MXPA06007619A - Diaza-spiropiperidine derivatives - Google Patents

Abstract

The present invention relates to compounds of formula (I);wherein A-B is -CH2-CH2-, -CH2-O- or -O-CH2-;X is hydrogen or hydroxy;Rl is aryl, optionally substituted by one or two substituents, selected from the group consisting of halogen, lower alkyl, cyano, CF3, -OCF3, lower alkoxy, -SO2-lower alkyl or by heteroaryl, R2 is aryl, optionally substituted by one or two substituents, selected from the group consisting of halogen, lower alkyl, CF3 or lower alkoxy;R3 is hydrogen or lower alkyl;n is 0, 1 or 2;and to their pharmaceutically active salts. The compounds of formula I may be used in the treatment of neurological and neuropsychiatric disorders.

Description

DERIVATIVES D? DIAZA-ESPIROPIPERIDINA Description of the Invention The present invention relates to compounds of the formula: where: A-B is -CH-CH2, -CH2-0- or -0-CH2-; X is hydrogen or hydroxyl; R1 is aryl, optionally substituted with one or two substitutes, selected from the group comprising halogen, lower alkyl, cyano, -CF3, -0CF3, lower alkoxy, lower alkyl-S0 or heteroaryl, R2 is aryl, optionally substituted with one or two substitutes, selected from the group comprising halogen, lower alkyl, CF3 or lower alkoxy; R3 is hydrogen or lower alkyl; n is 0, 1 or 2; and their pharmaceutically active salts. The present invention relates to compounds of the general formula I, with a pharmaceutical composition containing them and with their use in the treatment against disorders Ref.:173803 neurological and neuropsychiatric. Surprisingly, it has been found that the compounds of the general formula I are good inhibitors of the glycine transporter 1 (GlyT-1) and that they have a good selectivity for the inhibitors of the glycine transporter 2 (GlyT-2). Schizophrenia is a progressive and devastating neurological disease characterized by positive episodic symptoms such as delusions, hallucinations, disorders of thought and psychosis and persistent negative symptoms such as inability to affect, decreased attention and social withdrawal in addition to cognitive impairment (Lewis DA and Lieberman JA , Neuron, 2000, 28: 325-33). For decades, research has focused on the hypothesis of "dopaminergic hyperactivity" that leads to therapeutic interventions involving the blockade of the dopaminergic system (Vanderberg RJ and Aubrey KR., Exp. Opin. Ther. Targets, 2001, 5 (4 ): 507-518; Nakazato A. and Okuyama, S., et al., 2000, Exp. Opin. Ther.Patents, 10 (1): 75-98). This pharmacological approach treats very little the negative and cognitive symptoms that are the best predictors of functional outcome (Sharma, T., Br. J. Psychiatry, 1999, 174 (supplement 28): 44-51). During the mid-1960s, a complementary model of schizophrenia was proposed based on the psychomimetic action based on the blockade of the glutamatergic system by compounds such as phencyclidine (PCP) and related agents (ketamine) that are non-competitive antagonists of the NMDA receptor. Interestingly, in healthy volunteers, the psychomimetic action induced by PCP incorporates both positive and negative symptoms as well as cognitive dysfunction resembling schizophrenia in patients (Javitt DC et al., 1999, Biol. Psychiatry, 45: 668-679). and references here). Moreover, transgenic mice expressing at reduced levels of the NMDARl subunit show behavioral abnormalities similar to those observed in models of pharmacologically induced schizophrenia, which supports a model where reduced utility for the NMDA receptor results in behavior similar to Schizophrenia (Mohn AR et al., 1999. Cell, 98: 427-236). Neurotransmission of glutamate, particularly NMDA receptor activity, has a critical role in synaptic plasticity, learning and memory, so that apparently NMDA receptors serve as a stepped switch to open and close the threshold of synaptic plasticity and formation. of memory (Hebb DO, 1949, The organization of behavior, Wiley, NY, Bliss TV and Collingridge GL, 1993, Nature, 361: 31-39). Over-expressing transgenic mice for the NMDA NR2B subunit exhibit enhanced synaptic plasticity and superior ability for learning and memory (Tang JP et al., 1999, Nature: 401-63-69). Therefore, if a glutamate deficiency is involved in the pathophysiology of schizophrenia, which potentiates the transmission of glutamate, particularly through the activation of the NMDA receptor, it could produce both antipsychotic and potentiating effects of cognitive processes. It is known that the amino acid glycine has at least two important functions in the CNS. Acts as an inhibitory amino acid, binding to strychnine sensitive glycine receptors and also influences the excitatory activity, acting as an essential agonist with glutamate for the receptor function of N-methyl-D-aspartate (NMDA). Although glutamate is released in an activity-dependent manner from the synaptic terminals, glycine appears to be present at a more constant level and appears to regulate / control the receptor for its response to glutamate. One of the most effective ways to control the synaptic concentrations of the neurotransmitter is to influence its reabsorption at the synapses. Neurotransmitter transporters, by removing neurotransmitters from the cell space, can control their extracellular lifetime and thereby regulate the magnitude of synaptic transmission (Gainetdinov RR et al., 2002, Trends in Pharm. Sci., 23 (8): 367-373). The glycine transporters, which are part of the chlorine and sodium family of the neurotransmitter transporters, have an important function in the termination of postsynaptic glycinergic actions and the maintenance of a low concentration of glycine to reabsorb glycine in the nerve terminals. presynaptic and surrounding processes. Two different glycine transporter genes (GlyT-1 and GlyT-2) have been cloned from the brain of mammals that give rise to two transporters with a homology of -50% of the amino acid sequence. GlyT-1 presents four isoforms resulting from the alternative use of the promoter and alternative introns removal (la, Ib, le and Id). Only two of these isoforms have been discovered in the brain of rodents (GlyT-la and GlyT-lb). GlyT-2 also presents a certain degree of heterogeneity. Two isoforms of GlyT-2 (2a and 2b) have been identified in rodent brains. GlyT-1 is known to be located in the CNS and peripheral tissues, whereas GlyT-2 is specific to the CNS. GlyT-1 has a predominantly glial distribution and is not only found in areas corresponding to strychnine-sensitive receptors but also outside these areas, where it has been postulated that it is involved in the regulation of NMDA receptor function (Lopez-Corcuera B et al., 2001, Mol. Mem. Biol., 18: 13-20). Therefore, a strategy to enhance the NMDA receptor activity is to generate the concentration of glycine in the local microenvironment of the synaptic NMDA receptors by inhibiting the GlyT-1 transporter (Bergereon R. et al., 1998, Proc. Nati. Acad. Sci., USA, 95: 15730-15734; Chen L. et al., 2003, J. Neurophysiol., 89 (2): 691-703). Inhibitors of glycine transporters are suitable for the treatment of neurological and neuropsychiatric disorders. Most of the disease states involved are psychosis, schizophrenia (Armer RE and Miller DJ, 2001, Exp. Opin. Ther.Patents, 11 (4): 563-572), psychotic mood disorders and severe major depressive disorders, disorders of mood associated with psychotic disorders such as depression or acute mania associated with bipolar disorders and mood disorders associated with schizophrenia (Pralong ET et al., 2002, Prog. Neurobiol., 67: 173-202), autistic disorders (Carlsson ML , 1998, J. Neural Transm. 105: 525-535), cognitive disorders such as dementia, including senile dementia and age-related or Alzheimer-type dementia, memory disorders in mammals including humans, attention deficit and pain disorders (Armer RE and Miller DJ, 2001, Exp. Opin. Ther.Patents, 11 (4): 563-572).

Therefore, increased activation of NMDA receptors by inhibiting GlyT-1 leads to agents for the treatment of psychosis, schizophrenia, and dementia. other diseases where cognitive processes such as disorders and attention deficit in Alzheimer's disease are diminished. The objects of the present invention are the compounds of the formula I, the use of the compounds of the formula I and their pharmaceutically acceptable salts for the preparation of medicaments for the treatment against diseases related to the activation of NMDA receptors by means of inhibition. of GlyT-1, its preparation, medicaments based on a compound according to the invention and its production as well as the use of a compound of the formula I in the. control or prevention of diseases such as psychosis, memory dysfunction and learning, schizophrenia, dementia and other diseases where cognitive processes are diminished as the attention deficit disorders of Alzheimer's disease. Preferred indications using the compounds of the present invention are schizophrenia, cognitive decline and Alzheimer's disease. Moreover, the invention includes all racemic mixtures, and all their corresponding enantiomers and / or optical isomers.

As used herein, the term "lower alkyl" denotes a straight or branched saturated catenary group containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2- butyl, t-butyl and the like. Preferred alkyl groups are groups with 1-4 carbon atoms. The term "halogen" denotes chlorine, iodine, fluorine and bromine. The term "aryl" denotes a cyclic and aromatic hydrocarbon radical comprising one or more fused rings wherein at least one ring is aromatic in nature, for example phenyl or naphthyl. The term "heteroaryl" denotes a cyclic or aromatic hydrocarbon radical, containing 1, 2 or 3 heteroatoms selected from the group comprising oxygen, sulfur or nitrogen, for example pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isothiazolyl or isoxazolyl. The term "pharmaceutically acceptable acid addition salts" encompasses salts with organic and inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid , methanesulfonic acid, p-toluenesulfonic acid and the like.

