Title of Invention

DIAZA-SPIROPIPERIDINE DERIVATIVES

Abstract

Abstract The present invention relates to compounds of formula (I); wherein A-B is -CH2-CH2-5 -CH2-0- or -0-CH2-; X is hydrogen or hydroxy; R<1 > is aryl, optionally substituted by one or two substituents, selected from the group consisting of halogen, lower alkyl, cyano, CF3, -OCF3, lower alkoxy, -S02-lower alkyl or by heteroaryl, R<2 > is aryl, optionally substituted by one or two substituents, selected from the group consisting of halogen, lower alkyl, CF3 or lower alkoxy; R<3 >is hydrogen or lower alkyl; n is 0, 1 or 2; and to their pharmaceutical active salts. The compounds of formula I may be used in the treatment of neurological and neuropsychiatry disorders.

Full Text

Diaza-spiropiperidine derivatives The present invention relates to compounds of formula wherein A-B is -CH2-CH2-> -CH2-O- or -0-CH2s X is hydrogen or hydroxy; R1 is aryl, optionally substituted by one or two substituents., selected from the group consisting of halogen, lower alkyl, cyano, CF3, -OCF3, lower alkoxy, -SCVlower alkyl or by heteroaryl, R is aryl, optionally substituted by one or two substituents, selected from the group consisting of halogen, lower alkyl, CF3 or lower alkory; a R is hydrogen or lower alky!; a is 0,1 or 2; and to their pharmaceutically active salts. The present invention related to compounds of general formula I, to pharmaceutical composition containing them and their use in the treatment of neurological and neuropsychiatric disorders. It has surprisingly been found that the compounds of general formula I are good inhibitors of the glycine transporter 1 (GlyT-1), and that they have a good selectivity to glycine transporter 2 (GlyT-2) inhibitors. Schizophrenia is a progressive and devastating neurological disease characterized by episodic positive symptoms such as delusions, hallucinations, thought disorders and psychosis and persistent negative symptoms such as flattened affect, impaired attention and social withdrawal, and cognitive impairments (Lews DA and Lieberman JA, Neuroi% 2000, 28:325-33). For decades research has focused on the "dopaminergic hyperactivity" hypothesis which has led to therapeutic interventions involving blockade of the dopaminergic system (Vandenberg RJ and Aubrey KR., Exp. Opin. Tner. Targets, 2001, 5(4): 507-518; Nakazato A and Oknyama 2 et al., 2000, Ety. Opvru Ther. Patents, 10(1): 75-98). This pharmacological approach poorly address negative and cognitive symptoms which, are the best predictors of functional outcome (Shaxma T., Br J. Psychiatry* 1999, 174(suppl. 28): 44-51). A complementary model of schizophrenia was proposed in the mid-19605 based upon the psychotomimetic action caused by the blockade of the glutamate system by compounds like phencydidine (PCP) and related agents (ketamine) which are noncompetitive NMDA receptor antagonists. Interestingly in healthy volunteers, PCP-induced psychotomimetic action incorporates positive and negative symptoms as well as cognitive dysfunction, thus closely resembling schizophrenia in patients (Javitt DC et al., 1999, Biol Psychiatry, 45: 668-679 and refs. herein). Furthermore transgenic mice expressing reduced levels of the NMDAR1 subunit displays behavioral abnormalities similar to those observed in pharmacologically induced models of schizophrenia, supporting a model in which reduced NMDA receptor activity results in schizophrenialike behavior (Mohn AR et al., 1999, CeK, 98:427-236). Glutamate neurotransmission, in particular NMDA receptor activity, plays a critical role in synaptic plasticity, learning and memory, such as the NMDA receptors appears to serve as a graded switch for gating the threshold of synaptic plasticity and memory formation (Hebb DO, 1949, The organization of behavior, Wiley, NY; Bliss TV and Collingridge GL, 1993, Nature, 361: 31-39). Transgenic mice overexpressing the NMDA KR2B subunit exhibit enhanced synaptic plasticity and superior ability in learning and memory (Tang JP et al., 1999, Nature. 401- 63-69). Thus, if a gLutamate deficit is implicate in the pathophysiology of schizophrenia, enhancing glutamate transmission, in particular via NMDA receptor activation, would be predicted to produce both anti-psychotic and cognitive enhancing effects. The amino acid glycine is known to have at least two important functions in the CNS. It acts as an inhibitory amino acid, binding to strychnine sensitive glycine receptors, and it also influences excitatory activity, acting as an essential co-agonist with glutamate for N-mefhyl-D- aspartate (NMDA) receptor function. While glutamate is released in an activity-dependent manner from synaptic terminals, glycine is apparently present at a more constant level and seems, to modulate/control the receptor for its response to glutamate. One of the most effective ways to control synaptic concentrations of neurotransmitter is to influence their re-uptake at the synapses. Neurotransmitter transporters by removing neurotransmitters from the extracellular space, can control their extracellular lifetime and thereby modulate the magnitude of the synaptic transmission (Gainetdinov RR et al, 20023 Trends in Pharm. Sri., 23(8): 367-373). Glycine transporters, which form part of the sodium and chloride family of neurotransmitter transporters, play an important role in the termination of post-synaptic glycinergic actions and maintenance of low extracellular glycine concentration byre-uptake of glycine into presynaptic nerve terminals and surrounding fine glial processes. Two distinct glycine transporter genes have been cloned (GlyT-1 and GlyT-2) from mammalian brain, which give rise to two transporters with ~50 % amino acid sequence homology. GlyT-1 presents four isoforms arising from alternative splicing and alternative promoter usage (la, lb, 1c and Id). Only two of these isoforms have been found in rodent brain (GlyT-la and GlyT-lb). GlyT-2 also presents some degree of heterogeneity. Two GlyT-2 isoforms (2a and 2b) have been identified in rodent brains. GlyT-1 is known to be located in CNS and in peripheral tissues, whereas GlyT-2 is specific to the CNS. GlyT-1 has a predominantly glial distribution and is found not only in areas corresponding to strychnine sensitive glycine receptors but also outside these areas, where it has been postulated to be involved in modulation of NMDA receptor function (Lopez-Corcuera B et aL, 2001, Mol Mem. Biol, 18:13-20). Thus, one strategy to enhance NMDA receptor activity is to elevate the glycine concentration in the local microenvironment of synaptic NMDA receptors by inhibition of GlyT-1 transporter (Bergereon R. Et aL, 1998, Proc Natl Acad. Set. USA, 95:15730-15734; Chen L et aL, 2003, J. Neurophysiol, 89 (2): 691-703). Glycine transporters inhibitors are suitable for the treatment of neuroligical and neuropsychiatric disorders.The majority of diseases states implicated are psychoses, schizophrenia (Armer RE and Miller DJ, 2O01, Exp. Opin. Ther. Patents, 11 (4): 563-572), psychotic mood disorders such as severe major depressive disorder, mood disorders associated with psychotic disorders such as acute mania or depression associated with bipolar disorders and mood disorders associated with schizophrenia, (Pralong ET et aL, 2002, Prog. NeurobioU 67:173-202), autistic disorders (Carlsson ML, 1998, J. Neural Transm. 