboxylate (40% in toluene, 0.54 mmol) were added sequentially and stirred at room temperature overnight. The solvent was evaporated and the residue was purified by chromatography on silica gel (dichloromethane) to yield the desired product (143 mg, 61%), MS: m/e = 566.1 (M+H + ). Example 122 8-(3,5-Bis-trifluoromethyl-benzoyl)-3- ran-3-yl-methyl-l-phenyl-l,3,8-triaza- spiro [4.5] decane-2,4-dione The tide compound, MS: m/e = 566.1 (M + ), was prepared in accordance with the general method of example 121 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-l,3,8-triaza- spiro[4.5]decane-2,4-dione and 3-furane methanol. Example 123 (S)-8-(3,5-Bis-tjifluoromemyl-benzoyl)-3-(5-oxo-pyrrolidin-2-yl-methyl)-l-phenyl- 1 ,3,8-triaza-spiro [4.5] decane-2,4- dione The tide compound, MS: m/e = 583.1 (M + ), was prepared in accordance with the general method of example 121 from 8-(3,5-bis-trifluoromefhyl-benzoyl)-l-phenyl-l,3,8-triaza- spiro[4.5]decane-2,4-dione and (S)-5-(hydroxymethyl)-2-pyrrolidinone. Example 124 8-(3,5-Bis-trifluoromethyl-benzoyl)-3-(5-methyl-isoxazol-3-yl-methyl)-l-o-tolyl-l,3,8- triaza-spiro [4.5] decane-2,4-dione The tide compound, MS: m/e = 595.0 (M + ), was prepared in accordance with the general method of example 121 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-tolyl-l,3,8-triaza- spiro[4.5]decane-2,4-dione and 5-methylisoxazole-3-methanol. Example 125 8-(3,5-Bis-txifluoromethyl-benzoyl)-3-furan-3-yl-ethyl-l-o-tolyl-l,3,8-triaza- spiro [4.5] decane-2,4-dione The tide compound, MS: m/e = 580.1 (M + ), was prepared in accordance with the general method of example 121 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-tolyl-l,3,8-triaza- spiro[4.5]decane-2,4-dione and 3-furane-methanol. Example 126 8-(3,5-Bis-trifluorome yl-benzoyl)-3-furan-2-yl-methyl-l-o-tolyl-l,3,8-triaza- spiro[4.5]decane-2,4- dione The tide compound, MS: m/e = 580.0 (M + ), was prepared in accordance with the general method of example 121 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-toIyl-l,3,8-triaza- spiro[4.5]decane-2,4-dione and furfuryl alcohol. Example 127 8-(3,5-Bis-triiluoromemyl-benzoyl)-3-thiophen-2-yl-methyl-l-o-tolyl-l,3,8-triaza- spiro [4.5] decane-2,4-dione The tide compound, MS: m/e = 596.0 (M + ), was prepared in accordance with the general method of example 121 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-tolyl-l,3,8-triaza- spiro[4.5]decane-2,4-dione and 2-thiophene methanol. Example 128 8-(3,5-Bis-trifluoromethyl-benzoyl)-3-(2-morpholin-4-yl-ethyl)-l-o-tolyl-l,3,8-triaza- spiro [4.5] decane-2,4-dione The tide compound, MS: m/e = 613.1 (M + ), was prepared in accordance with the general method of example 121 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-tolyl-l,3,8-triaza- spiro[4.5]decane-2,4-dione and N-(2-hydroxyethyl)morpholine. Example 129 8- (3,5-Bis-trifluoromethyl-benzoyl)-4-hydroxy- 1 ,3-diphenyl- 1 ,3,8-triaza- spiro [4.5] decan-2-one To a solution of l-benzyl-piperidin-4-one (18.9 g, 100 mmol) in acetic acid (150 mL) were added at 0°C aniline (10.2 g, 110 mmol) and trimethylsilylcyanide (12.5 mL, 100 mmol). The suspension was stirred for 22 h at room temperature. The reaction mixture was than added to ice- water (350 mL) and ammonia was added until pH 9. After that the mixture was extracted with dichloromethane, the organic phases were pooled, washed with brine and dried with MgSO . The solvent was evaporated and the residue crystallized from diethylether to yield the intermediate amino nitrile (19.2 g, 66 %). To a solution of the intermediate amino nitrile (5.0 g, 17.2 mmol) in dichloromethane(50 mL) was added phenyl isocyanate (2.20 mL, 20 mmol). Stirring continued for 1 h at room temperature. Evaporation of the solvent yielded a white solid, which was used without further purification in the next step. The white solid was suspended in IN hydrochloric acid (50 mL) and refluxed for 2 h. The pH was adjusted to exacdy 7 by adding 15% sodium hydroxide solution and the mixture was than extracted with dichloromethane. Organic phases were pooled, dried with MgSO 4 and evaporated. Chromatography on silica gel (hexane, ethyl acetate 1:1) yielded the intermediate n-benzyl protected spiropiperidine(5.54 g, 78 %). The n-benzyl protected spiropiperidine (4.0 g, 9.7 mmol) was dissolved in tetrahydrofuran (50 ml) and diisobutyl aluminium hydride (24 mL, 1M in THF) were added at 0°C. The reaction mixture was stirred at room temperature overnight and the solvent was evaporated. Chromatography of the residue on silica gel (hexane, ethyl acetate, triethyl amine 40:10:1) gave the reduced intermediate (874 mg, 22%). The intermediate (870 mg, 2.1 mmol) was dissolved in methanol (30 mL) and palladium on charcoal (10%, 200 mg) and 5 drops of concentrated hydrochloric acid were added. After stirring in a hydrogen atmosphere (1 bar) at room temperature overnight the mixture was filtered and the solvent was evaporated. The residue was dissolved in dichloromethane (20 ml), triethyl amine (1.2 mL, 8.5 mmol) and 3,5-bistrifluoromethyl benzoylchloride (0.42 mL, 2.3 mmol) were added and the mixture was stirred at room temperature overnight. Water was added, the organic layer was separated and dried. The solvent was evaporated and the residue was purified by chromatography on silica gel (hexane, ethyl acetate 1:1) to yield the desired product (497 mg, 42%), MS: m/e = 564.1 (M+H + ). Example 130 8-(3,5-Bis-trifluoromethyl-benzoyl)-4-methoxy-l,3-diphenyl-l,3,8-triaza- spiro [4.5] decan-2-one The tide compound, MS: m/e = 578:0 (M + ), was obtained as a byproduct of example 129. Example 131 