Preferred compounds of formula I are those of the formula where: A-B is -CH2-CH2 or -CH2-0-; X is hydrogen or hydroxyl; R1 is phenyl, optionally substituted with one or two substitutes, selected from the group comprising halogen, lower alkyl, cyano, -CF3, -OCF3, lower alkoxy, lower alkyl-SO2 or heteroaryl, R2 is phenyl, optionally substituted with one or two substitutes selected from the group comprising halogen or lower alkoxy, R3 is hydrogen; n is 1; and their pharmaceutically active salts. Most preferred are compounds where n is 1 and A-B is -CH2-CH2-. Especially preferred compounds of this group are those where R1 and R2 are both phenyl, optionally substituted with lower alkyl, halogen or CF3, for example the following compounds: cis-rac-4-phenyl-8- (2-phenyl-cyclohexyl) -2, 8-diaza-spiro [4.5] decan-1-one, cis-rac-4-phenyl-8- (2-p-tolyl-cyclohexyl) -2, 8-diaza-spiro [4.5] decane-1 -one, cis-rac-8- [2- (4-fluoro-phenyl) -cyclohexyl] -4-phenyl-2, 8-diaza-spiro [.5] decan-1-one, cis-rac-4- (4-fluoro-phenyl) -8- [2- (4-fluoro-phenyl) -cyclohexyl] -2,8-diaza-spiro [4.5] decan-1-one, cis-rac-4- (4-fluoro) phenyl) -8- [2- (4-trifluoromethyl-phenyl) -cyclohexyl] -2,8-diaza-spiro [4.5] decan-1-one, 8- [2- (4-fluoro-phenyl) -2 -hydroxy-cyclohexyl] -4-phenyl-2, 8-diaza-spiro [.5] decan-l-one, 4- (4-fluoro-phenyl) -8- [2- (3-fluoro-phenyl) - 2-hydroxy-cyclohexyl] -2,8-diaza-spiro [4.5] decan-1-one, 4- (4-fluoro-phenyl) -8- [2- (2-fluoro-phenyl) -2-hydroxy- cyclohexyl] -2, 8-diaza-spiro [4.5] decan-1-one, 8- [2- (3-chloro-pheny l) -2-hydroxy-cyclohexyl] -4- (4-fluoro-phenyl) -2, 8-diaza-spiro [4.5] decan-1-one or 4- (4-fluoro-phenyl) -8-trans- (4-hydroxy-4-phenyl-tetrahydro-pyran-3-yl) -2,8-diaza-spiro [4.5] decan-1-one. Other compounds are preferred where X is hydrogen. The invention also relates to compounds, wherein X is hydroxyl. The objects of the present invention are other compounds wherein n is 1 and A-B is -CH2-0-.

The compounds of the present formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by the processes described below, which comprise: a) reacting a compound of the formula with a compound of the formula to obtain a compound of the formula I for X = hydrogen, where the substitutes are as defined above, b) reacting a compound of the formula with a compound of the formula RxBr is 8 to obtain a compound of the formula I for X = hydroxyl where the substitutes are as defined above, or c) if desired, separate the racemic forms obtained in their corresponding enantiomers, and if desired, convert the obtained compounds to pharmaceutically acceptable acid addition salts. The compounds of the formula I can be prepared according to the variant processes a), b) or c) and with the following Reaction Schemes 1, 2 and 3. The following abbreviations have been used: LDA = lithium diisopropylamide TFA = trifluoroacetic acid DCM = dichloromethane THF = tetrahydrofuran PMHS = polymethylhydrosiloxane DMSO = dimethylsulfoxide Starting with the appropriately l-protected-piperidin-4-alkylcarboxylate 2, treatment with an appropriate base, usually LDA, followed with treatment with an appropriately substituted nitroalkene 3, results in the formation of. a nitroalkane 4. The reduction of the amino group facilitated by Raney-Ni and hydrogen, normally at a pressure of 60 bar and a temperature of 55 ° C in EtOH as a solvent, results in the formation of 5. The subsequent cyclization by heating in toluene with reflux provides the amide 6. Removal of the protecting group by conventional conditions (treatment with TFA in DCM for R = Boc; or hydrogenolysis with Pd / C in DCM, MeOH for R = Bn) provides the diazaspiropiperidines 7 (Scheme of Reaction 1). Reaction Scheme 1 Step 1 Step 2 An additional reaction of compounds of formula 7 with the corresponding compounds of formula 11 (which can be prepared by the reaction of arylhalides of formula 8 with BuLi and the subsequent reaction with epoxide of the formula 9 to provide alcohols of formula 10, which are oxidized to the corresponding ketones of formula 11 with Dess-Martin Periodinano) in the presence of Ti (0Pr-i) 4 and NaBH (OAc) 3 provide compounds of formula I (Reaction Scheme 2). Alternatively, the reaction of the compounds of formulas 7 and 11 in the presence of Ti (OPr-i) and NaBH (OAc) 3 (with or without the presence of PMHS) also provide products of formula I. An alternative strategy where The general reductive amination of the ketones of the formula 11 with compounds of the formula 12 in a Dean-Stark trap yields an intermediate enamine which can be reduced at the site in the compound of the formula 13. The follow-up of steps 1-3 as described in Reaction Scheme 1 produce the compounds of formula I.

Reaction Scheme 2 The compounds of the formula I for X = OH are prepared by reacting the compounds of the formula 7 with an oxide of the formula 9 in ethanol with reflux. The resulting β-aminoalcohol of formula 14 can be oxidized to ketone, preferably a complex with pyridine S03 in the presence of triethylamine in DMSO to produce compounds of formula 15, which are then subjected to treatment with arylithium reagents formed with a halogen exchange -metal) to provide access to the desired products of formula I (Reaction Scheme 3).

Reaction Scheme 3 All the compounds of formulas 1, 4, 5, 6, 7, 11, 10, 13, 14, 15 are normally formed during the sequence of the reactions in an equal mixture of enantiomers (R, R, S) -, ( S, S, R) -, (R, R, R) - and (S, S, S) - (racemic forms), following the procedures described below. They can be separated into non-racemic chiral enantiomers by high-performance liquid chromatography (preparative HPLC) either a Chiralpak OD or AD column (5 x 50 cm) at room temperature using a mobile phase of ethanol: heptane with lightning detection UV at 220 nM.

The acid addition salts of the basic compounds of the formula I can be converted to the corresponding free bases by treatment with at least one stoichiometric equivalent of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia and the similar. The compounds of the formula I and their pharmaceutically usable acid addition salts have pharmacological properties of value. Specifically, it is found that the compounds of the present invention of glycine transporter I (GlyT-1). The compounds were investigated according to the test provided below.

Solutions and Materials Complete medium DMEM: F-12 nutritive mixture (Gibco Life- technologies), fetal bovine serum (FBS) 5%, (Gibco Life- technologies), Penicillin / Streptomycin 1% (Gibco life technologies), hygromycin 0.6 mg / ml (Gibco life technologies), 1 mM Glutamine (Gibco life technologies). Absorption buffer (UB): 150 mM NaCl, 10 M Hepes-Tris, pH 7.4, 1 mM CaCl2, 2.5 mM KCl, 2.5 mM MgSO4, 10 M (+) D-glucos.

Flp-in ™ -CHO (Invitrogen catalog number R758-07) cells stably transfected with mGlyTlb cDNA. Analysis of inhibition of glycine uptake (mGlyT-lb) On day 1, mammalian cells (Flp-in ™ -CHO), transfected with mGlyT-lb cDNA, are plated at a density of 40,000 cells / well in a complete F-12 medium, without hygromycin in 96-well culture plates. On day 2, the medium is aspirated and the cells are washed twice with an absorption buffer (UB). Then the cells are incubated for 20 minutes at 22 ° C either (i) without potential competitor, (ii) 10 mM non-radioactive glycine, (iii) a concentration of potential inhibitor. A range of inhibition of the concentrations of the potential to generate data to calculate the concentration of the inhibitor resulting in 50% of the effect (for example, IC50, the concentration of the competitor that inhibits glycine uptake by 50%). Then a solution containing 60 nM [3 H] -glycine (11-16 Ci-mmol) and 25 μM non-radioactive glycine is added immediately. The plates were incubated with a new agitation and the reaction was terminated by aspirating the mixture and washing (3 times) with ice cold UB. The cells were lysed with a scintillation liquid, shaken for 3 hours and the radioactivity of the cells counted using a scintillation counter. The activity with the glycine transporter inhibitor I (GlyT-1) is dependent on its racemic or enantiomeric form. Preferred compounds showed an IC5o (nM) at GlyT-1 <; 100 The compounds of the formula I and their pharmaceutically acceptable salts of the compositions of the formula I can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example, in the form of tablets, coated tablets, troches, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, administration can be effected rectally, for example, in the form of suppositories, parenterally, for example, in the form of injectable solutions. The compounds of the formula I can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. For example, lactose, corn starch or its derivatives, talc, stearic acid or its salts and the like can be used as carriers for tablets, coated tablets, troches and gelatin capsules. Suitable carriers for gelatin capsules can be, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance, a carrier is usually not 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. For example, suitable carriers for suppositories are natural or hardened oils, waxes, semiliquid or liquid polyol fats and the like.