105: 525-535), cognitive disorders such as dementias, including age related dementia and senile dementia of the Alzheimer type, memory disorders in a mammal, including a human, attention deficit disorders and pain (Armer RE and Miller DJ, 2001, By. Opin. Ther. Patents, 11 (4): 563-572). Thus, increasing activation of NMD A receptors via GlyT-i inhibition may lead to agents that treat psychosis, schizophrenia, dementia and other diseases in which cognitive processes are impaired, such as attention deficit disorders or Alzheimer's disease. Objects of the present invention are the compounds of formula I per se, the use of compounds of formula I and their pharmaceutical^ acceptable salts for the manufacture of medicaments for the treatment of diseases related to activation of NMD A receptors via Glyt-1 inhibition their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula I in the control or prevention of illnesses such as psychoses, disfunction in memory and learning, schizophrenia, dementia and other diseases in which cognitive processes are impaired, such as attention deficit disorders or Alzheimer's disease. The preferred indications using the compounds of the present invention are schizophrenia, cognitive impairment and Alzheimer's disease. Furthermore, the invention includes all racemic mixtures, all their corresponding enantiomers and/or optical isomers. As used herein, the term ftlower alkyl1 denotes a saturated straight- or branched-chain group containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyi, 2-butyl, t-butyl and the like Preferred akcyl groups are groups with 1-4 carbon atoms. The term ,rhalogen" denotes chlorine, iodine, fluorine and bromine. The term "aryl denotes a monovalent cyclic aromatic hydrocarbon radical consisting of one or more fused rings in which at least one ring is aromatic in nature, for example phenyl or naphthyl. The term "heteroaryl" denotes a cyclic aromatic hydrocarbon radical, containing one, two or three heteroatoms, selected from the group consisting of oxygen, sulphur or nitrogen, for example pyridyl, pyrazinyl, pyrinridinyl, pyridazinyl, triazinyl, thiazolyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isothiazolyl or isoxazolyl. The term "pharmaceutical 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, methane-sulfonic acid, p-toluenesulfonic acid and the like. X is hydrogen or hydroxy; R1 is phenyl, optionally substituted by one or two substituents, selected from the group consisting of halogen> lower alkyl, cyano, CF3> -OCF5, lower alkoxy, -SCVlower alkyi or by heteroaryl, R" is phenyl, optionally substituted by one or two substituents, selected from the group consisting of halogen or lower alkoxy; R is hydrogen; n is 1; and their pharmaceutical^ active salts. Most preferred are compounds, wherein n is 1 and A-B is -CH2-CH2-. Especially preferred compounds from this group are those, wherein R and R~ are both phenyl, optionally substituted by lower alkyi, halogen or CF3, for example the following compounds: ds-rac-4-phenyl-8-(2-phenyl-cycloher^l)-2,8-dia2a-spiro[4.5]decan*l-one, cis-rac4-phenyl-8-(2-p-tolyl-cyclohexyl)-2?8-diaza-spiro [4.5] decan- 1-one, ris-rac-8-[2-(4-fluoro-phenyl)-cydo ds-rac-4-(4-fluoro»phenyl)-8-[2-(4-fluoro-phenyl)-qrcloheryl]-238-diaza-spiro [4.5] decan-1-one, ds-rac^-(4-fluoro-phenyl)-8-[2-(4-tr$^ spiro[4.5] decan-1-one, 8-[2-(4-fluoro-phenyl)-2-hydrox)^c7clohex^d]"4-phenyl-2,8-diaza-spiro[4.5]decan-l-one, 4-(4-fluoro-phenyl)-8-[2-(3-fluoro-phen7l)-2-hydrox)'-cydoher)7'l]-2?8-diaza-spiro [4.5] decan- 1-one, 4-(4-fluoro-phenyl)-8-[2-(2-fluoro-phenyl)'2-hydroxy-qrdohex5i]-2,8-diaza-1 spiro [4.5]decan-l-one, 8-[2-(3-diloro-phenyl)-2-hydroxy-spiro [4.5] decan-1-one or 4-(4-fluoro-phenyl)-8~tra7?s-(4-hy spiro [4.5] decan- 1-one. Preferred are further compounds, wherein X is hydrogen. The invention relates also to compounds, wherein X is hydroxy. Objects of the present invention are further compounds, wherein n is 1 and A-B is -CH2-O-. The present compounds of formula I and their pharmacerrtically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which process comprises 1 a) reacting a compound of formula wherein the substituents are as defined above, or b) reacting a compound of formula wherein the substituents are as defined above, or c) if desired, separating the obtained racemic forms into corresponding enantiomers, and if desired, converting the compounds obtained into pharmaceutical^ acceptable add addition salts. The compounds of formula I maybe prepared in accordance with process variant a), b) or c) and with the following schemes 1, 2 and 3. The following abbreviations have been used: LDA = lithium diisopropylamide TFA = trifluoroacetic acid DCM = dichloromethane THF = tetrahydrofuran P2\4HS = polymethylhydxosiloxane DMSO = dimethylsulfoxide Starting from an appropriately l-protected-piperidine-4-alk57'lcarborylate 2, treatment with an appropriate base, usually LDA, followed by treatment with an appropriately substituted nitro alkene 3 results in formation of the nitro alkane 4 Reduction to the amino group facilitated by Raney-Ni and hydrogen, usually at 60 bar pressure and at 55 °C in EtOH as solvent results in the formation of 5. Subsequent cyclisation by heating in toluene under reflux affords the amide 6. Removal of the protecting group under standard conditions (TFA treatment in DCM for R = Boc; or hydrogenolysis with Pd/C in DCM3 MeOH for R = Bn) affords the diazaspiropiperidines 7 (Scheme 1). Further reaction of compounds of formula 7 with corresponding compounds of formula 11 (which can be prepared by reaction of the arylhalides of formula 8 with BuLi and subsequent reaction with an epoxide of formula 9 to give the alcohols of formula 10, which are oxidized to the corresponding ketones of formula 11 with Dess-Martin Periodinane) in the presence of Ti(OPr-i)4 and NaBH(OAc)3 to give compounds of formula I (Scheme 2). Alternatively, reaction of compounds of formulas 7 and 11 in the presence of Ti(OPr-i)4 and NaBH(OAc)3 (with or without the presence of PMHS) also gives products of formula!. An alternative strategy where overall reductive amination of the ketones of formula 11 with compounds of formula 12 in a Dean-Stark trap affords an intermediate enamine, wThich can be reduced in situ to the compound formula 13. Following steps 1-3 as described in Scheme 1 affords compounds of formula L Compounds of formula I for X = OH are prepared by reacting compounds of formula 7 -with an oxides of formula 9 in refluxing ethanol. The resulting ft—arninoalcohol of formula 14 can then be oxidised to the ketone, preferably, with pyridine.S03 complex in the presence of triethylamine in DMSO to give compounds of formula 15, which are then treated with aryl lithium reagents (formed by halogen-metal exchange) to provide access to the desired products of formula I (Scheme 3). All compounds of formulas I, 4, 5,6,7,11,10,13,14,15 are usually formed during the sequence of reactions into an equal mixture of (R,R,S)-> (S,S,R)-, (R>R,R)- and (S>S,S)-enantiomers (racemic forms), following the procedures described below. They may separated into chiral non-racemic enantiomers by preparative HPLC using either a Chiralpak OD or AD column (5 x 50 cm) at room temperature using an ethanol: heptane mobile phase with UV detection at 220 nM. The acid addition salts of the basic compounds of formula I may be converted to the corresponding free bases by treatment with at least a stoichiometric equivalent of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodiiam bicarbonate, ammonia, and the like. The compounds of formula I and their pharmaceutical^ usable addition salts possess valuable pharmacological