8- (3,5-Bis-trifluoromethyl-benzoyl)- 1-o-tolyl- 1 ,3,8-triaza-spiro [4.5] decan-2-one To a solution of l-benzyl-piperidin-4-one (37.8 g, 200 mmol) in acetic acid (300 mL) were added at 0°C o-toluidine (23.8 g, 220 mmol) and trimethylsilylcyanide (25.0mL, 200 mmol). The suspension was stirred for 22 h at room temperature. The reaction mixture was than added to ice- water (500 mL) and ammonia was added until pH 9. After that the mixture was extracted with dichloromethane, the organic phases were pooled, washed with brine and dried with MgSO 4 . The solvent was evaporated and the residue crystallized from diethylether to yield the intermediate amino nitrile (46.2 g, 75 %). The intermediate amino nitrile (29.5 g, 96 mmol) was dissolved in acetic acid (200 L), PtO 2 (1.3 g, 5.7 mmol) was added and the reaction mixture was hydrogenated at 2.7 bar at room temperature for 3 days. Acetic acid was evaporated and the residue was treated with saturated sodium bicarbonate solution until pH 9. The mixture was than extracted with dichloromethane. Organic phases were pooled and dried with MgSO 4 . Evaporation yielded 21.2 g (71%) of an oil. To a solution of the intermediate triamine(3.2g, 10.2 mmol) in dichlorornethane(330 mL) and triethylamine (2.9 mL, 20.5 mmol) was added at -20°C trichloromethyl chloroformat (0.446 mL, 3.6 mmol) in dichloromethane (30 mL). The reaction mixture was then stirred at room temperature overnight. Water (50 mL) was added and te mixture was extracted with dichloromethane. Organic phases were pooled and dried with MgSO 4 . Evaporation and chromatography on silica gel (dichloromethane/methanol 99:1) yielded the intermediate N-benzyl protected spiropiperidine(1.4g, 41%). The intermediate N-benzyl protected spiropiperidine (3.05g, 9.1 mmol) was dissolved in methanol (120 mL) and palladium on charcoal (10%, 610 mg) and 20 drops of concentrated hydrochloric acid were added. After stirring in a hydrogen atmosphere (1 bar) at room temperature overnight the mixture was filtered and the solvent was evaporated. The residue was dissolved in dichloromethane (100 ml), triethyl amine (3.73 mL, 26.6 mmol) and 3,5-bistrifluoromethyI benzoylchloride (2.45 mL, 8.9 mmol) were added and the mixture was stirred at room temperature overnight. Water was added, the organic layer was separated and dried. The solvent was evaporated and the recrystallized from dichloromethane to yield the desired product as white crystalls (3.29 g, 76%), MS: m/e = 486.3 (M+H + ). Example 132 8-(3,5-Bis-trifluoromemyl-benzoyl)-3-(2-pyrroHdιn-l-yl-ethyl)-l-o-tolyl-l,3,8-triaza- spiro [4.5]decan-2-one The tide compound, MS: m/e = 583.2 (M+H + ), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-tolyl-l,3,8- triaza-spiro [4.5] decan-2-one and l-(2-chloroethyl)-pyrrolidine. Example 133 8- (3,5-Bis-trifluoromethyl-benzoyl)-3-methyl- 1-o-tolyl- 1,3,8-triaza-spiro [4.5] decan-4- one The tide compound, MS: m/e = 500.2 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-tolyl-l,3,8- triaza-spiro[4.5]decan-4-one and iodomethane in 1,2-dimethoxyethane as solvent. Example 134 8-(3,5-Bis-trifluoromemyl-benzoyl)-3-(2-methyl-tMazol-4-yl-methyl)-l-o-tolyl-l,3,8- triaza-spiro [4.5] decan-4-one The tide compound, MS: m/e = 597.0 (M+H + ), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-tolyl-l,3,8- triaza-spiro[4.5]decan-4-one and 4-chloromethyl-2-methyl-thiazole in 1,2- dimethoxyethane as solvent. Example 135 8-(3,5-Bis-trifluoromethyl-benzoyl)-l-(2-chloro-phenyl)-l,3,8-triaza-spiro[4.5]decane- 2,4-dione To a solution of l-(3,5-bis-trifluoromethyl-benzoyl)-4-(2-chloro-phenylamino)- piperidine-4-carbonitrile (5.0 g, 10.5 mmol) in dichloromethane(50 mL) was added chlorosulfonyl isocyanate (1 mL, 11.5 mmol). Stirring continued for 1 h at room temperature. Evaporation of the solvent yielded a white foam, which was used without further purification in the next step. The white foam was suspended in IN hydrochloric acid (50 mL) and refluxed for 2 h. The obtained suspension was filtered to yield 5.4 g of a solid residue. Chromatography on silica gel (hexane, ethyl acetate 2:1) and recrystallization from ethyl acetate/n-hexane yielded the desired product (2.9 g, 53%), mp 153-154°C, MS: m/e = 520.1 (M+H + ). Example 136 Rac-8-(3,5-Bis-trifluoromethyl-benzoyl)-2-methyl-3-phenyl-l-o-tolyl-l,3,8-triaza- spiro [4.5] decan-4-one The tide compound, MS: m/e = 576.0 (M+H + ), was prepared in accordance with the general method of example 62 from (rac)-8-(3,5-bis-triπuoromethyl-benzoyl)-2-methyl-l- o-tolyl-l,3,8-triaza-spiro [4.5] decan-4-one and 4 phenylboronic acid. Example 137 Rac-8-(3,5-Bis-trifluoromethyl-benzoyl)-3-(2-methoxy-ethyl)-2-mefhyl-l-o-tolyl-l,3,8- triaza-spiro [4.5] decan-4-one The tide compound, MS: m/e = 542.2 (M+H + ), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-l- o-tolyl-l,3,8-triaza-spiro[4.5]decan-4-one and 2-chloroethyl- methyl ether. Example 138 Rac-8-(3,5-Bis-trifluoromelhyl-benzoyl)-3-cyclopropylmethyl-2-methyl-l-o-tolyl-l,3,8- triaza-spiro [4.5] decan-4-one The tide compound, MS: m/e = 554.2 (M+H + ), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-l- o-tolyl-l,3,8-triaza-spiro[4.5]decan-4-one and cyclopropyl methyl bromide. Example 139 Rac-8-(3,5-Bis-trifluoromethyl-benzoyl)-3-(2,2-difluoro-ethyl)-2-methyl-l-o-tolyl-l,3,8- triaza-spiro [4.5] decan-4-one The tide compound, MS: m/e = 564.2 (M+H + ), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-l- o-tolyl-l,3,8-triaza-spiro[4.5]decan-4-one and 2,2-difluoroefhyl bromide. Example 140 Rac-8-(3,5-Bis-txhluoromethyl-benzoyl)-2-methyl-3-(3-methyl-but-2-enyl)-l-o-tolyl- 1 ,3 ,8-triaza-spiro [4.5] decan-4-one The tide compound, MS: m/e = 568.2 (M+H + ), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-mefhyl-l- o-tolyl-l,3,8-triaza-spiro[4.5]decan-4-one and l-bromo-3-methyl-2-butene. Example 141 Rac-8-(3,5-Bis-trifluoromethyl-benzoyl)-2-methyl-3-(2-morpholin-4-yl-ethyl)-l-o-tolyl- l,3,8-triaza-spiro[4.5]decan-4-one The tide compound, MS: m/e = 613.2 (M+H + ), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-l- o-tolyl-l,3,8-triaza-spiro[4.5]decan-4-one and 4-(chloroethyl)morphoHne. Example 142 8- (3,5-Bis-trifluoromethyl-benzoyl)-3- ( 1-methyl- lH-imidazol-2-yl-methyl)- 1-o-tolyl- 1 ,3,8-triaza-spiro [4.5] decan-4-one The tide compound, MS: m/e = 580.3 (M+H + ), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-tolyl-l,3,8- triaza-spiro[4.5]decan-4-one and 2-chloromethyl-l-methyl-lH-imidazole. Example 143 8-(3,5-Bis-1xifluoromethyl-benzoyl)-l-(2-chloro-phenyl)-3-(l-methyl-lH-imidazol-2- ylmethyl)- 1,3,8-triaza-spiro [4.5] decane-2,4-dione The tide compound, MS: m/e = 614.1 (M+H + ), was prepared in accordance with the general method of example 121 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-(2-chloro- phenyl)-l,3,8-triaza-spiro[4.5]decane-2,4-dione and l-methylirnidazole-2 -methanol. Example 144 8-(3,5-Bis-trifluoromethyl-benzoyl)-l-(2-chloro-phenyl)-3-(l,5-dimethyl-lH-pyrazol-3- ylmethyl)- 1 ,3,8-triaza-spiro [4.5] decane-2,4-dione The tide compound, MS: m/e = 627.1 (M + ), was prepared in accordance with the general method of example 121 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-(2-chloro-phenyl)- l,3,8-triaza-spiro[4.5]decane-2,4-dione and l,5-dimethylpyrazole-3-methanol. Example 145 8-(3,5-Bis-trifluorome yl-benzoyl)-l-(2-cUoro-phenyl)-3-(l,5-dimefhyl-lH-pyrazol-3- ylmethyl)-l,3,8-triaza-spiro[4.5]decane-2,4-dione The tide compound, MS: m/e = 585.1 (M + ), was prepared in accordance with the general method of example 121 from 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(3-dimethylamino- propyl)-l-o-tolyl-l,3,8-triaza-spiro[4.5]decane-2,4-dione and 3-dimethylamino-l-propyl chloride. Example 146 (rac)-8-(3,5-Dimethoxy-benzoyl)-2-melhyl-l-o-tolyl-l,3,8-triaza-spiro[4.5]decan-4-one The tide compound, MS: m/e = 424.5 (M+H + ), was prepared in accordance with the general method of example 91 from l-benzyl-piperidin-4-one, 1-methyl aniline, methyl magnesium bromide and 3,5-dimethoxy benzoyl chloride. Example 147 (rac)-8-(3,5-Dichloro-benzoyl)-2-methyl-l-o-tolyl-l,3,8-triaza-spiro[4.5]decan-4-one The tide compound, MS: m/e = 432.4 (M+H + ), was prepared in accordance with the general method of example 91 from l-benzyl-piρeridin-4-one, 1-methyl aniline, methyl magnesium bromide and 3,5-dichloro benzoyl chloride. Example 148 (rac)-8-(3-Fluoro-5-trifluoromethyl-benzoyl)-2-methyl-l-o-tolyl-l,3,8-triaza- spiro [4.5] decan-4-one The tide compound, MS: m/e = 450.4 (M+H + ), was prepared in accordance with the general method of example 91 from l-benzyl-piperidin-4-one, 1-methyl aniline, methyl magnesium bromide and 3-fluoro-5-trifluoromefhyl-benzoyl chloride. Example 149 (rac)-8-(3,5-Difluoro-benzoyl)-2-methyl-l-o-tolyl-l,3,8-triaza-spiro[4.5]decan-4-one The tide compound, MS: m/e = 400.5 (M+H + ), was prepared in accordance with the general method of example 91 from l-benzyl-piperidin-4-one, 1-methyl aniline, methyl magnesium bromide and 3,5-difluoro-benzoyl chloride. Example 150 8-(3,5-Bis-txifluoromethyl-benzoyl)-3-cyclopropylmethyl-l-o-tolyl-l,3 ) 8-triaza- spiro [4.5] decan-2-one The tide compound, MS: m/e = 540.4 (M+H + ), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-tolyl-l,3,8- triaza-spiro[4.5]decan-2-one and cyclopropyl methyl bromide. Example 151 8-(3,5-Bis-txifluoromethyl-benzoyl)-3-methyl-l-o-tolyl-l,3,8-triaza-spiro[4.5]decan-2- one The tide compound, MS: m/e = 500.2 (M+H + ), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromefhyl-benzoyl)-l-o-tolyl-l,3,8- triaza-spiro[4.5]decan-2-one and methyl iodide. Example 152 8-(3,5-Bis-trifluoromemyl-benzoyl)-3-(2-morpholin-4-yl-ethyl)-l-o-tolyl-l,3,8-triaza- spiro [4.5] decan-2-one The tide compound, MS: m/e = 599.1 (M+H + ), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-tolyl-l,3,8- triaza-spiro[4.5]decan-2-one and 4-(chloroethyl)morpholine. Example 153 8-(3,5-Bis-txifluoromethyl-benzoyl)-3-(2-mefhoxy-ethyl)-l-o-tolyl-l,3,8-triaza- spiro [4.5] decan-2-one The tide compound, MS: m/e = 544.2 (M+H + ), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-tolyl-l,3,8- triaza-spiro[4.5]decan-2-one and 2-chloromethyl methyl ether. Example 154 8-(3,5-Bis-trifluoromethyl-benzoyl)-3-(3-dunethylamino-propyl)-l-o-tolyl-l,3,8-triaza- spiro [4.5] decan-2-one The tide compound, MS: m/e = 571.1 (M+H + ), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-tolyl-l,3,8- triaza -spiro [4.5] decan-2-one and 3-dimethylamino-l-propyl chloride. Example 155 3-Acetyl-8- (3,5-bis-trifluoromethyl-benzoyl)- 1-o-tolyl- 1 ,3,8-triaza-spiro [4.5] decan-2-one The tide compound, MS: m/e = 528.1 (M+H + ), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-tolyl-l,3,8- triaza-spiro[4.5]decan-2-one and acetyl chloride. Example 156 (rac)-8-(3,5-Bis-trifluoromethyl-benzoyl)-4-phenyl-2,8-diaza-spiro[4.5]decane-l,3-dione To a solution sodium ethoxide (prepared by slow addition of 22 g, 0.96 mol Na to dry 800 mL ethanol) was added benzyl cyanide (113 g, 1.05 mol) and N-benzyl-4-piperidone (90 g, 0.48 mol) at room temperature. The reaction mixture was stirred at 85°C for 3 h and the solvent was evaporated. The residue was poured into a mixture of ice (1 kg) and concentrated hydrochloric acid (200 mL). The pH was