Moreover, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking or masking agents or antioxidants. They may also contain other substances of therapeutic value. Medicaments containing a compound of the formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention as well as a process for their production, which comprises converting one or more of the compounds of the formula I and / or one of its pharmaceutically acceptable acid addition salts and, if desired, one or more therapeutically valuable substances in a galenic form of administration together with one or more therapeutically inert carriers. 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 production of schizophrenia, cognitive impairment and Alzheimer's disease. The dose can vary within wide limits and certainly, should be adjusted to the individual requirements in each particular case. In the case of oral administration, the dose for adults may vary from about 0.01 mg to about 1000 mg daily of the composition of the general formula I or of the corresponding amount of one of its pharmaceutically salts. The daily dose can be administered in a single dose or in diluted doses and in addition, the upper limit can be exceeded when this is indicated. The following examples illustrate the present invention without limiting it. All temperatures are given in degrees Celsius. Preparation of Structural Blocks 11 Rac-2- (4-fluoro-phenyl) -cciohexanone rac-2- (4-fluoro-phenyl) cyclohexanol a) To a solution of l-bromo-4-fluorobenzene (12.5 ml, 114 mmol) in diethyl ether (250 ml) at -78 ° C BuLi is added (1.6M, 68 mL, 109 mmol) in an argon atmosphere. After a period of 5 minutes at this temperature, cyclohexenoxide (11.0 ml, 109 mmol) is added followed by the addition of borotrifluoride-dethylethrate (13.8 ml, 109 mmol) whereupon the temperature is increased to approximately -50 ° C. . After a period of 4 hours at this temperature, the reaction is quenched by the addition of ammonium chloride (saturated200 ml) and diluted with water (50 ml). The product is then extracted with diethyl ether (3 x 100 ml) and the combined organic extracts are dried over sodium sulfate. Filtration and evaporation yield the title compound, (11.9 g, 56%) as white crystals after triturating from hexane. MS m / e = 194.1 (M). rac-2- (4-fluoro-phenyl) -cycothexanone bi) To a solution of rac-2- (4-fluoro-phenyl) -cyclohexanol (3.8 g, 20 mmol) in DCM (320 ml) is added Dess periodinnate -Martin [1, 1, 1-tris (acetyloxy) -1, 1-dihydro-1,2-benziodoxol-3- (1H) -one] (10 g, 24 mmol) at room temperature and after a period of two hours the reaction mixture is washed with sodium hydrogen carbonate (10%, 150 ml). The organic phase is then separated and washed with sodium thiosulfite (10%, 150 ml) and dried over sodium sulphate, filtered and evaporated. Purification by silica gel wall chromatography, eluting with ethyl acetate: hexane (1: 4) affords the title compound (3.4 g, 89%) as white crystals. MS: m / e = 192.1 (M). rac-2- (4-fluoro-phenyl) -cciohexanone bii) Alternatively, to a solution of rac-2- (4-fluoro-phenyl) -cyclohexanol (7.5 g, 39 mmol) in dry DMSO (67 ml) was add triethylamine (27 ml, 190 mmol) in an argon atmosphere and the resulting mixture is cooled to 0 ° C and then a solution of a pyridine and sulfur trioxide complex (18.4) is added dropwise over a period of 15 minutes. g, 116 mol) in dry DMSO (98 ml). After one hour, the mixture is diluted with water (200 ml) and the product is extracted with DCM (2 x 100 ml). The combined organic extracts are dried over sodium sulfate, followed by filtration and evaporation. Purification by filtration through silica gel, eluting with ethyl acetate: hexane (1: 4) gives the title compound (7.1 g, 95%) as white crystals. MS: m / e = 192.1 (M). Rac-2-p-tolyl-cislohexanone Rac-2-p-tolyl-cyclohexanol a) To a solution of p-tolylbromide (17.1 g, 100 mmol) in THF (100 ml) is added magnesium (2.43 g, 100 mmol) ) and then the resulting mixture is cooled to -20 ° C and complex (CuBr-dimethylsulfide complex (2.0 g, 10 mmol) is added and the mixture is stirred at -20 ° C for a period of 10 minutes. dropwise a solution of cyclohexene oxide (10 ml, 100 mmol) in THF (10 ml) and the reaction is heated to 0 ° C at which time the exothermic reaction begins, maintaining an ice bath, the temperature can be maintained below 25 ° C. The reaction mixture is stirred at a temperature of 0-5 ° C for an additional period of two hours, then it is quenched with an ammonium chloride solution (saturated, 30 ml) and the product is extracted. with tert-butyl methyl ether The combined organic extracts are washed with water, dried over sodium sulfate, filtered and evaporated. hexane provides the title compound (9.9g, 52%) as white crystals. MS: m / e = 190.1 (M). rac-2-p-tolyl-cyclohexanone b) As described for step b) of Structural Block 11, rac-2-p-tolyl-cyclohexanol (4.86 g, 26 mmol) is converted to the title compound obtained in the manner of white crystals. MS: m / e = 188.1 (M). rac-2- (4-trifluoromethyl-phenyl) -cyclohexanol rac-2- (4-trifluoromethyl-phenyl) -cyclohexanol a) As described for step a) of Structural Block 11, 4-bromo-benzotrifluoride (10.0 g) is converted , 44 mmol) to the title compound (5.64 g, 52%) which is obtained as a white solid. MS: m / e = 244.1 (M). rac-2- (4-trifluoromethyl-phenyl) -cycothexanone b) As described for step b), of Structural Block 11, rac-2- (4-trifluoromethyl-phenyl) -cyclohexanol (5.5 g, 23 mmol) was convert to the title compound (5.26 g, 96%) which is obtained as a light yellow oil. MS: m / e = 242.1 (M). rac-2- (4-trifluoromethoxy-phenyl) -cciohexanone rac-2- (4-trifluoromethoxy-phenyl) -cyclohexanol a) As described for step a) of Structural Block 11, l-bromo-4- (trifluoromethoxy) Benzene (10.3 g, 43 mmol) is converted to the title compound (6.7 g, 60%) which is obtained as a white solid. MS: m / e = 260.1 (M). rac-2- (4-trifluoromethoxy-phenyl) -cciohexanone b) As described for step b) of Structural Block 11, rac-2- (4-trifluoromethoxy-phenyl) -cyclohexanol (6.6 g, 25 mmol) is converted to the title compound (5.36 g, 82%) which is obtained as a white solid. MS: m / e = 258.2 (M). rac-2- (3-fluoro-phenyl) -cciohexanone rac-2- (3-fluoro-phenyl) -cyclohexanol a) As described for step a) of Structural Block 11, l-bromo-3-fluorobenzene (10.0) g, 57 mmol) is converted to the title compound (5.1 g, 46%) which is obtained as a white solid. MS: m / e = 194.1 (M). rac-2- (3-fluoro-phenyl) -cciohexanone As described for step b) of the Structural Block 11, rac-2- (3-fluoro-phenyl) -cyclohexanol (5.0 g, 26 mmol) is converted to the title compound (3.9 g, 80%) which is obtained as a white solid. MS: m / e = 192.1 (M). rac-2- (3-trifluoromethyl-phenyl) -cissohexanone rac-2- (3-trifluoromethyl-phenyl) -cyclohexanol a) As described for step a) of Structural Block 11, 3-bromobenzotrifluoride (10.0 g, 44 mmol ) is converted to the title compound (4.87 g, 45%) which is obtained as a white solid. MS: m / e = 244.1 (M). rac-2- (3-trifluoromethyl-phenyl) -cycothexanone b) As described for step b) of Structural Block 11, rac-2- (3-trifluoromethyl-phenyl) -cyclohexanol (4.7 g, 19 mmol) becomes in the title compound (4.34 g, 93%) which is obtained as a light yellow oil. MS: m / e = 242.1 (M). rac-2- (3-fluoro-4-methyl-phenyl) -cciohexanone rac-2- (3-fluoro-4-methyl-phenyl) -cyclohexanol a) As described for step a) of Structural Block 11, 4 -bromo-2-fluorotoluene (10.0 g, 53 mmol) is converted to the title compound (6.33 g, 58%) which is obtained as a white solid. MS: m / e = 208.3 (M). rac-2- (3-fluoro-4-methyl-phenyl) -cciohexanone b) As described for step b) of Structural Block 11, rac-2- (3-fluoro-4-methyl-phenyl) cyclohexanol (6.2 g, 30 mmol) is converted to the title compound (5.53 g, 91%) which is obtained as a white solid. MS: m / e = 206.1 (M). rac-2- (4-methyl-3-trifluoromethyl-phenyl) -cissohexanone rac-2- (4-methyl-3-trifluoromethyl-phenyl) -cyclohexanol a) As described for step a) of Structural Block 11, 4-Methyl-3- (trifluoromethyl) bromobenzene (4.2 g, 18 mmol) is converted to the title compound (1.95 g, 43%) which is obtained as a white solid. MS: m / e = 258.2 (M). rac-2- (4-methyl-3-trifluoromethyl-phenyl) -cciohexanone b) As described for step b) of Structural Block 11, rac-2- (4-methyl-3-trifluoromethyl-phenyl) -cyclohexanol ( 1.91 g, 7 mmol) is converted to the title compound (1.8 g, 95%) which is obtained as a white solid. MS: m / e = 256.1 (M). rac-2- (4-fluoro-3-methyl-phenyl) -cciohexanone rac-2- (-fluoro-3-methyl-phenyl) -cyclohexanol a) As described for step a) of Structural Block 11, 5- Bromo-2-fluorotoluene (10.0 g, 53 mmol) is converted to the title compound (5.47 g, 50%) which is obtained as a white solid. MS: m / e = 208.2 (M). rac-2- (4-fluoro-3-methyl-phenyl) -cciohexanone b) As described for the bi-step of the Block Structural 11, rac-2- (4-fluoro-3-methyl-phenyl) -cyclohexanol (5.4 g, 26 mmol) is converted to the title compound (14.7 g, 88%) which is obtained as a light yellow oil.