properties. Specifically, it has been found that the compounds of the present invention are good inhibitors of the glycine transporter I (GlyT-1). The compounds were investigated in accordance with the test given hereinafter. Solutions and materials DMEM complete medium: Nutrient mixture F-12 (Gibco Life-technologies),-fetal bovine serum (FBS) 5 %, (Gibco life technologies). Penicillin/Streptomycin! % (Gibco life technologies), Hygromycin 0.6 mg/ml (Gibco life technologies), Glutamine 1 rnlsl Gibco life technologies) Glycine uptake inhibition assay frnGlyT-lb) On day 1 mammalian cells, (Hp~in™-CHO), transfected with mGlyT-lb cDNA > were plated at the density of 40,000 cells/well in complete F-12 medium, without hygromycm in 96-well culture plates. On day 2, the medium was aspirated and the cells were washed twice with uptake buffer (UB). The cells were then incubated for 20 min at 22°C with either (i) no potential competitor, (ii) 10 mM non-radioactive glycine, (iii) a concentration of a potential inhibitor. A range of concentrations of the potential inhibitor was used to generate data for calculating the concentration of inhibitor resulting in 50 % of the effect (e.g. IC50, the concentration of the competitor inhibiting glycine uptake of 50 %). A solution was then immediately added containing [~H]-glycine 60 nM (11-16 Ci/mmol) and 25 pM non-radioactive glycine. The plates were incubated with gentle shaking and the reaction was stopped by aspiration of the mixture and washing (three times) with ice-cold UB. The cells were lysed with scintillation liquid, shaken 3 hours and the radioactivity in the cells was counted using a scintillation counter. The activity as inhibitor of the glycine transporter I (GlyT-1) is dependent on its racemic or enantiomeric form. The compounds of formula I and the pharmaceutically acceptable salts of the compounds of formula I 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, drag6es> hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions. The compounds of formula I can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose,corn starch or derivatives thereof, talc, stearic adds or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragdes and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are however usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like. The pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varjing the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances. Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts and., if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers. The most preferred indications in accordance with the present invention axe those, which include disorders of the central nervous system, for example the treatment or prevention of schizophrenia, cognitive impairment and Alzheimer's disease. The dosage can vary -within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage maybe administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated. The following examples illustrate the present invention without limiting it All temperatures are given in degree Celsius. . Preparation of Building blocks 11 rac-2-(4-Fluoro-phenvl')-q?rclohexanol a) To a solution of l-bromo-4-ftuorobenzene (12.5 mL, 114 mmol) in diethylether (250 mL) at -78 °C was added BuLi (1.6 M, 68 mL, 109 mmol) under argon. After 5 min at this temperature, qrclohexenoxide (11.0 mL, 109 mmol) was added followed by the addition ofborontrifluoride-diethyletherate (13.8 mL, 109 mmol) whereby the temperature increased to approx. -50 °C. After 4 h at this temperature the reaction was quenched by the addition of ammonium chloride (saturated, 200 mL) and diluted with water (50 mL). The product was then extracted with diethylether (3 x 100 mL) and the combined organic extracts dried over sodium sulfate. Filtration and evaporation afforded the title compound (11.9 g, 56 %) as white crystals after trituration from hexane. MS : m/e =194.1 (M). rac-2-f4-Huoro-phenylVcvrlohexanone bi) To a solution of rac-2-(4-fluoro-phenyl)-cyclohexanol (3.8 g, 20 mmol) in DCM (320 mL) was added Dess-Martin periodinane [l,l)l-tris(acetylox7)-l,l-dihydro-l?2-benziodcxol-3-(lH)-one] (10 g, 24 mmol) at room temperature and after 2 h the reaction mixture was washed with sodium hydrogen carbonate (10 %, 150 mL). The organic phase w^as then separated and washed with sodium thiosulfite (10 %, 150 mL) and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography through silica gel, eluting with ethyl acetate: hexane (1:4) afforded the title compound (3.4 g, 89 %) as white crystals. MS : m/e = 192.1 (M). rac-2-(4-Fluoro-pheirri)-cvclohexanone bii) Alternatively to a solution of rac-2-(4-fluoro-phenyl)~cyclohexanol (7.5 g, 39 nmol) in dry DMSO (67 mL) was added triethyiamine (27 mL, 190 mmol) under argon ind the resulting mixture cooled to 0 °C and then a solution of sulfur trioxide pyridine complex (18.4 g, 116 mmol) in dry DMSO (98 mL) was added dropwise over 15 min. After 1 h, the mixture was diluted with water (200 mL) and the product extracted with DCM (2 x 100 mL). The combined organic extracts were then dried over sodium sulfate, followed by filtration and evaporation. Purification by filtration through silica gel, eluting with ethyl acetate: hexane (1: 4) afforded the title compound (7.1 g, 95 %) as white crystals. MS: m/e = 192.1 (M). rac-2-p-Tolyl-cyclohexanone rac-2-ft-Tolvl-cyclohexanol a) To a solution of p-tolylbromide (17.1 g, 100 mmol) in dry THF (100 mL) was added magnesium (2.43 g,100 mmol) and then the resulting mixture was cooled to -20 °C and (CuBr-dimethylsulfide complex (2.0 g> 10 mmol) was added and the mixture stirred at - 20 °C for 10 min. Then a solution of cyclohexene oxide (10 mL, 100 mmol) in dry THF (10 mL) was added dropwise and the reaction warmed to 0 °C at which point an exothermic reaction initiates. With ice-bath cooling the temperature can be maintained below 25 °C. The reaction mixture was then stirred at 0 - 5 °C for an additional 2 h, then quenched with ammonium chloride solution (saturated, 30 mL) and the product extracted with tert-buiyl methyl ether. The combined organic extracts were then washed with water, dried over sodium sulfate, filtered and evaporated. Recrystallisation from hexane afforded the title compound (9.9 g, 52 %) as white crystals. MS : m/e = 190.1 (M). rac-2^-Tolvl-cvclohexanone b) As described for building block 11 step bi, rac-2-£~tolyl-qrclohexanol (4.86 g, 26 mmol) was converted to the title compound (4.68 g, 97 °/o) which was obtained as white crystals. MS : m/e = 188.1 (M). rac-2-(4-Trifluoromethyl-phenyI)-cycloh.esaiione rac-2-(4'TrifluQrometfayl"phenTiV^clob.exanol a) As described for "building block 11 step a, 4-bromo-benzotrifluoride (10.0 gs 44 mmol) was converted to the title compound (5.64 g, 52 %) which was obtained as a white solid MS : m/e = 244.1 (M). rac-2-f4-Trifluoromethvl-phenTlVarclobesanone b) As described for building block 11 step bi, rac-2-(4-txifluorometbyl-plienyl)- qndohexanol (5.5 g, 23 mmol) was converted to the title compound (5.26 g, 96 %) which was obtained as a white solid. MS : m/e = 242.1 (M). rac-2-(4-Trifluoromethox5r-phenyl)-C5rclohexanone rac-2- (4~Trifluorometho:KV-phenvl) -cyclohexanol a) As described for building block 11 step a>l-bromo-4-(trifLuoromethoxy)benzene (103 g, 43 mmol) was converted to the title compound (6.7 g, 60 %) which was obtained as a white solid MS : m/e = 260.1 (M). rac-2-(4-Trifluoromethoxy-phenvl')-cvclohexanoDe b) As described for building block 11 step