then adjusted to 9 addition of solid sodium hydroxide and the mixture was extracted three times with ethyl acetate (500 mL each). Organic phases were pooled and dried with MgSO . The solvent was evaporated and chromatography on silica gel (hexane, ethyl acetate, triethyl amine 80:20:1) gave (1-benzyl- piperidin-4-ylidene)-phenyl-acetonitrile as yellow crystalls (135 g, 97%). To a solution of the intermediate (l-benzyl-piperidin-4-ylidene)-phenyl-acetonitrile (135 g, 0.47 mol) in ethanol (400 mL) was added potassium cyanide (30 g, 0.47 mol) in water (80 L). Stirring continued at 90°C overnight. The solvent was evaporated. The residue was taken up in 2N hydrochloric acid (300 mL) and concentrated hydrochloric acid (50 mL) was added to adjust at pH 1-2. The reaction mixture was stirred at reflux overnight. After cooling to room temperature solid sodium carbonate until pH 8-9 was added and the mixture was extracted three times with methylene chloride (300 mL each). Organic phases were pooled, dried with MgSO and evaporated. The crude product was suspended in ethyl acetate (300 mL) and left at room temperature overnight. The crystalls were filtered off and dried to give 106 g (68%) of the intermediate (rac)-8-benzyl-4-phenyl-2,8-diaza- spiro [4.5] decane-l,3-dione. The intermediate (rac)-8-benzyl-4-phenyl-2,8-diaza-spiro[4.5]decane-l,3-dion (4.0 g, 12 mmol) was dissolved in methanol (100 mL) and concentrated hydrochloric acid(l mL) and palladium on charcoal (10%, 0.60 g) were added. After stirring in a hydrogen atmosphere (1 bar) at room temperature overnight the mixture was filtered and the solvent was evaporated. The residue was dissolved in dichloromethane (100 ml), triethyl amine (5.5 mL, 40 mmol) and 3,5-bistrifluoromethyl benzoylchloride (2.7 mL, 15 mmol) were added and the mixture was stirred at room temperature overnight. Water was added, the organic layer was separated and dried. The solvent was evaporated and the residue was purified by flash chromatography on silica gel (hexane, ethyl acetate, triethyl amine 30:10:1) to yield the desired product (3.44 g, 59%), MS: m/e = 485.3 (M+H + ). Example 157 (rac)-8-(3,5-Bis-trifluoromethyl-benzoyl)-2-methyl-4-phenyl-2,8-diaza-spiro[4.5]decane- 1,3-dione The tide compound, MS: m/e = 499.2 (M+H + ), was prepared in accordance with the general method of example 121 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-phenyl- 2,8-diaza-spiro[4.5]decane-l,3-dione and methyl iodide. Example 158 (rac)-8-(3,5-Bis-trifluoromeΛyl-benzoyl)-2-(2-morpholin-4-yl-ethyl)-4-phenyl-2,8- diaza-spiro [4.5] decane-l,3-dione The tide compound, MS: m/e = 598.1 (M+H + ), was prepared in accordance with the general method of example 121 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-phenyl- 2,8-diaza-spiro[4.5]decane-l,3-dione and N-(2-hydroxyethyl)-morpholine. Example 159 (rac)-8-(3,5-Bis-tτifluoromemyl-benzoyl)-4-phenyl-2-(2-pyrroHdin-l-yl-ethyl)-2,8-diaza- spiro [4.5] decane- 1 ,3-dione The tide compound, MS: m/e = 582.2 (M+H + ), was prepared in accordance with the general method of example 121 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-phenyl- 2,8-diaza-spiro [4.5] decane- 1,3-dione and 1 - (2-hydroxyethyl)-pyrrolidine. Example 160 (rac)-8-(3,5-Bis-trifluoromethyl-berιzoyl)-2-(3-dimethylamino-propyl)-4-phenyl-2,8- diaza-spiro [4.5] decane- 1 ,3-dione The tide compound, MS: m/e = 570.2 (M+H + ), was prepared in accordance with the general method of example 121 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-phenyl- 2,8-diaza-spiro[4.5]decane-l,3-dione and 3-dimefhylamino-l-propanol. Example 161 (rac)-8-(3,5-Bis-trifluoromethyl-benzoyl)-4-phenyl-2,8-diaza-spiro[4.5]decan-l-one (rac)-8-Benzyl-4-phenyl-2,8-diaza-spiro[4.5]decane-l,3-dion (10.0 g, 30 mmol, synthesis described in example 156) was dissolved in toluene (200 mL). Diisobutyl aluminium hydride (220 mL, 1M in THF, 220 mmol) was slowly added while cooling with an ice bath so that the reaction temperature did not exceed 10°C. The reaction mixture was stirred at room temperature for 2 days. A mixture of methanol (6 mL) and water (6 mL) was added at room temperature. The resulting gel was filtered through dicalit and washed with methylene chloride. The filtrate was evaporated to give 8-benzyl-3-hydroxy-4-phenyl-2,8- diaza-spiro[4.5]decan-l-one as a mixture of diastereomers (8.0 g, 80%). The intermediate 8-benzyl-3-hydroxy-4-phenyl-2,8-diaza-spiro[4.5]decan-l-one (8.0 g, 23.8 mmol) was dissolved in glacial acetic acid (50 mL) and refluxed for 1.5 h. The reaction mixture was poured into ice water (500 mL) and adjusted to pH 8-9 by addition of solid sodium hydroxide. The mixture was extracted three times with ethyl acetate (300 mL each). Organic phases were pooled, dried with magnesium sulfate and evaporated. The crude product was recrystallized from methylene chloride to give 8-benzyl-4-phenyl-2,8- diaza-spiro[4.5]dec-3-en-l-one as white crystalls (2.64 g, 35 %). The intermediate 8-benzyl-4-phenyl-2,8-diaza-spiro[4.5]dec-3-en-l-one (3.7 g, 11.6 mmol) was dissolved in methanol (100 mL) and concentrated hydrochloric acid(l mL) and palladium on charcoal (10 %, 0.60 g) were added. After stirring in a hydrogen atmosphere (1 bar) at room temperature overnight the mixture was filtered and the solvent was evaporated. The residue was dissolved in dichloromethane (100 ml), triethyl amine (8.1 mL, 58 mmol) and 3,5-bistrifluoromethyl benzoylchloride (2.65 mL, 15 mmol) were added and the mixture was stirred at room temperature overnight. Water was added, the organic layer was separated and dried. The solvent was evaporated