MS: m / e = 206.1 (M). rac-2- (4-sloro-3-trifluoromethyl-phenyl) -cciohexanone rac-2- (4-chloro-3-trifluoromethyl-phenyl) -cycothexanone a) As described for step a) of Structural Block 11, 5 -bromo-2-chlorobenzotrifluoride (8.32 g, 30 mmol) is converted to the title compound (4.4 g, 52%) which is obtained as a white solid. MS: m / e = 278.1 (M). rac-2- (4-chloro-3-trifluoromethyl-phenyl) -cciohexanone b) As described for step b) of Structural Block 11, rac-2 - '(4-chloro-3-trifluoromethyl-phenyl) -cyclohexanol (4.3 g, 15 mmol) is converted to the title compound (4.13 g, 97%) which is obtained as a white solid. MS: m / e = 276.1 (M).

Preparation of Structural Blocks 7 Rac-4-phenyl-2, 8-diaza-spiro [4.5] decan-1-one rac-l-benzyl-4- (2-nitro-l-phenyl-ethyl) ethyl ester - piperidine-4-carboxylic a) Prepare an LDA solution (14 mmol) by treating diisopropylamine (1.37 g, 14 mmol) with BuLi (1.6 M, 8.5 ml, 14 mmol) at a temperature of -78 ° C in Dry THF (10 ml) in an argon atmosphere and allowed to warm to -20 ° C. This solution is cooled to -60 ° C and added to a solution of l-benzyl-piperidin-4-ethylcarboxylate (3.05 g, 12 mmol) in THF (8 ml) at a temperature of -60 ° C and heated to -40 ° C for a period of one hour whereupon a solution of trans-beta- is added dropwise. Nitrostyrene (1.93 g, 13 mmol) in THF (8 ml). The reaction mixture is heated at room temperature for one hour and then quenched with ammonium chloride (saturated, 40 ml) and the product is extracted with ethyl acetate (2 x 40 ml). Then, the combined organic extracts are washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography on silica gel eluting with DCM: MeOH (9: 1) gives 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-1-benzyl-4- (2-ethyl) ethyl ester is hydrogenated -nitro-l-enyl-ethyl) -piperidine-4-carboxylic acid (3.18 g, 8 mmol) in dry EtOH (240 ml) in the presence of Ra-Ni (3 g) at 60 bar at a temperature of 55 ° C for a period of 3 hours. After cooling and decompressing the reaction vessel, the mixture is filtered over celite and the filtrate is evaporated to leave the title compound (2.9 g, 99%) as a translucent oil. MS: m / e = 367.4 (M + H). rac-8-benzyl-4-f-enyl-2, 8-diaza-spiro [4.5] decan-1-one c) A solution of rac-4 ethyl ester is heated in reflux for a period of 4 hours. (2-amino-1-phenyl-ethyl) -l-benzyl-piperidine-4-carboxylic acid (2.9 g, 8 mmol) in toluene (30 ml). After cooling to room temperature and evaporating, the mixture is purified by chromatography on silica gel eluting with DCM: MeOH: NH 4 HH (95: 4.5: 0.5) to yield the title compound (1.47 g, 58%) as a solid white color. MS: m / e = 321.4 (M + H). rac-4-phenyl-2, 8-diaza-spiro [.5] decan-1-one d) A suspension of rac-8-benzyl-4-phenyl-2, 8-diaza-spiro [4.5] decan is hydrogenated -1-one (28.8 g, 90 mmol) in MeOH: DCM (4: 1,500 ml) in the presence of Pd (10% on C, 14 g, 132 mmol) at 2 bar for 48 hours at room temperature.

After filtering over celite, the reaction mixture is evaporated and the residue is dissolved in NaOH (2 N, 200 ml). The product is extracted with DCM (3 x 150 ml) and the combined organic extracts are dried over sodium sulfate. Filtration and evaporation provide the title compound (13.1 g, 63%) as a white solid after triturating with diethyl ether. MS: m / e = 231.4 (M + H).JF.

Reaction Scheme I, Step 1: Derivative-F * of the protective group Boc Rac-4- (4-fluoro-phenyl) -2, 8-diaza-spiro [4.5] desan-l-one ester-1-tert-butyl ester of piperidin-1,4-dicarboxylic acid and 4-ethyl ester a) To a solution of ethyl isonipecotate (20 g, 127 mmol) in dioxane: water (1: 1, 120 ml) is 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 is kept at this temperature for a period of two hours.

The product is then extracted with ethyl acetate (3 x 100 ml) and the combined organic extracts are washed with HCl (1N, 100 ml), brine (100 ml), dried over sodium sulfate, filtered and evaporated. Purification by Kugelrohr distillation gives the title compound (29.0 g, 89%) as a colorless liquid, bp 140 ° C at 0.13 mbar. MS: m / e = 275.2 (M + NH). 1-tert-butyl ester of rac-4- [1- (4-fluoro-phenyl) -2-nitro-ethyl] -piperidin-1,4-dicarboxylic ester and 4-ethyl ester b) An LDA solution is prepared by Treating diisopropylamine (6.98 g, 69 mmol) with BuLi (1.6 M, 41.3 mL, 66 mmol) at a temperature of -78 ° C in dry THF (45 mL) under an argon atmosphere and heating to -20 ° C. C. The solution is then cooled to -60 ° C and added to a solution of piperidin-1-dicarboxylic acid-1-butyl ester and 4-ethyl ester (15.44 g, 60 mmol) in dry THF (45 ml). at -60 ° C and warming to -40 ° C over a period of one hour whereupon a solution of 4-fluoro-trans-beta-nitrostyrene (10.02 g, 60 mmol) in dry THF is added dropwise ( 40 ml). The reaction mixture is warmed to room temperature over a period of one hour and then quenched with ammonium chloride (saturated, 250 ml) and the product extracted with diethyl ether (3 x 100 ml). The combined organic extracts are washed with brine, dried over sodium sulfate, filtered and evaporated to yield the title compound (26.7 g, 99%) as a light yellow gum. MS: m / e = 442.4 (M + NH 4). ethyl ester of rac-4- (2-amino-1-phenyl-ethyl) -1-tert-butyl-piperidin-1 -dicarboxylic acid c) A solution of 1-tert-butyl ester of rac acid is hydrogenated -4- [1- (4-Fluoro-phenyl) 2-nitro-ethyl] -piperidin-1,4-dicarboxylic acid and 4-ethyl ester (26.6 g, 60 mmol) in dry EtOH (600 mL) in the presence of Ra -Ni (25 g) at 50 bar at a temperature of 50 ° C for a period of 20 hours. After cooling and decompressing the reaction vessel, the mixture is filtered over celite and the filtrate is evaporated to leave the title compound (23.4 g, 99%) as a translucent oil which is used directly in the next step. tert-butyl ester of rac-4- (4-fluoro-phenyl) -l-oxo-2, 8-diaza-spiro [4.5] decan-8-carboxylic acid d) It is heated at reflux for a period of 18 hours a 4- (2-Amino-1-phenyl-ethyl) -l-tert-butyl-piperidin-1,4-dicarboxylic acid ethyl ester solution (23.4 g, 60 mmol) in toluene (200 ml). After cooling to room temperature, evaporation produces the title compound (17.17 g, 83%) as a white solid after the hot pentane is triturated. MS: m / e = 349.3 (M + H). rac-4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one e) Stirred vigorously at a temperature of 0 ° C for a period of 15 minutes. 4- (4-fluoro-phenyl) -l-oxo-2, 8-diaza-spiro [4.5] decan-8-carboxylic acid tert-butyl ester (46.0 g, 132 mmol) in DCM (260 ml) containing TFA (150 mL, 1.32 mol). The reaction mixture is poured into NaOH (3 N, 200 ml) and the product is extracted with DCM (3 x 100 ml). The combined organic extracts are washed with water (100 ml) and brine (100 ml) and then dried over sodium sulfate. Filtration and evaporation yield the title compound (22.14 g, 68%) as a white solid after triturating the ethyl acetate. MS: m / e = 249.2 (M + H). Example 1 Cis-rac-4-phenyl-8- (2-phenyl-cyclohexyl) -2,8-diaza-spiro [4.5] ecan-1-one cis-rac-1- (2-phenyl-) ethyl ester cyclohexyl) -piperidine-4-carboxylic acid a) A solution of ethyl isonipecotate (3.7 g) is heated to reflux with a Dean-Stark trap for a period of 13 hours., 24 mmol), 2-phenylcyclohexanone (5.0 g, 29 mmol) in toluene (50 ml) containing para-toluenesulfonic acid (446 mg, 2 mmol). After cooling to room temperature, the mixture is evaporated to leave approximately 15 ml of solution and then diluted with 1,2-dichloroethane (120 ml) and then acetic acid (0.95 ml) is added followed by the addition in portions of triacetoxyborohydride sodium (7.3 g, 33 mmol). After a period of 3.5 hours, the mixture is quenched with NaOH (3 N, 50 ml), diluted with water (50 ml) and the organic layer is separated. The organic layer is then evaporated and dried to leave a residue which is purified by chromatography on silica gel eluting with heptane: ethyl acetate (9: 1) to (4: 1) to (3: 2) to provide the title compound. title as a light yellow oil (5.5 g, 75%). MS: m / e = 316.2 (M + H). cis-rac-4- (2-nitro-l-phenyl-ethyl) -1- (2-phenyl-cyclohexyl) -piperidine-4-carboxylic acid ethyl ester b) As described for step a) of the Structural Block 7, the 1- (2-phenyl-cyclohexyl) -piperidine-4-carboxylic acid ethyl ester (1.0 g, 3 mmol) is converted to the title compound (1.1 g, 73%) which is obtained as an off-white solid . MS: m / e = 465.4 (M + H). cis-rac-4-phenyl-8- (2-phenyl-cyclohexyl) -2,8-diaza-spiro [4.5] decan-1-one c) As described for step b) of Structural Block 7, the ester Ethyl 4- (2-nitro-l-phenyl-ethyl) -l- (2-phenyl-cyclohexyl) -piperidine-4-carboxylic acid (1.0 g, 2 ptnol) is converted to the amino compound (810 mg, 87 %) that is obtained as a light yellow oil and used directly in the next step. MS: m / e = 435.4 (M + H). d) As described for step c) of Structure block 7, the amino compound (810 mg, 2 mmol) is converted to the title compound (607 mg, 93%) which is obtained as a white solid. MS: m / e = 389.4 (M + H).