bi, rac-2-(4-trifluoromethox7-phenyl)- cyclohexanol (6.6 g, 25 mmol) was converted to the title compound (5.36 g, 82 %) which was obtained as a white solid. MS : m/e = 258.2 (M). rac-2-(3-Huoro-phenyl)-cyclohexanone rac-2"(3-RuorO"phenvl)-cs^clohexanol a) As described for building block 11 step a, l-bromo-3-fluorobenzene (10.0 g> 57 mmol) was converted to the title compound (5.1 g, 46%) which was obtained as a white solid MS: m/e = 194.1 (M). rac-2~f3-Fluoro-phenvl)-cvclohexanone As described for building block 11 stepbi, rac-2-(3-flnoro-phenyl)-cyclohexanol (5.0 g, 26 mmol) was converted to the title compound (3.9 g> 80 %) which was obtained as a white solid. MS : m/e = 192.1 (M). rac- 2- (3-Trifluoromethyl-phenyl)-q^cloliesaBone rac-2-f3-Tri£Luoromethvl-pbenyIVcydohes:aiiol a) As described for building block 11 step a, 3-bromobenzotrifluoride (10.0 g, 44 mmol) was converted to the title compound (4.87 g, 45 %) which was obtained as a white solid. MS: m/e = 244.1 (M). rac- 2- f 3-Trifluorometfavl-phenvD -ovdohexanone b) As described for building block 11 step bi> rac-2-(3-txifluorometliyl-phenyl)- cydohexanol (4.7 g, 19 mmol) was converted to the title compound (4.34 g, 93 %) which was obtained as a light yellow oil. MS : m/e = 242.1 (M). rac-2-(3-Fluoro«4-methyl-phenyl)-cyclohexanone rac- 2- (3 -Fluoro-4-methvl-phenvl) - cydohexanol a) As described for building block 11 step a, 4-bromo-2-fluorotoluene (10.0 g> 53 mmol) was converted to the title compound (6.33 g, 58 %) which was obtained as a white solid. MS: m/e = 208.3 (M). rac- 2- f 3 -Huoro-4-methvl-phenvl) -cydohexanone b) As described for building block 11 step bi, rac-2-(3-Huoro-4-methyl-phenyl)- cydohexanol (6.2 g, 30 mmol) was converted to the title'compound (5.53 g, 91%) which was obtained as a white solid. MS : m/e = 206.1 (M). rac-2-(4-Methyl-3-trifluoromethyl-phenyl)-qrclohexanone rac-2- (4-Methyi- 3-trifluor omethvl-phenvD -cvclohexanol a) As described for building block 11 step a, 4-methyl-3-(trifluoromefhyl)bromobenzene (4.2 g, 18 mmol) was converted to the title compound (1.95 g, 43 %) which was obtained as a white solid. MS : m/e = 258.2 (M). rac-2-f4-MethYl-3-lriflnoro b) As described for building block 11 step bi, rac-2-(4-metiiyl-3-trifluorometiiyl-phenyl)-cyclohexanol (1.91 g, 7 mmol) was converted to the title compound (1.8 g, 95 %) which was obtained as a white solid. MS : m/e = 256.1 (M). rac-2- (4-Huoro- 3-methyl-phenyl)-cyclohexanone rac-2-(4-Fluoro-3-methvl-phenvl)-cvfclohexanol a) As described for building block 11 step a, 5-bromo-2-fluorotoluene (10.0 g, 53 mmol) was converted to the title compound (5.47 g, 50 %) which was obtained as a white solid. MS:m/e = 208.2 (M). rac- 2- f 4-Pluoro-3-meth.vl-phen vl) -cyclohexanone b) As described for building block 11 step bi, rac-2-(4-fluoro-3~methyl-phenyl)- cyclohexanol (5.4 g> 26 mmol) was converted to the title compound (14.7 g, 88 %) which was obtained as a light yellow oil. MS : m/e = 206.1 (M). rac-2-(4-Chloro-3-trifluoromethyl»phenyl)-cyclohexanone rac-2-(4-CHoro-3-trifluoromethyl-phenyl)-cvclohexanol a) As described for building block 11 step a, 5-bromo-2-chlorobenzotrifluoride (832 g, 30 mmol) was converted to the title compound (4.4 g, 52 %) which was obtained as a white solid. MS : m/e = 278.1 (M). rac-2-(4-Chloro-3-trifluoromeliiyl-phenvl)--cvclohexanone b) As described for building block 11 step bi> rac-2-(4-chloro-3-trifluorometh)i-phenyl)- cyclohexanol (4.3 g? 15 mmol) was converted to the title compound (4.13 g, 97 %) which was obtained as a white solid. MS : m/e = 276.1 (M). Preparation of Building blocks 7 rac-4-Phenyl-2,8-diaza-spiro[4.5]decan-l-one rac-l-Ben2^i-4-(2-nitro-l-nhenvl-ethvlVpberidine-4-carbo^rlic acid ethvl ester a) An LDA (14 mmol) solution was prepared by treating diisopropylamine (137 g, 14 mmol) with BuLi (1.6 M, 8.5 mL, 14 mmol) at -78 °C in 'dry THF (10 mL) under argon and aflowing to warm up to -20 °C. This solution was then cooled to -60 °C added to a solution of l-benzyl-piperidine-4-ethyl carbozylate (3.05 g, 12 mmol) in TUP (8 mL) at -60 °C and allowed to warm up to -40 °C over 1 h whereupon a solution of fraru-beta-nitrostyrene (1.93 g513 mmol) in THF (8 mL) was added dropwise. The reaction mixture was allowed to warm up to room temperature over 1 h and then quenched with ammonium chloride (saturated, 40 mL) and the product extracted with ethyl acetate (2 x 40 mL). The combined organic extracts were then washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography on silica gel eluting with DCM: MeOH (9 :1) afforded the title compound (4.1 g, 84 %) as a light yellow gum. MS :m/e = 397.4 (M+H). rac-4-(2-amino-1-phenyl-ethyl)-1-benzyl piperidine-4-carboxylic acid ethyl ester b) A solution of rac-l-benzyl-4-(2-nitro-l-phenyl-ethyl)-piperidine-4-carboxylic acid ethyl ester (3.18 g, 8 mmol) in dry EtOH (240 mL) was hydrogenated in the presence of Ra-Ni (3 g) at 60 bar at 55 °C for 3 h. After cooling and decompression of the reaction vessel, the mixture was filtered over celite and the filtrate evaporated to leave the title compound (2.9 g, 99 %) as a clear oil. MS : m/e = 367.4 (M+H). rac-8-Benzvl-4-phenvl-2,8-diaza-spiro [4.5] decan-1-one c) A solution of rac-4-(2-amino-l-phenyl-ethyl)-l-ben2yl-piperidine-4-carborj:rlic add ethyl ester (2.9 g, 8 mmol) in toluene (30 mL) was heated under reflux for 4 h. After cooling to room temperature and evaporation the mixture was purified by chromatography on silica gel eluting with DCM: MeOH : NILOH (95 :4.5: 0.5) to afford the title compound (1.47 g, 58 %) as a white solid. MS : m/e = 321.4 (M+H). rac-4-Phenvl-2,8-diaza-spiro[4.5]decan-l-one d) A suspension of rac-8-benz}i-4-phenyl-2J8-diaza-spiro[4.5]decan-l-one (28.8 g, 90 mmol) in MeOH: DCM (4 : 1, 500 mL) was hydrogenated in the presence of Pd (10% on Q 14 g> 132 mmol) at 2 bar for 48 h at room temperature. After filtration over celite, the reaction mixture was evaporated and the residue dissolved in NaOH (2 N, 200 mL). The product was extracted with DCM (3 x 150 mL) and the combined organic extracts dried over sodium sulfate. Filtration and evaporation afforded the title compound (13.1 g, 63 °/o) as a white solid after trituration from diethylether. MS: m/e = 231.4 (M+H). Scheme 1, Step 1: F-derivative from Boc protecting group rac-4-(4-Ruoro-phenyl)-278-diaza-spiro[4.5]decan-l-one Piperidine-l,4-dicarboxvIic acid 1-tert-butvl ester 4-ethvl ester a) To a solution of ethyl isonipecotate (20 g, 127 mmol) in dioxane; water (1: 1> 120 mL) was added triethylamine (12.87 g,127 mmol) at 0 °C followed by di-tert-butyl dicarbonate (35.2 g, 161 mmol) and the resulting mixture maintained at this temperature for 2 h. The product was then extracted with ethyl acetate (3 x 100 mL) and the combined organic extracts washed with HQ (1 N, 100 mL), brine (100 mL), dried over sodium sulfate, filtered and evaporated. Purification by Kugelrohr distillation afforded the title compound (29.0 g, 89 %) as a colourless liquid, bp 140 °C at 0.13 mbar. MS : m/e = 275.2 (M+NH4). rac-44l-f4-Huoro-phenvl)-2-m1xo-e& 1-tert-butvl ester 4-etfavl ester b) An LDA solution was prepared by treating diisopropylamine (6.98 g, 69 mmol) with BuLi (1.6 M, 413 mL, 66 mmol) at -78 °C in dry THF (45 mL) under argon and allowing to warm up to -20 °C This solution was then cooled to -60 DC added to a solution of piperidine-l,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (15.44 g, 60 mmol) in dry THF (45 mL) at -60 DC and allowed to warm up to -40 °C over 1 h whereupon a solution of 