and the residue was purified by flash chromatography on silica gel (methylene chloride/methanol 98:2) to yield the desired product (4.65 g, 85%), MS: m/e = 471.2 (M+H + ). Example 162 (rac)-8-(3,5-Bis-trifluoromethyl-benzoyl)-2-methyl-4-phenyl-2,8-diaza-spiro[4.5]decan- 1-one The tide compound, MS: m/e = 485.3 (M+H + ), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-phenyl- 2,8-diaza-spiro[4.5]decan-l-one and methyl iodide. Example 163 (rac)-8-(3,5-Bis-trifluoromethyl-benzoyl)-4-phenyl-2-(2-pyrroUdin-l-yl-ethyl)-2,8-diaza- spiro [4.5] decan- 1 -one The tide compound, MS: m/e = 568.3 (M+H + ), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-phenyl- 2,8-diaza-spiro[4.5]decan-l-one and l-(2-chloroethyl)-pyrrolidine. Example 164 (rac)-8-(3,5-Bis-trifluoromethyl-benzoyl)-2-(2-methoxy-ethyl)-4-phenyl-2,8-diaza- spiro [4.5] decan- 1 -one The tide compound, MS: m/e = 529.2 (M+H + ), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-phenyl- 2,8-diaza-spiro [4.5] decan- 1 -one and 2-chloroethyl-methyl-ether. Example 165 (rac)-8-(3,5-Bis-trifluoromethyl-benzoyl)-2-(2-morpholin-4-yl-ethyl)-4-phenyl-2,8- diaza-spiro [4.5] decan- 1-one The tide compound, MS: m/e = 584.1 (M+H + ), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-phenyl- 2,8-diaza-spiro[4.5]decan-l-one and 4-(2-chloroethyl)-morpholine. Example 166 (rac)-8-(3,5-Bis-trifluoromethyl-benzoyl)-2-(3-dimethylamino-propyl)-4-phenyl-2,8- diaza-spiro [4.5] decan- 1-one The tide compound, MS: m/e = 556.2 (M+H + ), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-phenyl- 2,8-diaza-spiro [4.5] decan- 1 -one and 3-dimethylamino-l-propyI chloride. Example 167 (rac)-8-(3,5-Bis-trifluoromethyl-benzoyl)-4-phenyl-2-pyridin-3-yl-methyl-2,8-diaza- spiro [4.5] decan- 1-one The tide compound, MS: m/e = 562.3 (M+H + ), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-phenyl- 2,8-diaza-spiro [4.5] decan- 1 -one and 3-(chloromethyl)pyτidine. Example 168 (rac)-(3,5-Bis-trifluoromethyl-phenyl)-(2-methyl-4-phenyl-2,8-diaza-spiro[4.5]dec-8-yl)- methanone (rac)-8-Benzyl-4-phenyl-2,8-diaza-spiro [4.5] decane- 1,3-dion (3.0 g, 9.0 mmol, synthesis described in example 156) was dissolved in dry tetrahydrofuran (50 mL) and triphenylphosphin (3.1 g, 11.7 mmol), methanol (0.374 g, 11.7 mmol) and diefhylazodicarboxylate (5.35 mL, 40% in toluene, 11.7 mmol) were added sequentially and stirred at room temperature overnight. The solvent was evaporated and the residue was purified by chromatography on silica gel (dichloromethane/methanol/triethyl amine 98: 1 : 1 ) to yield the intermediate (rac) -8-benzyl-2-methyl-4-phenyl-2,8-diaza- sρiro[4.5]decane-l,3-dion (2.57g, 82 %). Lithium aluminium hydride (1.39 g, 37 mmol) was dissolved in tetarhydrofuran (20 mL) and the intermediate (rac)-8-benzyl-2-methyl-4-phenyl-2,8-diaza-spiro[4.5]decane-l,3- dion (2.55 g, 7.32 mmol, dissolved in 20 mL dry tetrahydrofuran) was added slowly. The reaction mixture was stirred at room temperature for 2 h. Water (1.4 mL), sodium hydroxide (15% in water, 1.5 mL) and water (4.2 mL) were added dropwise. The precipitate was filtered off and the filtrate was evaporated. The residue was purified by flash chromatography (hexane/ethyl acetate/triethyl amine 30:20.1) to yield the intermediate (rac)-8-benzyl-2-methyl-4-phenyl-2,8-diaza-spiro [4.5] decane (1.40 g, 60 %). The intermediate (rac)-8-benzyl-2-methyl-4-phenyl-2,8-diaza-spiro [4.5] decane (1.29 g, 2.51 mmol) was dissolved in methanol (50 mL) and concentrated hydrochloric acid(0.3 mL) and palladium on charcoal (10 %, 0.214 g) were added. After stirring in a hydrogen atmosphere (1 bar) at room temperature overnight the mixture was filtered and the solvent was evaporated. The residue was dissolved in dichloromethane (50 ml), triethyl amine (2.04 mL, 20 mmol) and 3,5-bistrifluoromethyl benzoylchloride (0.95 mL, 5.2 mmol) were added and the mixture was stirred at room temperature overnight. Water was added, the organic layer was separated and dried. The solvent was evaporated and the residue was purified by flash chromatography on silica gel (hexane/ethyl acetate/triethyl amine 10:20:1) to yield the desired product (1.18 g, 62 %), MS: m/e = 471.2 (M+H + ). Example 169 8-(3,5-Bis-trifluoromethyl-benzoyl)-4-o-tolyl-2,8-diaza-spiro[4.5]dec-3-en-l-one The tide compound, MS: m/e = 483.1 (M+H + ), was prepared in accordance with the general methods of example 156 and 161 from o-tolyl cyanide and N-benzyl-4-piperidone. Reduction of the double bond with hydrogen was not successful and the 2,8-diaza- spiro[4.5]dec-3-en-l one core was obtained instead of the 2,8-diaza-spiro[4.5]decan-l-one core. Example 170 8- (3,5-Bis-1 ifluoromeΛyl-benzoyl)-2-methyl-4-o-tolyl-2,8-diaza-spiro [4.5] dec-3-en- 1- one The tide compound, MS: m/e = 497.1 (M+H + ), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-4-o-tolyl-2,8- diaza-spiro[4.5]dec-3-en-l-one and methyl iodide. Example 171 8-(3,5-Bis-μifluoromethyl-benzoyl)-2-cyclopropylmethyl-4-o-tolyl-2,8-diaza- spiro[4.5]dec-3-en-l-one The tide compound, MS: m/e = 537.2 (M+H + ), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-4-o-tolyl-2,8- diaza-spiro[4.5]dec-3-en-l-one and cyclopropyl methyl bromide. Example 172 8-(3,5-Bis-trifluoromethyl-benzoyl)-2-(2-pyrrolidin-l-yl-ethyl)-4-o-tolyl-2,8-diaza- spiro [4.5] dec-3-en- 1 -one The tide compound, MS: m/e = 580.1 (M+H + ), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-4-o-tolyl-2,8- diaza-spiro[4.5]dec-3-en-l-one and l-(2-chloroethyl)-pyrrolidine. Example 173 8-(3,5-Bis-txifluoromethyl-benzoyl)-2-(2-morpholin-4-yl-ethyl)-4-o-tolyl-2,8-diaza- spiro [4.5] dec-3-en- 