Example 2 Cis-ras-4-phenyl-8- (2-p-tolyl-cyclohexyl) -2,8-diaza-spiro [4.5] desan-l-one A mixture is stirred at room temperature for a period of 3 hours. of rac-2-p-tolyl-cyclohexanone (410 mg, 2 mmol), rac-4-phenyl-2, 8-diaza-spiro [4.5] decan-1-one (502 mg, 2 mmol) and titanium isopropoxide (IV) (810 uL, 3 mmol). The mixture is then diluted with THF (5 ml) and then a solution of polymethylhydroxysiloxane (261 mg, 4 mmol) in THF (5 ml) is added and the resulting solution is stirred at room temperature overnight. To this solution is added Na (CN) BH3 (245 mg) and the resulting mixture is stirred for 3 hours at room temperature. Then NaOH (3M, 10 ml) is added and the mixture is stirred for a period of one hour. The resulting precipitate is filtered on celite and the filtrate is 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: 4.5: 0.5) gives the title compound (250 mg, 29%) which is obtained as a solid White color. MS: m / e = 403.6 (M + H).

Example 3 Cis-ras-4- (4-fluoro-phenyl) -8- (2-p-tolyl-cyclohexyl) -2,8-diaza-spiro [4.5] desan-1-one cis-rac-ethyl ester -l- (2-p-tolyl-cyclohexyl) -piperidine-4-carboxylic acid a) As described for example la, rac-2-p-tolyl-cyclohexanone (4.2 g, 22 mmol) is converted to the compound of title (3.7 g, 48%) which is obtained as a light yellow oil. MS: m / e = 330.4 (M + H). cis-rac-4- [1- (4-fluoro-phenyl) -2-nitro-ethyl] -1- (2-p-tolyl-cyclohexyl) -piperidine-4-carboxylic acid ethyl ester b) As described for example Ib, the cis-rac-1- (2-p-tolyl-cyclohexyl) -piperidine-4-carboxylic acid ethyl ester (700 mg, 2 mmol) is converted into the title compound (880 mg, 83 mg). %) that is obtained as a yellow gum. MS: m / e = 497.3 (M + H). cis-rac-4- (4-fluoro-phenyl) -8- (2-p-tolyl-cyclohexyl) -2, 8-diaza-spiro [4.5] decan-1-one c) As described in the example, , cis-rac-4- [1- (4-fluoro-phenyl) -2-nitro-ethyl] -1- (2-p-tolyl-cyclohexyl) -piperidine-4-carboxylic acid ethyl ester (880 mg, 2 mmol) is converted to the amino compound (670 mg, 81%) which is 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 ainino compound (665 mg, 1 irmol) is converted to the title compound (130 mg, 22%) which is obtained as a light yellow solid. MS: m / e = 421.2 (M + H).

Example 4 Cis-ras-4- (3,4-dichloro-f-enyl) -8- (2-p-tolyl-cislohexyl) -2,8-diaza-spiro [4.5] decan-1-one ethyl acid ester cis-rac-4- [1- (3, -dichloro-f-enyl) -2-nitro-ethyl] -1- (2-p-tolyl-cyclohexyl) -piperidine-4-carboxylic acid a) As described for Example Ib, rac-1- (2-p-tolyl-cyclohexyl) -piperidine-4-carboxylic acid ethyl ester (700 mg, 2 mmol) is converted to the title compound (772 mg, 66%) which is obtained as a solid yellow color. MS: m / e = 547.2 (M). b) As described for the example, cis-rac-4- [1- (3,4-dichloro-phenyl) -2-nitro-ethyl] -1- (2-p-tolyl) ethyl ester. cyclohexyl) -piperidine-4-carboxylic acid (772 mg, 1 mmol) is converted to the title compound (43 mg, 6%) which is obtained as a yellow gum. MS: M / e = 471.3 (M).

Example 5 cis-rac-4- (4-methoxy-f-enyl) -8- (2-p-tolyl-cyclohexyl) -2,8-diaza-spiro [4.5] decan-1-one ethyl ester of cis-acid rac-4- [1- (4-methoxy-f-enyl) -2-nitro-ethyl] -1- (2-p-tolyl-cyclohexyl) -piperidine-4-carboxylic acid a) As described for example Ib , the rac-1- (2-p-tolyl-cyclohexyl) -piperidine-4-carboxylic acid ethyl ester (700 mg, 2 mmol) is converted into the title compound (620 mg, 57%) which is obtained as a yellow rubber. MS: m / e = 509.4 (M + H). cis-rac-4- (4-methoxy-phenyl) -8- (2-p-tolyl-cyclohexyl) -2, 8-diaza-spiro [4.5] decan-1-one b) As described for the example, , the cis-rac-4- [1- (4-methoxy-phenyl) -2-nitro-ethyl] -1- (2-p-tolyl-cyclohexyl) -piperidine-4-carboxylic acid ethyl ester (620 mg , 1 mmol) is converted to the title compound (410 mg, 70%) which is obtained as a yellow gum. MS: m / e = 433.5 (M + H). Example 6 cis-rac-8- [2- (4-fluoro-phenyl) -cyclohexyl] -4-phenyl-2, 8-diaza-spiro [4.5] decan-1-one As described for Example 2, rac -2- (4-fluoro-phenyl) -cciohexanone (417 mg, 2 mmol) is 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 is obtained as a white solid. MS: m / e = 407.5 (M + H). Alternatively cis-rac-8- [2- (4-fluoro-phenyl) -cislohexyl] -4-phenyl-2, 8-diaza-spiro [4.5] decan-1-one cis-rac-1 ethyl ester [2- (4-Fluoro-phenyl) -cyclohexyl] -4- (2-nitro-l-phenyl-ethyl) -piperidine-4-carboxylic acid a) As described for Example Ib, the cis-acid ethyl ester rac-1- [2- (4-fluoro-phenyl) -cyclohexyl] -piperidine-4-carboxylic acid (800 mg, 2.4 mmol) is converted to the title compound (677 mg, 59%) which is obtained as a gum light yellow color. MS: m / e = 483.3 (M). cis-rac-8- [2- (4-fluoro-phenyl) -cyclohexyl] -4-phenyl-2, 8-diaza-spiro [4.5] decan-1-one b) As described for the example le, the 1- [2- (4-Fluoro-phenyl) -cyclohexyl] -4- (2-nitro-1-phenyl-ethyl) -piperidine-4-carboxylic acid ethyl ester (627 mg, 1.3 mmol) becomes the amino compound (497 mg, 85%) which is obtained as a light yellow oil and used directly in the next step. MS: m / e = 453.6 (M). c) As described for Example Id, the amino compound (497 mg, 1.1 mmol) is converted to the title compound (197 mg, 4.4%) which is obtained as an off-white solid. MS: m / e = 407.3 (M + H).