4-fluoro-tra7w-beta-nitrost}7rene (10.02 g, 60 mmol) in dry THF (40 mL) was added dropwise. The reaction mixture was allowed to warm up to room temperature over 1 h and then quencbed with ammonium chloride (saturated, 250 mL) and the product extracted with diethylether (3 x 100 mL). The combined organic extracts were then washed "with brine, dried over sodium sulfate, filtered and evaporated to afford the title compound (26.7 g, 99 %) as a light yellow gum. MS : rn/e = 442.4 (M+NH4). rac-4-f2~Amfoo-l-phenvl-ethvD-l-te^ arid ethyl ester c) A solution of rac-4-[l-(4-fluoxo-pbenyl)-2-rd1xo-etliyl]-piperidine-l,4-dicarbox3iic acid 1-tert-butyl ester 4-ethyl ester (26.6 g, 60 mmol) in dryEtOH (600 mL) was hydxogenated in the presence of Ra-Ni (25 g) at 50 bar at 50 °C for 20 h After cooling and decompression of the reaction vessel, the mixture was filtered over celite and the filtrate evaporated to leave the title compound (23.4 g, 99 %) as a clear oil "which was used directly in the next step. rac~4-f4-Huoro-phenvlVl-oxo-2,S-diaza-spiro[4.5l decane-8-carboxvlic acid tert-butyl ester d) A solution of 4-(2-ammo-l-phenyl-eti^ acid ethyl ester (23.4 g, 60 mmol) in toluene (200 mL) -was heated under reflux for 18k After cooling to room temperature, evaporation afforded the title compound (17.17 g, 83 %) as a white solid after trituration from hot pentane. MS : m/e = 349.3 (M+H). rac-4-f4-Fluoro'phenvl)-2,8-diaza-spiro[4.5ldecan-l-one e) A solution of 4-(4-fLuoro-phLen"^}-l-oxo-2?8-diaza-spiro[4.5]decane-8-carbor57lic add tert-butyl ester (46.0 g, 132 mmol) in DCM (260 mL) containing TFA (150 mL, 1.32 mol) was stirred vigorously at 0 °C for 15 min. The reaction mixture was then poured into NaOH (3 N, 200 mL) and the product extracted with DCM (3 x 100 mL). The combined organic extracts were then washed with water (100 mL) and brine (100 mL) and then dried over sodium sulfate. Filtration and evaporation afforded the title compound (22.14 g, 68 %) as a white solid after trituration from ethyl acetate. MS ; m/e = 249.2 (M+H). Example 1 cis-rac-4-Pbenyl-8-(2-phenyl-cyclohex5rl)"2,8-diaza-spiro[4.5]decan-l-one cis-rac-l-(2-Phenyl"^dohex^yl)-piperidine-4-carbox\rlic acid ethyl ester a) A solution of ethyl isonipecotate (3.7 g> 24 mmol), 2-phenylcyclohexanone (5.0 g, 29 mmol) in toluene (50 mL) containing para-toluenesulfonic acid (446 mg, 2 mmol) was heated under reflux with a Dean-Stark trap for 13 h. After cooling to room temperature the mixture was evaporated to leave approximately 15 mL of solution and then diluted with l>2-dichloroethane (120 mL) and then acetic acid (0.95 mL) was added followed by the portionwise addition of sodium triacetoxyborohydride (7.3 g, 33 mmol). After 3.5 b the mixture was quenched with NaOH (3 N, 50 mL)5 diluted -with water (50 mL) and the organic layer separated. The organic layer was then dried and evaporated to leave a residue which, was purined by silica gel chromatography eluting "with heptane : ethyl acetate (9 : 1) to (4 :1) to (3 : 2) to afford the title compound as a light yellow oil (5.5 g, 75 %). MS : m/e = 316.2 (M+H). cis-rac4-f2-Nitro-l-phenTl-^ ethyl ester b) As described for building block 7 step a, l-(2-phenyl-c7dohexyl)-piperidine-4- carboxylic acid ethyl ester (1.0 g, 3 mmol) was converted to the title compound (1.1 g, 73 %) which was obtained as an off-white solid. MS : m/e = 465.4 (M+H). c^-rac-4-Phenyl-8-(2-pheny^ c) As described for building block 7 step b, 4-(2-nitro-l-phenyl-ethyi)-l-(2-plienyl- cfclohe)C7l)-piperidine--4"Cafbosylic acid ethyl ester (1.0 g, 2 mmol) was converted to the amino compound (810 mg, 87 %) which was obtained as a light yellow oil and used directly in the next step. MS : m/e = 435,4 (M+H). d) As described for example building block 7 step c, the amino compound (810 mg, 2 mmol) was converted to the title compound (607 mg, 93 %) which was obtained as a white solid. MS : m/e = 389.4 (M+H). Example 2 Cis-rac-4-Phenyl-8-(2-p-tolyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-l-one A mixture of rac-2-p-tolyi-cyclohexanone (410 mg, 2 mmol), rac-4~phenyl-2,8-diaza-spiro[4.5]decan-l-one (502 mg, 2 mmol) and titanium(IV) isopropoxide (810 uL, 3 mmol) were stirred at rt for 3 h. The mixture was then diluted with THF (5 mL) and then a solution of pol^nnethylhydroxysiloxane (261 mg, 4 mmol) in THF (5 mL) was added and the resulting solution stirred at rt overnight To this solution Na(CN)BH3 (245 mg) wTas added and the resulting mixture stirred at rt for 3 h. Then NaOH (3M, 10 mL) was added and the mixture stirred for 1 h. The resulting precipitate was then filtered off over celite and the filtrate was washed with brine, dried and evaporated to leave a light yellow foam. Purification by chromatography on silica gel eluting with DCM: MeOH iNHzOH (25%) (98 : 2 : 0.1 to 95 : 4.5 : 0.5) afforded the title compound (250 mg, 29 %) which was obtained as a white solid. MS : m/e = 403.6 (M+H). Example 3 cis-rac-4-(4-Ruoro~phenyl)-8-(2~p-toly^ cis-rac-l"f2-p-Tolv]-c^rclQhe^)-piperidine-4r-carbor^mc aad etnyi ester a) As described for example la, rac-2-p-tolyl-q'dohexanone (4.2 g> 22 mmol) was converted to the title compound (3.7 g, 48 %) which was obtained as a light yellow oil. MS : m/e = 330.4 (M+H). ds-rac-4^1-(4-Huoro-phenvlV2-nitro-et^^^ carborvlic add ethyl ester b) As described for example lb, ds-rac-l-(2-p-tolyl-cyclohex5i)-piperidine-4-carborylic add ethyl ester (700 mg, 2 mmol) was converted to the title compound (880 mg, 83 %) which was obtained as a yellow gum. MS : m/e = 497,3 (M-f H). qs-rac4-(4-Huoro-phenTiV8-(2-p-toM c) As described for example 1c, ds-Tac-4-[l-(4-flaoro-phenyl)-2-nitro-ethyl]-l-(2-p- tolyl-cyclohexyl)-piperidine--4-carboxylic add ethyl ester (880 mg, 2 mmol) was converted to the amino compound (670 mg, 81 %) which was obtained as a yellow gum and used directly in the next step. MS : m/e = 467.3 (M+H). d) As described for example Id, the amino compound (665 mg, 1 mmol) was converted to the title compound (130 mg, 22 %) which was obtained as a light yellow solid. MS: m/e = 421.2 (M+H). Example 4 ds-rac-4-(3,4-DicUoro-^^ one ris-rac-4-fl43,4-Didbloro-phe^ carborvlic add ethyl ester a) As described for example lb, rac-l-(2-p-tolyl-qrclohexyi)-piperidine-4-carbox}iic add ethyl ester (700 mg, 2 mmol) was converted to the title compound (772 mg, 66 %) which was obtained as a yellow solid. MS : m/e = 547.2 (M). b) As described for example lc, ds-rac-4-[l-(3>4-dichloro-phenyl)-2-nitro-ethyi]-l-(2-p-tolyl-q-clohex^i)-piperidine-4-carbox5THc acid ethyl ester (772 mg, 1 mmol) was converted to the title compound (43 mg, 6 %) which was obtained as a yellow gum. MS: m/e = 471.3 (M). Example 5 ds-rac-4^4-Met3io:^-phen^ [4.5] decan- 1-one ds-rac-44l-(4-Metitoxy-phenviy2-iH^ carboxvlic acid ethyl ester a) As described for example lb, rac-l-(2-p-tolyl-c5^cloliexyl)--piperidine-4-carboxjrlic acid ethyl ester (700 mg, 2 mmol) was converted to the title compound (620 mg, 57 %) which was obtained as a yellow gum. MS : m/e = 509.4 (M-fH). ris-rac^f4-Methory-ph^ b) As described for example 1c, ds-rac«4-[l-(4-metbox}r-pbenyl)-2-nilxo-ethyl]-l-(2-p- tolyl-qdbhexyl)-piperidine-4-carboxflic acid ethyl ester (620 mg, 1 mmol) was converted to the title compound (410 mg, 70 %) which was obtained as a yellow gum. MS:m/e = 433.5 (M+H). Example 6 ds-rac-8-[2-(4-Fluoro-phenyI)-cyclohexy'l]-4-phenyl-2,8"dia2a-spiro[4.5]decan-l-one As described for example 2, rac-2-(4-ftuoro-phenyl)-cyclobexanone (417 mg, 2 mmol) was converted to the title compound (150 mg, 17 %) (using 