1-one The tide compound, MS: m/e = 596.1 (M+H + ), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-4-o-tolyl-2,8- diaza-spiro[4.5]dec-3-en-l-one and l-(2-chloroethyl)-morpholine. Example 174 8-(3,5-Bis-trifluoromethyl-benzoyl)-2-(3-dimethylamino-propyl)-4-o-tolyl-2,8-diaza- spiro[4.5]dec-3-en-l-one The tide compound, MS: m/e = 568.2 (M+H + ), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-4-o-tolyl-2,8- diaza-spiro[4.5]dec-3-en-l-one and 3-dimethylamino-l-propyl chloride. Example 175 8-(3,5-Bis-tτifluoromemyl-benzoyl)-2-pyridin-3-yl-methyl-4-o-tolyl-2,8-diaza- spiro[4.5]dec-3-en-l-one The title compound, MS: m/e = 574.1 (M+H + ), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl~benzoyl)-4-o-tolyl-2,8- diaza-spiro[4.5]dec-3-en-l-one and 3-chloromethyl pyridine. Example 176 (rac)-8- (3,5-Bis-trifluoromethyl-benzoyl)-4-o-tolyl-2,8-diaza-spiro [4.5] decan- 1-one The tide compound, MS: m/e = 485.3 (M+H + ), was prepared in accordance with the general methods of example 156 and 161 from o-tolyl cyanide and N-benzyl-4-piperidone. Reduction with hydrogen was performed for three days to also reduce the double bond. Example A l-(3,5-Bis-trifluoromethyl-benzoyl)-piperidin-4-one A solution of 3,5-bis-trifluoromethyl-benzoyl chloride (17.4 g, 63 mmol) in dichloromethane (30 mL) was added with cooling to a solution of 4-piperidone trifluoroacetate (13.4 g, 63 mmol) and triethylamine (22 mL, 158 mmol) so that the temperature did not rise above 20 °C. Stirring continued for 2 h at room temperature. Water was added, the phases were separated and the water phase was extracted with dichloromethane. The organic phases were pooled, dried with MgSO 4 and the solvent was evaporated. Chromatography on silica gel (ethyl acetate/n-hexane 1:1) yielded the desired product (20.2 g, 94 %), m.p. 155-157 °C and MS: m/e = 339.1 (M + ). Example B l-(3,5-Bis-trifluoromethyl-benzoyl)-4-(3-cUoro-phenylamino)-piperidme-4-carbordtrile To a solution of l-(3,5-bis-trifluoromethyl-benzoyl)-piperidin-4-one (5.1 g, 15 mmol) in acetic acid (20 mL) were added with cooling 3-chloroaniline (1.7 mL, 16.5 mmol) and trimethylsilylcyanide (1.9 L, 15 mmol) so that the temperature did not rise above 20 °C The suspension was stirred for 6 h at room temperature. The reaction mixture was than added to ice-water (350 mL), ammonia (55 mL, 25%) was added to the mixture which was stirred for 15 min. After that the mixture was extracted with dichloromethane, the organic phases were pooled, washed with brine and dried with MgSO 4 . The solvent was evaporated and the residue crystallized from ethylacetate to yield the desired product (5.3 g, 74 %), m.ρ. 205-207 °C and MS: m/e = 476.1 (M+H + ). Example C l-(3,5-Bis-μifluoromethyl-benzoyl)-4-(4-cMoro-phenylamino)-piperidine-4-carbonitrile The tide compound, m.p. 176-180 °C and MS: m/e = 474.1 (M-H " ), was prepared in accordance with the general method of example B from l-(3,5-bis-trifluoromethyl- benzoyl)-piperidin-4-one and 4-chloroaniline. Example D l-(3,5-Bis-trifluoromethyl-benzoyl)-4-(3,4-dichloro-phenylamino)-piperidine-4- carbonitrile The tide compound, m.p. 195-197 °C and MS: m/e = 512.1 (M+H + ), was prepared in accordance with the general method of example B from l-(3,5-bis-trifluoromethyl- benzoyl)-piperidin-4-one and 3,4-dichloroaniline. Example E l-(3,5-Bis-trifluoromethyl-benzoyl)-4-o-tolylammo-piperidine-4-carbonitrile The tide compound, m.p. 141-142 °C and MS: m/e = 456.3 (M+H + ), was prepared in accordance with the general method of example B from l-(3,5-bis-trifluoromethyl- benzoyl)-piperidin-4-one and 2-methylaniline. Example F l-(3,5-Bis-trifluoromemyl-benzoyl)-4-(2-cMoro-phenylarmno)-piperidine-4-carbonitrile The tide compound, MS: m/e = 474.1 (M-H " ), was prepared in accordance with the general method of example B from l-(3,5-bis-trifluoromethyl-benzoyl)-piperidin-4-one and 2-chloroaniline. Example G l-(3,5-Bis-txifluoromemyl-benzoyl)-4-(2-memoxy-phenylammo)-piperiάιne-4- carbonitrile The tide compound, MS: m/e = 472.2 (M+H + ), was prepared in accordance with the general method of example B from l-(3,5-bis-trifluoromethyl-benzoyl)-piperidin-4-one and o-anisidine. Example H 4-Benzylamino-l-(3,5-bis-trifluoromethyl-benzoyl)-piperidine-4-carbonitrile The tide compound, MS: m/e = 456.3 (M+H + ), was prepared in accordance with the general method of example B from l-(3,5-bis-trifluoromethyl-benzoyl)-piperidin-4-one and benzylamine. MS m/e (%): 586 (M+H + , 100). Example AA Tablets of the following composition are manufactured in the usual manner: mg/tablet Active substance 5 Lactose 45 Corn starch 15 Microcrystalline cellulose 34 Magnesium stearate 1 Tablet weight 100 Example BB Capsules of the following composition are manufactured: mg/capsule Active substance 10 Lactose 155 Corn starch 30 Talc 5 Capsule fill weight 200 The active substance, lactose and corn starch are firsdy mixed in a mixer and then in a comminuting machine. The mixture is returned to the mixer, the talc is added thereto and mixed thoroughly. The mixture is filled by machine into hard gelatine capsules. Example CC Suppositories of the following composition are manufactured: mg/supp. Active substance 15 Suppository mass 1285 Total 1300 The suppository mass is melted in a glass or steel vessel, mixed thoroughly and cooled to 45°C. Thereupon, the finely powdered active substance is added thereto and stirred until it has dispersed completely. The mixture is poured into suppository moulds of suitable size, left to cool, the suppositories are then removed from the moulds and packed individually in wax paper or metal foil.