Example 7 cis-rac-4- (4-fluoro-phenyl) -8- [2- (4-fluoro-phenyl) -cyclohexyl] -2,8-diaza-spiro [4.5] desan-1-one ethyl ester of cis-rac-1- [2- (4-fluoro-phenyl) -cyclohexyl] -piperidine-4-carboxylic acid a) As described for example la, rac-2- (4-fluoro-phenyl) -cycothexanone ( 7.0 g, 36 mmol) is converted to the title compound (4.5 g, 38%) which is obtained as a light yellow oil. MS: m / e = 334.3 (M + H). cis-rac-1- [2- (4-fluoro-phenyl) -cyclohexyl] -4- [1- (4-fluoro-phenyl) -2-nitro-ethyl] -piperidine-4-carboxylic acid ethyl ester b ) As described for Example Ib, the cis-rac-1- [2- (4-fluoro-phenyl) -cyclohexyl] -piperidine-4-carboxylic acid ethyl ester (1.0 g, 3 mmol) (using 4- fluoro- trans-beta-nitrostyrene instead of trans-beta-nitrostyrene) is converted to the title compound (1.2 g, 77%) which is obtained as a white solid. MS: m / e = 501.4 (M + H). cis-rac-4- (4-fluoro-phenyl) -8- [2- (4-fluoro-phenyl) -cyclohexyl] -2,8-diaza-spiro [4.5] decan-1-one c) As described for the example, cis-rac-1- [2- (4-fluoro-phenyl) -cyclohexyl] -4- [1- (4-fluoro-phenyl) -2-nitro-ethyl] - ethyl ester - piperidine-4-carboxylic acid (1.1 g, 2 mmol) is converted to the amino compound (1.0 g, 99%) which is 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) is converted to the title compound (670 mg, 71%) which is obtained as a white solid. MS: m / e = 425.2 (M + H). is-rac-4- (4-fluoro-phenyl) -8- [2- (4-fluoro-phenyl) -cyclohexyl] -2,8-diaza-spiro [4.5] decan-1-one e) Alternatively, stir at a temperature of 60 ° C overnight a mixture of rac-2- (4-fluoro-phenyl) -cidiohexanone (775 mg, 3 mmol), rac-4- (4-fluoro-phenyl) -2, 8 -diaza-spiro [4.5] decan-1-one (500 mg, 3 mmol) and titanium (IV) isopropoxide (887 uL, 3 mmol). The resulting solution is then cooled to room temperature and Na (CN) BH3 (245 mg, 4 mmol) is added and the resulting mixture is stirred at a temperature of 50 ° C for a period of 3 hours. NaOH (6M, 15 ml) is then added and the mixture is stirred for a period of one hour. The resulting mixture is filtered over celite and the filtrate is 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: 4.5: 0.5) gives the title compound (212 mg, 20%) which is obtained as a solid White color. MS: m / e = 425.2 (M + H). cis-rac-4- (4-fluoro-phenyl) -8- [2- (4-fluoro-phenyl) -cyclohexyl] -2,8-diaza-spiro [4.5] decan-1-one f) Alternatively, as is described for the example 2, rac-2- (4-fluoro-phenyl) -cciohexanone (500 mg, 3 mmol) is converted to the title compound (219 mg, 20%) which is obtained as a white solid. MS: m / e = 425.2 (M + H).

Example 8 cis-rac-4- (3,4-dichloro-phenyl) -8- [2- (4-fluoro-phenyl) -cyclohexyl] -2,8-diaza-spiro [4.5] decan-1-one ester Ethyl cis-rac-4- [1- (3,4-dichloro-phenyl) -2-nitro-ethyl] -1- [2- (4-fluoro-phenyl) -cyclohexyl] -piperidine-4-carboxylic acid a) As described for example Ib, the cis-rac-1- [2- (4-fluoro-phenyl) -cyclohexyl] -piperidin-4-carboxylic acid ethyl ester (800 mg, 2.4 mmol) (using 3 , 4-dichloro-omega-nitrostyrene instead of trans-beta-nitrostyrene) is converted to the title compound (779 mg, 59%) which is obtained as a light yellow foam. MS: m / e = 551.3 (M). cis-rac-4- (3,4-dichloro-phenyl) -8- [2- (4-fluoro-phenyl) -cyclohexyl] -2,8-diaza-spiro [.5] decan-1-one b) As described for the example, cis-rac-4- [1- (3,4-dichloro-phenyl) -2-nitro-ethyl] -1- [2- (4-fluoro-phenyl) ethyl ester -cyclohexyl] -piperidine-4-carboxylic acid (729 mg, 1.3 mmol) is converted to the amino compound (646 mg, 93%) which is obtained as a light yellow oil and used directly in the next step. described for Example Id, the amino compound (646 mg, 1.2 mmol) is converted to the title compound (270 mg, 46%) which is obtained as an off-white solid. MS: m / e = 475.2 (M).

Example 9 cis-ras-8- [2- (4-fluoro-phenyl) -syclohexyl] -4- (4-methoxy-phenyl) -2,8-diaza-spiro [4.5] decan-1-one ethyl ester of the cis-rac-1- [2- (4-fluoro-phenyl) -cyclohexyl] -4- [1- (4-methoxy-phenyl) -2-nitro-ethyl] -piperidine-4-carboxylic acid a) As describes for example Ib, the cis-rac-1- [2- (4-fluoro-phenyl) -cyclohexyl] -piperidine-4-carboxylic acid ethyl ester (800 mg, 2.4 mmol) (using 4-methoxy-beta) -nitrostyrene instead of trans-beta-nitrostyrene) is converted to the title compound (642 mg, 52%) which is obtained as a light yellow foam. MS: m / e = 513.4 (M + H). cis-rac-4- (3,4-dichloro-phenyl) -8- [2- (4-fluoro-phenyl) -cyclohexyl] -2,8-diaza-spiro [4.5] decan-1-one b) As The cis-rac-1- [2- (4-fluoro-phenyl) -cyclohexyl] -4- [1- (4-methoxy-phenyl) -2-nitro-ethyl acid ethyl ester is described for the example. ] -piperidine-4-carboxylic acid (601 mg, 1.2 mmol) is converted to the amino compound (523 mg, 92%) which is 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) is converted to the title compound (216 mg, 46%) which is obtained as a white foam. MS: m / e = 437.3 (M + H).

Example 10 cis-rac-4- (4-fluoro-phenyl) -8- [2- (4-trifluoromethyl-phenyl) -cyclohexyl] -2,8-diaza-spiro [4.5] decan-1-one ethyl ester of the cis-rac-1- [2- (4-trifluoromethyl-phenyl) -cyclohexyl] -piperidine-4-carboxylic acid a) As described for example la, rac-2- (4-trifluoromethyl-phenyl) -cycothexanone ( 5.0 g, 21 mmol) is converted to the title compound (2.7 g, 34%) which is obtained as a light yellow oil. MS: m / e = 384. 2 (M + H). cis-rac-4- [1- (4-fluoro-phenyl) -2-nitro-ethyl] -1- [2- (4-trifluoromethyl-phenyl) -cyclohexyl] -piperidine-carboxylic acid ethyl ester b) As described for example Ib, 1- [2- (4-trifluoromethyl-phenyl) -cyclohexyl] -piperidine-4-carboxylic acid ethyl ester (1.0 g, 3 mmol) is converted to the title compound (610). mg, 43%) which is obtained as a light yellow oil. MS: m / e = 551. 3 (M + H). cis-rac-4- (4-fluoro-phenyl) -8- [2- (4-trifluoromethyl-phenyl) -cyclohexyl] -2,8-diaza-spiro [4.5] decan-1-one c) As described for example, 4- [1- (4-fluoro-phenyl) -2-nitro-ethyl] -1- [2- (4-trifluoromethyl-phenyl) -cyclohexyl] -piperidin-4-ethyl ester carboxylic acid (610 mg, 1 mmol) is converted to the amino compound (345 g, 60%) which is 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) is converted to the title compound (268 mg, 85%) which is obtained as a white solid. MS: m / e = 475.4 (M + H).

Preparation of Structural Blocks 15 rac-8- (2-oxo-cyclohexyl) -4-phenyl-2,8-diaza-spiro [4.5] decan-1-one rac-8- (2-hydroxy-cyclohexyl) -4- phenyl-2, 8-diaza-spiro [4.5] decan-1-one a) A suspension of rac-4-phenyl-2, 8-diaza-spiro [4.5] decan-1-one is heated under reflux for 3 days (13.10 g, 56.9 mmol) and 7-oxa-bicyclo [4.1.0] heptane (5.58 g, 56.9 mmol) in ethanol (250 mL). After cooling to room temperature, the mixture is filtered and the filtrate is evaporated to give the title compound (18.14 g, 97%) which is obtained as an off-white solid. MS: m / e = 329.3 (M + H). rac-8- (2-oxo-cyclohexyl) -4-phenyl-2, 8-diaza-spiro [4.5] decan-1-one b) As described for step bi of Structural Block 11, 8- (2- hydroxy-cyclohexyl) -4-phenyl-2, 8-diaza-spiro [.5] decan-1-one (18.10 g, 55.0 mmol) is converted to the title compound (15.26 g, 76%) which is obtained as a light yellow solid after crushing from hot diethyl ether. MS: m / e = 327.2 (M + H). rac-4- (4-fluoro-phenyl) -8- (2-oxo-cyclohexyl) -2,8-diaza-spiro [4.5] decan-1-one rac-4- (4-fluoro-phenyl) -8 - (2-hydroxy-cyclohexyl) -2,8-diaza-spiro [4.5] decan-1-one a) As described for step a, l of Structural Block 15, rac-4- (4-fluoro) is converted phenyl) -2,8-diaza-spiro [4.5] decan-1-one (8.45 g, 34.0 mmol) in the title compound (11.63 g, 99%) which is obtained as an off-white solid. MS: m / e = 347.0 (M + H). rac-4- (4-fluoro-phenyl) -8- (2-oxo-cyclohexyl) -2,8-diaza-spiro [4.5] decan-1-one b) As described for step b of Structural Block 15 , 4- (4-fluoro-phenyl) -8- (2-hydroxy-cyclohexyl) -2,8-diaza-spiro [.5] decan-1-one (2.06 g, 6.0 mmol) is converted to the compound of title (1.26 g, 59%) which is 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-hydroxy-cislohexyl] -4-phenyl-2, 8-diaza-spiro [4.5] decan-1-one To a solution of l-bromo-4 -fluorobenzene (1.4 g, 8 'mmol) in dry THF (5 ml) in argon at a temperature of -78 ° C is added BuLi (1.6 M in hexanes, 5 ml, 8 mmol) and the mixture is kept at this temperature. temperature for a period of one hour. To this solution is added a solution of 8- (2-oxo-cyclohexyl) -4-phenyl-2, 8-diaza-spiro [.5] decan-1-one (687 mg, 2 mmol) in dry THF ( 15 ml) and the reaction mixture is heated at -20 ° C for a period of 2 hours before adding ammonium chloride (saturated, 20 ml). The resulting mixture is evaporated and water (20 ml) is added. The product is extracted with ethyl acetate (3 x 15 ml) and the combined organic extracts are 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) gives the title compound (380 mg, 45%) which is obtained as a white solid . MS: m / e = 423.5 (M + H).