4-phenyl-2,8-diaza-spiro[4.5]decan-1-one instead of 4-(4-fluoro-phenyl)-2,8-diaza-spiro[4.5]decan- 1-one) which was obtained as a white solid. MS : m/e = 407.5 (M-fH). Alternatively cis-rac-8-f2-f4-Fluoro-phenyl)-CTclo^ ris-ra£-l-f2-(4-Huoro-phenylVcy^ carboxvlic acid ethyl ester a) As described for example lb, ds-rac-l-[2-(4-fluoro-phen}d)-q7clohex)Tl]-piperidine-4-carboxylic acid ethyl ester (800 mg, 2.4 mmol) was converted to the title compound (677 mg, 59 %) which was obtained as a light yellow gum. MS : m/e = 483.3 (M). amino compound (497 mg, 85 %) which, "was obtained as a light yellow oil and used directly in the nert step. MS : m/e = 453.6 (M). c) As described for example Id, the amino compound (497 mg, 1.1 mmol) was converted to the title compound (197 mg, 4 4%) which was obtained as an off-white solid. MS: m/e = 4073 (M+H). Example 7 ds-rac-4-(4-Fluoro-plienyl)-8-[2-(4-fluoro--phenyl)-cyclohexyl]-2,8-dia2a« spiro[4.5] decan-1-one risHrac-l-[2-(4-Huoro-phenyl)-cvcl^^ acid ethyl ester a) As described for example la, rac-2-(4-fluoro-phenyl)-cyclohexanone (7.0 g, 36 mmol) was converted to the title compound (4.5 g, 38 %) which was obtained as a light yellow oil MS : m/e = 334.3 (M+H). cis-rac-1- |"2-(4"Ruoro-phenvl)-cvclohexii7l] -4-f l-(4-fluoro-phenvl)-2-nitro-ethvl1 -piperidine-4-carboxvlic arid ethyl ester b) As described for example lb, cis-rac-l-[2-(4-fluoro-plienyl)-c5'dohexyl]-piperidine-4- carboxylic acid ethyl ester (1.0 g> 3 mmol) (using 4-fluoro-ira7?5-beta-nitrostyrene instead of trans-beta-nitrostyrene) was converted to the title compound (1.2 g, 77 %) which was obtained as a white solid. MS ; m/e =501.4 (M+H), ris-rac-4r-(4-Ruoro-phenyl)-8-[2-(4-fluoro-phenvl)-cydohex^dl-2,8--diaza- spiro[4.5]decan-l-one c) As described for example lc, cis-rac-l-[2-(4-fluoro-plvenyl)"q^clohexyl]-4-[l-(4-fluoro-phenyl)-2-nitro-eth.yl]-piperidine-4-carbox5iic acid ethyl ester (1.1 g, 2 mmol) was converted to the amino compound (1.0 g, 99 %) which was obtained as a light yellow oil and used directly in the next step. MS : m/e = 471.3 (M+H). d) As described for example Id, the amino compound (1.05 g, 2 mmol) was converted to the title compound (670 mg, 71 %) which was obtained as a white solid. MS : m/e = 425.2 (M+H). riS"rac-4-^4-Fluoro-phenyl)-8-[2-f4-iLuoro-phenvl)-arclohervr11-2.8-diaza-spirof4.5l decan-1-one e) Alternatively a mixture of rac-2-(4-fluoro-phenyl)-cydohexanone (775 mg, 3 mmol), rac-4-(4-fLuoro-ph.enyi)-2,8"diaza-spiro[4.5]decan-l-one (500 mg, 3 mmol) and titanium(IV) isopropoxide (887 uL, 3 mmol) were stirred at 60 °C overnight. The resulting solution was then cooled to room temperature and Na(CN)BH3 (245 mg, 4 mmol) was added and the resulting mixture stirred at 50 DC for 3 h. Then NaOH (6M, 15 mL) was added and the mixture stirred for 1 h. The resulting mixture was then filtered off over celite and the filtrate was washed with brine, dried and evaporated to leave a light yellow foam. Purification by chromatography on silica gel eluting with DCM: MeOH: NH4OH (25 %) (98:2: 0.1 to 95 :45 : 0.5) afforded the title compound (212 mg, 20%) which was obtained as a white solid MS : m/e = 425.2 (M+H). cis-rac-4-(4"Ruoro-phenvl)-8-[2-f4-fluoro-phenyl)-cvdohe^T11-2,8-diaza-spiro [4.5] decan- 1-one f) Alternatively as described for example 2, rac-2-(4-fluoro-phenyl)-q7rclohe5canone (500 mg, 3 mmol) was converted to the tide compound (219 mg, 20 %) which was obtained as a white solid. MS : m/e = 425.2 (M+H). Example 8 cis-rac-4-(3,4DicHoro-phenyl)-8-[2-(4-fluoro-phenyl)-cyclohexyl]-2,8-diaza-spiro [4.5] decan- 1-one cis-rac-4-fl-(3,4-DicMoro-phenffi piperidine-4-carboxvlic add ethyl ester a) As described for example lb, cis-rac-l-[2-(4-fluoro-phenyl)-cyclohexyl]-piperidine-4-caxboxylic acid ethyl ester (800 mg, 2.4 mmol) (using 3,4-dicHoro-omega-nitrostyrene instead of tums-beta-nitrostyrene) was converted to the title compound (779 mg, 59 %) which was obtained as a light yellow foam. MS : m/e = 551.3 (M). cis-rac-4-f34-DicHoro-phenvlV8-[2-f4-fl^ spiro [4.5] decan-1-one t>) As described for example lc, cis-rac-4-[l-(3>4-dichloro-phenyl)-2-nitro-ethyl]-l-[2-(4-fluoro-phenyl)-cyclohex5i]-piperidine-4-caxbox5?lic acid ethyl ester (729 mg, 1.3 mmol) was converted to the amino compound (646 mg, 93 %) which was obtained as a light yellow oil and used directly in the next step. c) As described for example Id, the amino compound (646 mg, 1.2 mmol) was converted to the title compound (270 mg, 46 %) which was obtained as an off-white solid MS : m/e = 475.2 (M). Example 9 cis-rac-8-[2-(4-Huoro-phenyl)~cycto^ spiro [4.5] decan- 1-one ris-rac-l-[2-(4-Huoro-phenyl)-eyd^^ piperidine-4-carhoxvlic acid ethyl ester a) As described for example lb, cis-rac-l-[2-(4-fl.uoro-phenyl)"qrdohe5qi]-piperidiiie-4- carboxylic acid ethyl ester (800 mg, 2.4 mmol) (using 4^meliioxy-bet£-nitrostyrene instead of tram-beta-nitrostyrene) was converted to the title compound (642 mg, 52 %) which was obtained as a light yellow foam. MS : m/e = 513.4 (M+H). cis-rac-4-(3,4-Dichloro-phenvl)-8-[2-(4-:^^ spiro [4.51 decan- 1-one b) As described for example 1c, cis-rac-l-[2-(4-fluoro-phenyl)-q^clohexfl]-4-[l-(4-mettoxj^pheny!)-2-ni1xo-et3iyl]-piperidine-4-carboX}':lic acid ethyl ester (601 mg, 1.2 mmol) was converted to the amino compound (523 mg, 92 %) which was obtained as a light yellow oil and used directly in the next step. MS : m/e = 483.5 (M+H). c) As described for example Id, the amino compound (523 mg, 1.1 mmol) was converted to the title compound (216 mg, 46 %) which was obtained as a white foam. MS : m/e = 437.3 (M+H). Example 10 cis-rac-4-(4-Ruoro-phenyl)-8- [2- (4-trifluoromethyl-phenyl)-cyclohexyl] -2,8-diaza-spiro [4.5] decan- 1-one cis-rac-1 - f2- (4-TrifluoromethyI-phenyl) -cvclohexvll -piperidine-4-carboxvlic add ethyl ester a) As described for example la, rac-2-(4-trifLuoromeihyl-phenyl)-cyclohexanone (5.0 g, 21 mmol) was converted to the title compound (2.7 g, 34 %) which was obtained as a light yellow oil. MS : m/e = 384.2 (M+H). tis-rac-4-ri-f4-Huoro-T>henviy^ cycloIiex\rl]-pipendine-4:-cafboxNiic acid ethyl ester b) As described for example lb, l-[2-(4-trifiuorometh.yl-phenyl)-cyclohex57l]-piperidiiie- 4-carbosylic acid ethyl ester (1.0 g, 3 mrnol) was converted to the title compound (610 mg, 43 %) which was obtained as alight yellow oil. MS : m/e = 5513 (M+H). cis-rac-4-(4-Hiioro-phenvIV^ spiro f 4.51 decan-1-one c) As described for example lc, 4-[l-(4-fluoro~phenyl)-2-nitro~^ trifluoromethyl-pkeny^ acid ethyl ester (610 mg> 1 nnnol) was converted to the amino compound (345 mg, 60 %) which was obtained as a. light yellow oil and used directly in the next step. MS : m/e = 521.4 (M+H). d) As described for example Id, the amino compound (345 mg, 1 mmol) was converted to the title compound (268 mg> 85 %) which was obtained as a white solid MS: m/e = 475.4 (M+H). Preparation of Building blocks 15 rac-8-(2-Oxo-cycloheryl)-4-phenyl-2,8-diaza-spiro[4.5]decan-l-one rac-8-(2-Hvdroxv-crdohexyl)-4-phenvl-2,8-diaza-spiro[4.5ldecan-l-one a) A suspension of rac-4-phen'5'l-2,8-dia2:a, spiro[4.5}decan-l-one (13.10 g, 56.9 mmol) and 7-oxa-bicydo[4d.0]heptane (5.58 g, 56.9 mmol) in ethanol (250 ml) was heated under reflux for 3 days. After cooling to room temperature the mixture was filtered and the filtrate evaporated to afford the title compound (18.14 g, 97 %) which was obtained as off-white solid. MS : m/e = 329.3 (M+H). rac-8-f 2-Oxo—cvclohexvD-4-phenvl-2,8-dia^a'Spiro [4.5] decan-1-one b) As described for building block 11 step bi, 