Claims: Claims 1. Compounds of the general formula wherein R 1 is hydrogen, lower alkyl, lower alkenyl, phenyl or the following groups -(CH 2 ) m -non aromatic heterocyclyl, which is optionally substituted by lower alkyl, or is -(CH 2 ) m -heteroaryl, which is optionally substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, CF 3 , benzyl or cyano, or is -(CH 2 ) m -C(O)-NRR', -(CH 2 ) m -C(O)-lower alkyl, -(CH 2 ) m -C(0)-O-lower alkyl, -(CH 2 ) m -O-lower alkyl, -(CH 2 ) m -CH[C(O)-O-lower alkyl] 2 , -(CH 2 ) m CH(OH)-CH 2 -O-phenyl, -(CH 2 ) m -CH(CF 3 )OH, -(CH 2 ) ra -OH, -(CH 2 ) m -CN, ~(CH 2 ) m -NRR' , -(CH 2 ) m -cycloalkyl or -(CH 2 ) m -CHF ; R 2 is hydrogen, lower alkyl, halogen or lower alkoxy; R 3 is lower alkyl, lower alkoxy, halogen or CF 3 ; R,R' are the same or different and are hydrogen or lower alkyl; X is >N-, >C= or >CH-; X X 2 are independendy from each other hydrogen, hydroxy or lower alkoxy or may be together an oxo group; Y x /Y 2 are independendy from each other hydrogen, lower alkyl, -(CH 2 ) m -phenyl or may be together an oxo group; Z is a bond, -CH 2 - or -C(O)-; m is 0, 1, 2, 3 or 4; n is 2 or 3; n' 0 , 1 or 2 and pharmaceutically acceptable acid addition salts thereof. 2. A compound according to claim 1, wherein R 3 is trifluoromethyl and n is 2. 3. A compound according to claims 1 and 2, in which X is >N-, X X 2 are together an oxo group and Y Y 2 are both hydrogen. 4. A compound according to claim 3, which is 8-(3,5-Bis-trifluoromethyl-benzoyl)-3-(4,6-dimethoxy-[l,3,5]triazin-2-yl)-l-phenyl-l,3,8- triaza-spiro [4.5] decan-4-one, 8-(3,5-bis-trifluoromethyl-benzoyI)-l-(2-chloro-phenyI)-3-(4,6-dimethoxy-[l,3,5]triazin- 2-yl)- l,3,8-triaza-spiro[4.5] decan-4-one, 8-(3,5-,bis-trifluoromethyl-benzoyl)-3-pyridin-3-ylmethyl-l-o-tolyl-l,3,8-triaza- spiro [4.5] decan-4-one, 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-isopropylamino-ethyl)-l-o-tolyl-l,3,8-triaza- spiro [4.5 ] decan-4-one, 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-pyrrolidin-l-yl-ethyl)-l-o-tolyl-l,3,8-triaza- spiro [4.5] decan-4-one, 8-(3,5-bis-trifluoromethyl-benzoyl)-l-phenyl-3-pyridin-4-yl-l,3,8-triaza-spiro[4.5]decan- 4-one, 8-(3,5-bis-trifluoromethyl-benzoyl)-l-(2-chloro-phenyl)-3-methyl-l,3,8-triaza- spiro [4.5] decan-4-one, 8-(3,5-bis-trifluoromethyl-benzoyl)-l-(2-chloro-phenyl)-3-(3-dimethylamino-propyl)- 1,3,8-triaza-spiro [4.5] decan-4-one, 8-(3,5-bis-trifluoromelhyl-benzoyl)-l-(2-cUoro-phenyl)-3-pyridin-4-yl-l,3,8-triaza- spiro[4.5]decan-4-one and 8-(3,5-bis-trifluoromethyl-benzoyl)-3-methyl-l-o-tolyl-l,3,8-triaza-spiro[4.5]decan-4- one. 5. A compound according to claims 1 and 2, in which X is >N-, X X 2 are together an oxo group and one of Y Y 2 is hydrogen and the other is different from hydrogen. 6. A compound according to claim 5, which is (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-l-phenyl-l,3,8-triaza- spiro [4.5] decan-4-one, (rac)-8-(3,5-bis-trifIuoromethyl-benzoyl)-2-methyl-l-o-tolyl-l,3,8-triaza-spiro[4.5]decan- 4-one, (rac)-2-benzyl-8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-tolyl-l,3,8-triaza-spiro[4.5]decan- 4-one, (rac)-8-(3,5-bis-trifluoromefhyl-benzoyl)-2-phenyl-l-o-tolyl-l,3,8-triaza-spiro[4.5]decan- 4-one, (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-l-phenyl-3-pyridin-3-ylmethyl-l,3,8- triaza-spiro [4.5] decan-4-one, (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2,3-dimethyl-l-phenyl-l,3,8-triaza- spiro [4.5] decan-4-one, (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-l-phenyl-3-(2-pyrrolidin-l-yl-ethyl)- l,3,8-triaza-spiro[4.5]decan-4-one, (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-3-(3-dimethylamino-propyl)-2-methyl-l- phenyl- 1 ,3,8-triaza-spiro [4.5] decan-4-one, (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2,3-dimethyl-l-o-tolyl-l,3,8-triaza- spiro [4.5] decan-4-one, (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyI-3-(2-piperazin-l-yl-ethyl)-l-o-tolyl- l,3,8-triaza-spiro[4.5]decan-4-one, (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-3-(2-pyrrolidin-l-yl-ethyl)-l-o-tolyl- 1,3,8-triaza-spiro [4.5] decan-4-one, (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-3-(2-piperidin-l-yl-ethyl)-l-o-tolyl- l,3,8-triaza-spiro[4.5]decan-4-one, (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-methoxy-ethyl)-2-methyl-l-o-tolyl-l,3,8- triaza-spiro [4.5] decan-4-one, (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-3-(2-morpholin-4-yl-ethyl)-l-o-tolyl- l,3,8-triaza-spiro[4.5]decan-4-one and (rac)-8-(3,5-dichloro-benzoyl)-2-methyl-l-o-tolyl-l,3,8-triaza-spiro[4.5]decan-4-one. 7. A compound according to claims 1 and 2, wherein X is >N-, X X 2 and YVY 2 are oxo groups. 