Example 12 8- [2- (3-Fluoro-phenyl) -2-hydroxy-cyclohexyl] -4-phenyl-2,8-diaza-spiro [4.5] decan-1-one As described for example 11, convert 8- (2-oxo-cyclohexyl) -4-phenyl-2, 8-diaza-spiro [4.5] decan-l-one (500 mg, 1.53 mmol) in the title compound (348 mg, 50%) ( using 3-bromo-fluorobenzene instead of l-bromo-4-fluorobenzene) which is obtained as a white solid. MS: m / e = 423.4 (M + H).

Example 13 8- [2-droxy-2- (4-methoxy-phenyl) -cyclohexyl] -4-phenyl-2,8-diaza-spiro [4.5] decan-1-one As described for example 11, converted to 8- (2-oxo-cyclohexyl) -4-phenyl-2, 8-diaza-spiro [4.5] decan-1-one (500 mg, 1.53 mmol) in the title compound (88 mg, 15%) (using 4-bromoanisole instead of l-bromo-4-fluorobenzene) which is obtained as a white solid. MS: m / e = 435.6 (M + H).

Example 14 8- [2-Hydroxy-2- (3-methoxy-phenyl) -cyclohexyl] -4-phenyl-2, 8-diaza-spiro [4.5] decan-1-one As described for example 11, convert 8- (2-oxo-cyclohexyl) -4-phenyl-2, 8-diaza-spiro [4.5] decan-1-one (500 mg, 1.53 mmol) to the title compound (411 mg, 69%) ( using 3-bromoanisol instead of 1-bromo-4-fluorobenzene) which is obtained as a white solid. MS: m / e = 435.4 (M + H).

Example 15 4- (4-Fluoro-phenyl) -8- [2- (3-fluoro-phenyl) -2-hydroxy-cyclohexyl] -2,8-diaza-spiro [4.5] decan-1-one As described for example 11, 4- (4-fluoro-phenyl) -8- (2-oxo-cyclohexyl) -2,8-diaza-spiro [4.5] decan-1-one (200 mg, 1 mmol) is converted to the title compound (195 mg, 76%) (using l-bromo-3-fluorobenzene instead of l-bromo-4-fluorobenzene) q is obtained as a white solid.

Example 16 4- (4-Fluoro-phenyl) -8- [2- (2-fluoro-phenyl) -2-hydroxy-cyclohexyl] -2,8-diaza-spiro [4.5] decan-1-one As described for example 11, 4- (4-fluoro-phenyl) -8- (2-oxo-cyclohexyl) -2,8-diaza-spiro [.5] decan-1-one (200 mg, 1 mmol) is converted in the title compound (178 mg, 70%) (using 2-broofluorobenzene instead of l-bromo-4-fluorobenzene) which is obtained as a white solid.MS: m / e = 441.2 (M + H).

Example 17 8- [2- (3-Chloro-phenyl) -2-hydroxy-cyclohexyl] -4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one As described for him. Example 11, 4- (4-fluoro-phenyl) -8- (2-oxo-cyclohexyl) -2,8-diaza-spiro [4.5] decan-1-one (200 mg, 1 mmol) is converted into the compound of title (205 mg, 77%) (using l-bromo-3-chlorobenzene instead of 1-bromo-4-fluorobenzene) which is obtained as a white solid. MS: m / e = 457.3 (M).

Example 18 4-. { 2- [4- (4-fluoro-phenyl) -l-oxo-2,8-diaza-spiro [4.5] des-8-yl] -1-hydroxy-cislohexyl} -benzonitrile As described for example 11, 4- (4-fluoro-phenyl) -8- (2-oxo-cyclohexyl) -2,8-diaza-spiro [4.5] decan-1-one (200 mg) is converted , 1 mmol) in the title compound (118 mg, 45%) (using 4-bromobenzonitrile instead of l-bromo-4-fluorobenzene) which is obtained as a white solid. MS: m / e = 448.2 (M + H).

Example 19 4- (4-Fluoro-phenyl) -8- [2-hydroxy-2- (4-trifluoromethyl-phenyl) -cyclohexyl] -2,8-diaza-spiro [4.5] decan-1-one As described for example 11, 4- (4-fluoro-phenyl) -8- (2-oxo-cyclohexyl) -2,8-diaza-spiro [4.5] decan-1-one (200 mg, 1 mmol) is converted into the title compound (271 mg, 95%) (using 4-bromobenzotrif luoride instead of l-bromo-4-f luorobenzene) which is obtained as a white solid. MS: m / e = 491.2 (M + H).

Example 20 4- (4-f luoro-phenyl) -8- [2-hydroxy-2- (4-methanesulfonyl-f-enyl) -cyclohexyl] -2,8-diaza-spiro [4.5] decan-1-one As described for Example 11, 4- (4-f luoro-phenyl) -8- (2-oxo-cyclohexyl) -2,8-diaza-spiro [4.5] decan-1-one (200 mg, 1 mmol) it is converted to the title compound (16 mg, 6%) (using 4-bromophenylmethylsulfone instead of l-bromo-4-f luorobenzene) which is obtained as a white solid. MS: m / e = 501.5 (M + H).

Example 21 4- (4-f luoro-phenyl) -8- (2-hydroxy-2-p-tolyl-cyclohexyl) -2,8-diaz-a-spiro [4.5] decan-1-one As described for Example 11, 4- (4-fluoro-phenyl) -8- (2-oxo-cyclohexyl) -2,8-diaza-spiro [4.5] decan-1-one (200 mg, 1 mmol) is converted into the compound of title (178 mg, 70%) (using 4-bromotoluene instead of l-bromo-4-f luorobenzene) which is obtained as a white solid. MS: m / e = 437.4 (M + H).

Example 22% 4- (4-f luoro-phenyl) -8- (2-hydroxy-2-m-tolyl-cyclohexyl) -2, 8 -di za-spiro [4.5] decan-1-one As described for Example 11, 4- (4-fluoro-phenyl) -8- (2-oxo-cyclohexyl) -2,8-diaza-spiro [4.5] decan-1-one (200 mg, 1 mmol) becomes the title compound (229 mg, 90%) (using 3-bromotoluene instead of l-bromo-4-f luorobenzene) which is obtained as a white solid. MS. m / e = 437.3 (M + H). Example 23 4- (4-f luoro-phenyl) -8- (2-hydroxy-2-o-tolyl-cyclohexyl) -2,8-diaza-spiro [4.5] decan-l-one As described for the example 11, 4- (4-fluoro-phenyl) -8- (2-oxo-cyclohexyl) -2,8-diaza-spiro [4.5] decan-1-one (200 mg, 1 mmol) is converted to the compound of title (158 mg, 62%) (using 2-bromo toluene instead of l-bromo-4-f luorobenzene) which is obtained as a white solid. MS: m / e = 437.4 (M + H).

Example 24 8- [2- (4-tert-Butyl-phenyl) -2-hydroxy-cyclohexyl] -4- (4-f luoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one As described in Example 11, 4- (4-f luoro-phenyl) -8- (2-oxo-cyclohexyl) -2,8-diaza-spiro [4.5] decan-1-one (200 mg, 1 mmol ) is converted to the title compound (192 mg, 69%) (using l-bromo-4-tert-butylbenzene instead of l-bromo-4-fluorobenzene) which is obtained as a white solid. MS: m / e = 479.6 (M + H).

Example 25 4- (4-Fluoro-phenyl) -8- [2-hydroxy-2- (2-trifluoromethoxy-phenyl) -cyclohexyl] -2,8-diaza-spiro [4.5] decan-1-one As described for example 11, 4- (4-fluoro-phenyl) -8- (2-oxo-cyclohexyl) -2,8-diaza-spiro [4.5] decan-1-one (216 mg, 0.63 mmol) becomes the title compound (209 mg, 66%) (using l-bromo-2- (trifluoromethoxy) benzene instead of l-bromo-4-fluorobenzene) which is obtained as a white solid. MS: m / e = 507.3 (M + H).

Example 26 4- (4-Fluoro-phenyl) -8- [2-hydroxy-2- (4-imidazol-1-yl-phenyl) -cyclohexyl] -2,8-diaza-spiro [4.5] decan-1- as described for example 11, 4- (4-fluoro-phenyl) -8- (2-oxo-cyclohexyl) -2,8-diaza-spiro [4.5] decan-1-one (344 mg, 1.0 mmol ) is converted to the title compound (231 mg, 47%) (using 1- (4-bromophenyl) imidazole instead of l-bromo-4-fluorobenzene) which is obtained as a white solid. MS: m / e = 489.3 (M + H).