8-(2~hydroxy-cyclohex}i)-4-phenyl-2?8- diaza-spiro[4.5]decan-l-one (18.10 g, 55.0 mmol) was converted to the title compound (15.26 g, 76 °/o) which was obtained as a light yellow solid after trituration from hot diethylether. MS : m/e = 327.2 (M+H). rac-4-(4-Fluoro-phenyl)-8-(2-oxo-cyclohex5rl)-2,8"diaza-spiro[4*5]decaii-l-one rac-4-f4-Fluoro-phenvlV8"f2-hvdroxv-cvclohe^V2.8-diaza-spixoi4.5ldecan-l-one a) As described for building block 15 step a,l, rac-4-(4-fiuoro-phenyl)-2,8-diaza-spiro[4.5]clecan-l-one (8.45 g, 34.0 mmol) was converted to the title compound (11.63 g, 99 %) which was obtained as an off-white solid. MS : m/e = $47.0 (M+H). rac-4-f4-Fluoro-pbenylV8-(2-QXo-ny,S-diaza-spiror[4.5]decan-l-one h) As described for building block 15 step b, 4-(4-fLuoro-pbenyl)-8-(2-hydrox7-c7cloh.er57l)-238-diaza-spiro[45]decan-l-one (2.06 g, 6.0 mmol) was converted to the title compound (1.26 g, 59 %) which was obtained as a light yellow solid after purification by chromatography on silica gel eluting with DCM: MeOH (95 ; 5 to 85 : 15). MS : m/e = 345.2 (M+H). Example 11 8-[2-(4-Fluoro-phenyl)-2-hydror7-cyclohexyl]-4-phenyl-2?8-dia^a-spiro[4.5]decan-l^ one To a solution of l-bromo-4-fluorobenzene (1.4 g, 8 mmol) in dry THF (5 mL) under argon at— 78 °C was added BuLi (1.6 M in hexanes, 5 mL, 8 mmol) and the mixture maintained at this temperature for 1 h. To this solution was added a solution of 8-(2-oxo-q^clohesyl)-4-phenyl-2>8-dia2a-spiro[4.5]decan-l-one (687 mg, 2 mmol) in dry THF (15 rnL) and the reaction mixture allowed to warm up to - 20 °C after 2 h before ammonium chloride (saturated, 20 mL) was added. The resulting mixture was then evaporated and water (20 mL) added. The product was extracted with ethyl acetate (3 x 15 mL) and the combined organic extracts washed with brine (10 mL)> dried over sodium sulfate, filtered and evaporated to leave a light brown solid. Purification by chromatography on silica gel eluting with DCM : MeOH - NH4OH (0.5 %) (95 : 5 to 4: 1) afforded the title compound (380 mg, 45 %) which was obtained as a white solid. MS : m/e = 423.5 (M+H). Example 12 4r(4-fluoro-phenyl)-8-trans-(4-hydroxy-4-phenyl-tetrapyran-3-yl)-2,8-diaza- spiro[4.5] decan-1-one As described for example 11, 8-(2-oxo-C5Tclohex57l)-4-phenyl-2,8-diaza-spiro[4.5]decan-1-one (5O0 mg, 1.53 mmol) was converted to the title compound (348 mg, 50 %) (using S-bromo-fLuorobenzene instead of l-bromo-4-fluorobenzene) which was obtained as a white solid. MS : m/e = 423.4 (M+H). Example 13 4r(4-fluoro-phenyl)-8-trans-(4-hydroxy-4-phenyl-tetrapyran-3-yl)-2,8-diaza- spiro[4.5] decan-1-one As described for example 11, 8-(2-oxo-cyclohexyl)-4-phenyl-2,8-diaza-spiro[4.5]decan-1-one (500 mg, 1.53 mmol) was converted to the title compound (88 mg, 15 %) (using 4-bromoanisole instead of l-bromo-4-£luorobenzene) which was obtained as a white solid. MS :m/e = 435.6 (M+H). Example 14 4r(4-fluoro-phenyl)-8-trans-(4-hydroxy-4-phenyl-tetrapyran-3-yl)-2,8-diaza- spiro[4.5] decan-1-oneAs described for example 11, 8- (2 -oxo-cyclohexyl)-4-phenyl-2,8-diaza-spiro [4.5] decani-one (500 mg, 1.53 mmol) was converted to the title compound (411 mg, 69 %) (using 3-bromoanisole instead of l-bromo-4-fluorobenzene) which was obtained as a white solid. MS : m/e = 435.4 (M+H). Example 15 4-(4-Huoro-phenyl)-8-[2-(3-fluoro-phenyl)"2-hydroxy-cyclohexj4]-2,8-diaza-spiro [4.5 ] decan-1-one As described for example ll>4-(4-fluoro-phenyl)-8-(2-oxo-cyclohexyl)-2,8-diaza-spiro[4.5] decan-1-one (200 mg, 1 mmol) was converted to the title compound (195 mg, 76 %) (using l-bromo-3-fluorobenzene instead of l-bromo-4-fhiorobenzene) which was obtained as a white solid. Example 16 4-(4-Huoro-phenyl)-8-[2-(2-fluoro-phenyl)-2-hydroxy-cyclohexyl]-2,8-dia2a-spiro [4.5] decan- 1-one As described for example 11,4-(4-fLuoro-phenyl)-8-(2-oxo-qrdohex}rl)-2J8-diaza-spiro [4.5] decan-1-one (200 mg, 1 mmol) was converted to the title compound (178 mg, 70 %) (using 2-bromoftuorobenzene instead of l-bromo-4-fluorobenzene) which was obtained as a white solid MS : m/e = 441.2 (M+H). Example 17 8- [2-(3-CUoro-phenyl)-2«hydxox7-q^cloliesyl] -4- (4-fLuoro-phenyl)-2,8-diaza-spiro [4-5] decan- 1-one As described for example 11, 4-(4-£luoro«-plienyl)-8-(2-oxO"Cyrclotiexyi)-2>8«dia2a-spiro[4.5]decan-l-one (200 mg, 1 rnmol) was converted to the title compound (205 mg, 77 %) (using l-bromo-3-chloroberizene instead of l-bromo-4-fhiorobenzene) "which was obtained as a white solid. MS : m/e = 457.3 (M). Example 18 4-{2-[4-(4-fluro-phenyl)-1-oxo-2,8-diazo-spiro[4.5]dec-8-yl)-I-hydroxy-cyclohexyl} benzonitrile As described for example 11,4-(4-flnoro-phenyI)-8-(2-oxo-qrclohexyl)-2>8-diaza-spiro [4.5] decan-1-one (200 mg, 1 mmol) was converted to the title compound (118 mg, 45 %) (using 4-bromobenzonitrile instead of l-bromo-4-fluorobenzene) which was obtained as a white solid. MS : m/e = 448.2 (M+H). Example 19 4r(4-fluoro-phenyl)-8-trans-(4-hydroxy-4-phenyl-tetrapyran-3-yl)-2,8-diaza- spiro[4.5] decan-1-one As described for example 11,4-(4-fluoro-phenyl)-8-(2-oxo-C7clohex5i)-2,8-diaza-spiro[4.5] decan- 1-one (200 mg, 1 mmol) was converted to the title compound (271 mg, 95 %) (using 4-bromobenzotrifluoride instead of l-bromo-4-fluorobenzene) which was obtained as a white sohd. MS : m/e = 491.2 (M+H). Example 20 4r(4-fluoro-phenyl)-8-trans-(4-hydroxy-4-phenyl-tetrapyran-3-yl)-2,8-diaza- spiro[4.5] decan-1-one As described for example 11,4-(4-fluoro-phenyl)-8-(2-oxo-cydohex}rl)-238-diaza-spiro[4.5]decan-l-one (200 mg, 1 mmol) was converted to the title compound (16 mg, 6 %) (using 4-bromophenylmeth.yl sulfone instead of l-bromo-4-fluorobenzene) which was obtained as a white sohd. MS : m/e = 501.5 (M+H). Example 21 4r(4-fluoro-phenyl)-8-trans-(4-hydroxy-4-phenyl-tetrapyran-3-yl)-2,8-diaza- spiro[4.5] decan-1-one As described for example 11,4-(4-fluoro-phenyl)-8-(2-oxo-q^clohex)7'l)-2)8"diaza-spiro[4.5]decan-l-one (200 mg, 1 mmol) was converted to the title compound (178 mg, 70 %) (using 4-bromotoluene instead of l-bromo-4-fluorobenzene) which was obtained as a white solid. MS : m/e = 437.4 (M+H). Example 22 4-(4-Huoro-phenyl)-8"(2-hydrory-2-m-toiyi-cydohexyi)-2y8-dia7a-spiro [4.5] decan-1-one As described for example 11, 4-(4-fluoro-phenyl)-8-(2-oxo-cydohex5rl)-2,8-diaza-spiro[4.5]decan-l-one (200 mg, 1 mmol) was converted to the title compound (229 mg, 90 %) (using 3-bromotoluene instead of l-bromo-4-fluorobenzene) which was obtained as a white solid. MS : m/e = 437.3 (M+H). Example 23 4r(4-fluoro-phenyl)-8-trans-(4-hydroxy-4-phenyl-tetrapyran-3-yl)-2,8-diaza- spiro[4.5] decan-1-one As described for example 11, 4-(4-fluro-phenyl)-8-(2-oxo-cydohexyl)-2?8-dia2a-spiro[4.5]decan-l-one (200 mg, 1 mmol) was converted to the title compound (158 mg, 62 %) (using 2-bromotoluene instead of l-bromo-4-fluorobenzene) which was obtained as a white solid. MS : m/e = 437.4 (M+H). Example 24 S-[2-(4-tert-Butyl-phenyI)-2-hydroxy-cyclohexyl]-4-(4-fIuoro-phenyI)-2,8-diaza-- spiro[4.5]decan-l-one As described for example 11, 4-(4-fluoro-phenyl)-8-(2-oxo-q^dohex}Tl)'2?8-dia2:a-spiro[4.5]decan-l-one (200 mg, 1 mmol) was converted to the title compound (192 mg, 69 %) (using l-bromo-4-tert-butylbenzene instead of l-bromo-4-£hiorobenzene) which was obtained as a white solid. MS : m/e = 479.6 (M+H). Example 25 4r(4-fluoro-phenyl)-8-trans-(4-hydroxy-4-phenyl-tetrapyran-3-yl)-2,8-diaza- spiro[4.5] decan-1-one As described for example 11,4"(4-fluoro-phenyl)-8-(2-oxo-q^cloh.esyl)-2,8-dia2;a-spiro[4.5]decan-l-one (216 mg, 0.63 mmol) was converted