8. A compound according to claim 7, which is 8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-tolyl-l,3,8-triaza-spiro[4.5]decane-2,4-dione, 8-(3,5-bis-trifluoromethyl-benzoyl)-3-pyridin-3-ylmethyl-l-o-tolyl-l,3,8-triaza- spiro [4.5] decane-2,4-dione, 3-(lH-benzoimidazol-2-ylmethyl)-8-(3,5-bis-trifluoromethyl-benzoyl)-l-o-tolyl-l,3,8- triaza-spiro [4.5] decane-2,4-dione, 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-methyl-thiazol-4-ylmethyl)-l-o-tolyl-l,3,8- triaza-spiro [4.5] decane-2,4-dione, 8-(3,5-bis-trifluoromethyl-benzoyl)-3-furan-2-ylmethyl-l-phenyl-l,3,8-μiaza- spiro[4.5] decane-2,4-dione, 8-(3,5-bis-trifluoromethyl-benzoyl)-3-furan-2-ylmefhyl-l-o-tolyl-l,3,8-triaza- spiro [4.5] decane-2,4-dione and 8-(3,5-bis-trifluoromethyl-benzoyl)-3-thiophen-2-ylmethyl-l-o-tolyl-l,3,8-triaza- spiro [4.5] decane-2,4-dione. 9. A compound according to claims 1 and 2, wherein X is >C=. 10. A compound according to claim 9, which is 8-(3,5-bis-trifluoromethyl-benzoyl)-2-(2-pyrrolidin-l-yl-ethyl)-4-o-tolyl-2,8-diaza- spiro[4.5]dec-3-en-l-one and 8-(3,5-bis-trifluoromefhyl-benzoyl)-2-(3-dimethylamino-propyl)-4-o-tolyl-2,8-diaza- spiro[4.5] dec-3-en-l-one. 11. A compound according to claims 1 and 2, wherein X is >CH- 12. A compound according to claim 11, which is (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-o-tolyl-2,8-diaza-spiro[4.5]decan-l-one. 13. A medicament containing one or more compounds as claimed in any one of claims 1-12 and pharmaceutically acceptable excipients. 14. A medicament according to claim 13 for the treatment of diseases related to NK-1 receptor antagonists. 15. A process for preparing a compound of formula I as defined in claim 1, which process comprises a) reacting a compound of formula with a compound of formula to a compound of formula wherein L is a leaving group, for example halogen, such as chlorine, and the other substituents have the significances given above, or b) reacting a compound of formula with a compound of formula L-R' IV in the presence of sodium hydride or in the presence of potassium carbonate and CuCl, wherein in formula IV L is a leaving group, for example chlorine, to give a compound of formula wherein the other substituents have the significances given above with the proviso that R 1 is not -(CH 2 ) m -OH and X X 2 are not hydroxy, or c) reacting a compound of formula with a compound of formula OTBD S J m-1 v to a compound of formula wherein TBDMS is a tert-butyldimethylsilyl group and the further definitions of substituents is given above, or d) reacting a compound of formula after activation as mesylate with a corresponding amine of formula RR'NH to give a compound of formula wherein the definitions of substituents are given above, or e) reacting a compound of formula 1-1 with a compound of formula °-R" o VI to a compound of formula wherein R 4 is lower alkyl and the definitions of the other substituents are given above, or f) reacting a compound of formula with a compound of formula HO R B OH VII to a compound of formula wherein R 1 is phenyl or heteroaryl, optionally substitueted as described above and the definition of the remaining substituents is given above, or g) cyclizing a compound of formula VIII to a compound of formula 1-5 wherein the substituents are described above, or h) reacting a compound of formula with H,N ' to give a compound of formula 1-7 wherein the substituents are described above, or i) treating a compound of formula with hydrogen on Pd/C and then with (CF 3 ) 2 C 6 H 3 COCl to obtain a compound of formula wherein the substituents are given above, or modifying one or more substituents R -R 3 within the definitions given above, and if desired, converting the compound obtained into a pharmaceutically acceptable acid addition salt. 16. A compound according to any one of claims 1-12, whenever prepared by a process as claimed in claim 15 or by an equivalent method. 17. The use of a compound in any one of claims 1-12 for the treatment of diseases. 18. The use of a compound in any one of claims 1-12 for the manufacture of medicaments containing one or more compounds of formula I in accordance with claim 1 for the treatment of diseases related to NK-1 receptor antagonists. 19. The invention as hereinbefore described.

Inventors: GALLEY GUIDO, GODEL THIERRY, GOERGLER ANNICK, HOFFMANN TORSTEN, KOLCZEWSKI SABINE, ROEVER STEPHAN, GALLEY, GUIDO, GODEL, THIERRY, GOERGLER, ANNICK, HOFFMANN, TORSTEN, KOLCZEWSKI, SABINE, ROEVER, STEPHAN
Applicants: HOFFMANN LA ROCHE, F. HOFFMANN-LA ROCHE AG
Application year: 2001
Main classification: C07D471
IPC codes: A61K31, A61P1, A61P9, A61P11, A61P25, A61P27, A61P29, A61P37, A61P43, C07D471