Example 27 4- (4-Fluoro-phenyl) -8- [2-hydroxy-2- (4-methoxy-phenyl) -cyclohexyl] -2,8-diaza-spiro [4.5] decan-1-one As described for example 11, 4- (4-fluoro-phenyl) -8- (2-oxo-cyclohexyl) -2,8-diaza-spiro [4.5] decan-1-one (517 mg, 1.5 mmol) becomes the title compound (568 mg, 84%) (using 4-bromoanisole instead of l-bromo-4-fluorobenzene) which is obtained as a white solid. MS: m / e = 453.3 (M + H). Example 28 4- (4-Fluoro-phenyl) -8- [2-hydroxy-2- (3-methoxy-phenyl) -cyclohexyl] -2,8-diaza-spiro [4.5] decan-1-one As described for example 11, 4- (4-fluoro-phenyl) -8- (2-oxo-cyclohexyl) -2,8-diaza-spiro [4.5] decan-1-one (200 mg, 1 mmol) is converted into the title compound (199 mg, 76%) (using 3-bromoanisole instead of 1-bromo-4-fluorobenzene) which is obtained as a white solid. MS: m / e = 453.3 (M + H).

Example 29 4- (4-Fluoro-phenyl) -8- rans- (4-hydroxy-4-phenyl-tetrahydro-pyran-3-yl) -2,8-diaza-spiro [4.5] decan-1-one 4_ (4-fluoro-phenyl) -8- rans- (4-hydroxy-tetrahydro-pyran-3-yl) -2,8-diaza-spiro [4.5] decan-1-one a) As described for example 12a , (R) -4- (4-fluoro-phenyl) -8- (2-oxo-cyclohexyl) -2,8-diaza-spiro [4.5] decan-l-one (100 mg, 0.4 mmol) is converted into the title compound (57 mg, 41%) (using 3, 5-epoxytetrahydrofuran instead of oxa-bicyclo [4.1.0] heptane) which is 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-fluoro-phenyl) -8- (4-oxo-tetrahydro-pyran-3-yl) -2, 8-diaza-spiro [4.5] decan-1-one b) As described for the bi-step ) of Structural Block 11, becomes 4- (4-fluoro-phenyl) -8- rans- (4-hydroxy-tetrahydro-pyran-3-yl) -2, 8-diaza-spiro [4.5] decan-1- ona (128 mg, 0.37 mmol) in the title compound (100 mg, 79%) which is obtained as a white solid after being purified by chromatography on silica gel eluting with DCM: MeOH (9: 1). MS: m / e = 347.4 (M + H). 4- (4-fluoro-phenyl) -8- rans- (4-hydroxy-4-phenyl-tetrahydro-pyran-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-pyran-3-yl) -2,8-diaza-spiro [4.5] decan-1-one is converted (90 mg, 0.26 mmol) in the title compound (65 mg, 59%) (using phenylthio instead of 1-bromo-4-fluorobenzene) which is obtained as a white solid. MS: m / e = 425.4 (M + H).

Formulation of Tablet (Wet granulation) Product Ingredients mg / tablet 5mg 25mg lO O g 500 g 1 Compound of formula I 5 25 100 500 2, Anhydrous lactose DTG 125 105 30 150 3, Sta-Rx 1500 6 6 6 30 4. Cellulose 30 30 30 150 microcrystalline Magnesium stearate 1 1 1 1 Total 167 167 167 831 Manufacturing procedure 1. Mix products 1, 2, 3 and 4 and granulate with purified water. 2. Dry the granules at a temperature of 50 ° C. 3. Pass the granules through a suitable crushing equipment. . Add the product 5 and mix for a period of three minutes; Compress in a suitable press.

Capsule Formulation Product Ingredients g / caps? Lia 5 g 25mg lOOmg 500mg 1 . Compound of formula I 5 25 100 500 2 . Lactose hydrated 159 123 148 3. Corn starch 25 35 40 70 Four . Talc 10 15 10 25 . Magnesium stearate 1 2 2 5 Total 200 200 300 600 Manufacturing procedure 1. Mix products 1, 2 and 3 in a suitable mixer for a period of 30 minutes. 2. Add products 4 and 5 and mix for a period of 3 minutes. 3. Fill in a suitable capsule.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (14)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. The compounds of the general formula characterized in that: A-B is -CH2-CH2-, -CH2-0- or -0-CH2-; X is hydrogen or hydroxyl; R1 is aryl, optionally substituted with one or two substitutes, selected from the group comprising halogen, lower alkyl, cyano, CF3-, -OCF3, lower alkoxy, lower alkyl-SO2 or heteroaryl;
2. R2 is aryl, optionally substituted with one or two substitutes, selected from the group comprising halogen, lower alkyl, CF3 or lower alkoxy; R3 is hydrogen or lower alkyl; n has a value of 0, 1 or 2; and their pharmaceutically active salts. 2. The compounds of the formula I according to claim 1 characterized in that: A-B is -CH-CH2- or -CH2-0-; X is hydrogen or hydroxyl; R1 is phenyl, optionally substituted with one or two substitutes, selected from the group comprising halogen, lower alkyl, cyano, CF3, -0CF3, lower alkoxy, lower alkyl-SO2 or heteroaryl, R2 is phenyl, optionally substituted with one or two substitutes , selected from the group comprising halogen or lower alkoxy; R3 is hydrogen; n is 1; and their pharmaceutically active salts.
3. 3. The compounds of formula I according to claim 2, characterized in that A-B is -CH2-CH2-.
4. 4. The compounds of formula I according to claim 3, characterized in that R1 and R2 are both phenyl, optionally substituted with lower alkyl, halogen or CF3.
5. 5. The compounds of the formula I according to claim 4, characterized in that the compounds are cis-rac-4-phenyl-8- (2-phenyl-cyclohexyl) -2,8-diaza-spiro [.5] decan -1-one, cis-rac4-phenyl-8- (2-p-tolyl-cyclohexyl) -2, 8-diaza-spiro [4.5] decan-1-one, cis-rac-8- [2- (4 -fluoro-phenyl) -cyclohexyl] -4-phenyl-2, 8-diaza-spiro [4.5] decan-1-one, cis-rac-4- (4-fluoro-phenyl) -8- [2- (4 -fluoro-phenyl) -cyclohexyl] -2, 8-diaza-spiro [4.5] decan-1-one, cis-rac-4- (4-fluoro-phenyl) -8- [2- (4-trifluoromethyl-phenyl ) -cyclohexyl] -2, 8-diaza-spiro [4.5] decan-1-one, 8- [2- (4-fluoro-phenyl) -2-hydroxy-cyclohexyl] -4-phenyl-2, 8-diaza -spiro [.5] decan-1-one, 4- (4-fluoro-phenyl) -8- [2- (3-fluoro-phenyl) -2-hydroxy-cyclohexyl] -2, 8-diaza-spiro [ 4.5] decan-1-one, 4- (4-fluoro-phenyl) -8- [2- (2-fluoro-phenyl) -2-hydroxy-cyclohexyl] -2, 8-diaza-spiro [4.5] decan- 1-one, 8- [2- (3-chloro-phenyl) -2-hydroxy-cyclohexyl] -4- (4-fluoro-phenyl) -2, 8-diaza-spiro [4.5] decan-1-o na, 4- (4-fluoro-phenyl) -8- trans- (4-hydroxy-4-phenyl-tetrahydro-pyran-3-yl) -2, 8-diaza-spiro [.5] decan-1-one
6. 6. The compounds of the formula I according to claim 1, characterized in that X is hydrogen.
7. 7. The compounds of the formula I according to claim 1, characterized in that X is hydroxyl.
8. 8. The compounds of the formula I according to claim 2, characterized in that A-B is -CH-0-.
9. 9. The processes for the preparation of the compounds of the formula I and their pharmaceutically acceptable salts, characterized in that these processes comprise: a) reacting a compound of the formula with a compound of the formula to produce a compound of the formula I for X = hydrogen where the substitutes are as defined above, or b) reacting a compound of the formula or a compound of the formula R2Br 8 to produce a compound of the formula I for X = hydroxy where the substitutes are as defined above, or c) if desired, separate the racemic forms obtained in their corresponding enantiomers and, if desired, convert the compounds obtained in pharmaceutically acceptable acid addition salts.
10. 10. A compound according to claim 1, characterized in that it is prepared by a process according to claim 9 or by an equivalent method.
11. 11. A medicament characterized in that it contains one or more compounds according to claim 1 and pharmaceutically acceptable excipients.
12. 12. A medicament according to claim 11, characterized in that it is for the treatment against diseases based on the inhibitor of glycine absorption.
13. 13. A medicine according to claims 11 and 12 characterized in that the diseases are psychosis, pain, dysfunction of learning memory, schizophrenia, dementia and other diseases where cognitive processes such as attention deficit disorders or Alzheimer's disease are decreased .
14. 14. The use of a compound according to claim 1 for the preparation of medicaments for the treatment against psychosis, pain, neurodegenerative dysfunction in memory and learning, schizophrenia, dementia and other diseases where cognitive processes are reduced as the disorders of the attention deficit or Alzheimer's disease.