to the title compound (209 mg, 66 %) (using l-bromo-2-(trifluoroinethoxy)"beiizene instead of l-bromo-4-fluorobenzene) which was obtained as a white solid. MS : m/e = 507.3 (M+H). Example 26 4r(4-fluoro-phenyl)-8-trans-(4-hydroxy-4-phenyl-tetrapyran-3-yl)-2,8-diaza- spiro[4.5] decan-1-one As described for example 11,4-(4-fluoro-phenyl)-8-(2-oxo-cydohex5i)-2,8-diaza-spiro[4.5]decan-l-one (344 mg, 1.0 mmol) was converted to the tide compound (231 mg, 47 %) (using l-(4-bromophenyl)imidazole instead of l-bromo-4-fluorobenzene) which was obtained as a white solid MS : m/e = 489.3 (M+H). Example 27 4r(4-fluoro-phenyl)-8-trans-(4-hydroxy-4-phenyl-tetrapyran-3-yl)-2,8-diaza- spiro[4.5] decan-1-one As described for example 11,4-(4-fluoro-phen7l)-8-(2-oxo-cydohexyl)-2,8-diaza-spiro[4.5]decan-l-one (517 mg, 1.5 mmol) was converted to the title compound (568 mg, 84 %) (using 4-bromoanisole instead of l-bromo-4-fluorobenzene) which was obtained as a white solid. MS : m/e = 453.3 (M-hH). Example 28 4-(4-Huoro-phenyl)-8-[2-hydroxy-2-(3-methoxy-phenyI)-qrclohexyl]-2,8-diaza-spiro[4.5] decan-1-one As described for example ll,4-(4-fluoro-phenyl)-8-(2-oxo-q:rclohex5rl)-2?8-diaza-spiro[4.5]decan-l-one (200 mg, 1 mmol) was converted to the title compound (199 mg, 76 %) (using 3-bromoanisole instead of l-bromo-4-fhiorobenzene) which was obtained as a white solid. MS : m/e = 453.3 (M+H). Example 29 4r(4-fluoro-phenyl)-8-trans-(4-hydroxy-4-phenyl-tetrapyran-3-yl)-2,8-diaza- spiro[4.5] decan-1-one 4-(4-fluoro-phenyl)-8-trans-(4-hydroxy-tetrahydro-pyran-3-yl)-2-8-diaza- spiro[4.5] decan-1-one a) As described fox example 12a, (R)- 4-(4-fluoro-phenyl)-8-(2-oxo-cyolohexyl)-238- diaza-spiro[4.5]decan-l-one (100 mg, 0.4 mmol) was converted to the title compound (57 rng, 41 %) (using 3,5-eporytetrahydrofuran instead of oxa-bicyclo[4.1.0]heptane) which was obtained as a white solid after purification by chromatography on silica gel eluting with DCM: MeOH (9 :1). MS : m/e = 349.2 (M+H). 4-(4-Huoro-phenylV8-(4-oxo-te1xahydro-p^Tan-3-vl)-2>8"dia2a-spiro[4.5'!decan-l-one b) As described for building block 11 step bi) 4-(4-fluoro-phenyl)-8-trans-(4«hydrox7- tetrahydro-pyran'3-yi)-2)8-diaza-spiro[4-5]decan-l-one (128 mg, 0.37 mmol) was converted to the title compound (100 mg3 79 %) which was obtained as a white solid after purification by chromatography on silica gel eluting with DCM : MeOH (9 :1). MS: m/e = 347.4 (M+H). 4r(4-fluoro-phenyl)-8-trans-(4-hydroxy-4-phenyl-tetrapyran-3-yl)-2,8-diaza- spiro[4.5] decan-1-one c) As described for example 11,4-(4-fluoro-phenyl)-8-(4-oxo-tetrahydro-p}7ran-3-yl)- i 2,8-diaza-spiro[4.5]decan-l-one (90 mg, 0.26 mmol) was converted to the title compound (65 mg, 59 %) (using phenyllithium instead of l-bromo-4-fluorobenzene) which was obtained as a white solid. MS : m/e = 425.4 (M+H). Manufacturing Procedure 1. Mix items 1> 2> 3 and 4 and granulate with purified water. 2. Dry the granules at 50°C 3. Pass the granules through suitable milling equipment 4. Add item 5 and mix for three minutes; compress on a suitable press. Manufacturing Procedure 1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes. 2. Add items 4 and 5 and mix for 3 minutes. 3. Fill into a suitable capsule. Claims 1. Compounds of the general formula wherein A-B is -CH2-CH2-, -CH2-O or -O-CH2S X is hydrogen or hydroxy; R1 is aryl, optionally substituted by one or two substituents, selected from the group consisting of halogen, lower alkyi, cyano, CF3, -OCF3, lower alkoxyl -SO2-lower alkyl or by heteroaryl, R is aryl, optionally substituted by one or two substituents, selected from the group consisting of halogen, lower alkyi, CF3 or lower alkoxy, R is hydrogen or lower alkyl; n is 0, 1 or 2; and their pharmaceutically active salts. 2. Compounds of formula I according to claim 1 wherein A-B is -CH2-CHr or -CH2-0-; X is hydrogen or hydroxy; R1 is phenyl, optionally substituted by one or two substrtuents, selected from the group consisting of halogen, lower alkyl, cyano, CPS, -OCF3, lower alkoxy, -SC2 lower alkyi or by heteroaryl, R is phenyl, optionally substituted by one or two substitnents, selected from the group consisting of halogen or lower alkoxy; R is hydrogen; n is 1; and their pharmaceutical active salts. 3. Compounds of formula I according to claim 2, wherein A-B is -CH2-CH2-. 4. Compounds of formula I according to claim 3, wherein R1 and R2 axe both phenyl, optionally substituted by lower alkyl, halogen or CF3. 5. Compounds of formula I according to claim 4, wherein the compounds are ds-rac-4-phenyl-8-(2-phenyl-cydohexyl}d)-2,8-diaza-spiro[4.5]decan-l-one, ds-rac4-phenyl-8-(2-p-tolyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-l-one, ds-rac-8- [2-(4-fluoro-phenyl)-cydohexyl] -4-phenyl-2,8-diaza-spiro [4.5] decan-1 -one, cis-rac-4-(4-fluoro-phenyll)-8-[2-(4-fluoro-phenyl)-cycloheyl]-2,8-diaza- spiro [4.5] decan-1-one, cis-rac-4-(4-fluoro-phenyl)-8-[2-(4-trifluoromethyl-phenoyl)-2,8-diaza- spiro [4.5] decan-1-one, 8-[2-(4-fluoro-phenyl)-2-hydroxy-cyclohexyl])-4-phenyl)-cyclohexyl]-2,8-diaza-spiro[4.5] decan-1-one, 4- (4-fiuoro-phenyl)-8- [2-(3-fluoro-phenyl)-2-hydroxy-cyclohexyl] -2,8-diaza- spiro[4.5] decan-1-one, 3 4-(4-fluoro-phenyl)-8-[2-(2-fluoro-phenyl)-2-hydrory-cyclohexyl]-2?8-diaza- spiro[4.5]decan-l-one, 8-[2-(3-chloro-phenyl)-2hydroxy-cyclohexyl]-4-(4-fluoro-phenyl)-2,8-diaza-spiro [4.5] decan-1-one or 4-(4-iluoro-phenyl)-8-trans-(4-hydroxy-4-phenyl-tetrahydro-pyran-3-yl)-2,8-diaza- spiro[4.5]decan-l-one. 6. Compounds of formula I according to claim 1, wherein X is hydrogen. 7. Compounds of formula I according to claim 1, wherein X is hydroxy 8. Compounds of formula I according to claim 2, wherein A-B is -CH?-0-. 9. Processes for preparation of compounds of formula I and then: pharmaceutically acceptable salts, which process comprises a) reacting a compound of formula with a compound of formula to a compound of formula wherein the substituents are as defined above, or D b) reacting a compound of formula with a compound of formula R:Br 8 to a compound of formula wherein the substituents are as defined above, or c) if desired, separating the obtained racemic forms into corresponding enantiomers, and if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts. 10. A compound according to claim 1, whenever prepared by a process as claimed in claim 9 or by an equivalent method. 11. A medicament containing one or more compounds as claimed in claim 1 and pharmaceutical acceptable excipients. 12. A medicament according to claim 11 for the treatment of illnesses based on the glycine uptake inhibitor. 13. A medicament according to claims 11 and 12, wherein the illnesses are psychoses, pain, disfunction in memory and learning, schizophrenia, dementia and other diseases in which cognitive processes are impaired, such as attention deficit disorders or Alzheimer's disease. 14. The use of a compound as claimed in claim 1 for the manufacture of -medicaments for the treatment of psychoses, pain, neurodegenerative disfunction in memory and learning, schizophrenia, dementia and other diseases in which cognitive processes are impaired, such as attention deficit disorders or Alzheimer's disease. 15. The invention as herein before described. Dated this 6 day of July 2006

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2488-CHENP-2006 AMENDED PAGES OF SPECIFICATION 30-06-2011.pdf

2488-CHENP-2006 AMENDED CLAIMS 30-06-2011.pdf

2488-chenp-2006 correspondence others 05-08-2011.pdf

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