MXPA06007620A - Diaza-spiropiperidine derivatives as inhibitors of transporter 1 and glycine transporter 2 - Google Patents

Abstract

The present invention relates to compounds of formula (I) wherein A-B is CH2-CH2, -CH2-O-, O-CH2, CH2-S, -S-CH2-, CH2-C(O)-, C(O)-CH2-, .-N(R4)-CH2- or -CH2-N(R4)-;R1 is lower alkyl, lower alkenyl, cycloalkyl, or is aryl, optionally substituted by one or two substituents, selected from the group consisting of halogen, cyano, lower alkyl, CF3, OCF3 or lower alkoxy, or is heteroaryl, optionally substituted by one or two substituents selected from the group consisting of halogen, lower alkyl, CF3 or lower alkoxy;R2 is lower alkyl, cycloalkyl, or is aryl, optionally substituted by one or two substituents, selected from the group consisting of halogen, lower alkyl, CF3, lower alkoxy, or is heteroaryl, optionally substituted by one or two substituents, selected from the group consisting of halogen, lower alkyl, CF3, lower alkoxy, or is heteroaryl, optionally substituted by one or two substituents, selected from the group consisting of halogen, lower alkyl, CF3, or lower alkoxy;R3 is hydrogen, lower alkyl or benzyl;R4 is hydrogen or benzyl;n is 0, 1 or 2;and to pharmaceutically available salts thereof. The compounds of formula I may be used in the treatment of neurological and neuropsychiatric disorders.

Description

DIAZA-ESPIROPIPERIDINE DERIVATIVES AS INHIBITORS OF GLYCINE TRANSPORTER 1 AND GLYCINE CONVEYOR 2 Description of the Invention The present invention relates to compounds of the formula '' wherein: AB is CH2-CH2 / -CH2-0-, -0-CH2, -CH2-S-, -S-CH2-, -CH2- C (O) -, -C (0) -CH2 -, -N (R4) -CH2- or -CH2-N (R4) -; R1 is lower alkyl, lower alkenyl, cycloalkyl or is aryl, optionally substituted with one or two substitutes selected from the group comprising halogen, cyano, lower alkyl, CF3, OCF3 or lower alkoxy or is heteroaryl, optionally substituted with one or two selected substitutes of the group comprising halogen, lower alkyl CF3, lower alkoxy, or R2 is lower alkyl, cycloalkyl or aryl optionally substituted by one or two substitutes selected from the group comprising halogen, lower alkyl, CF3 or lower alkoxy or is heteroaryl optionally substituted by one or two Ref.:173824 substitutes selected from the group comprising halogen, lower alkyl, CF3 or lower alkoxy; R3 is hydrogen, lower alkyl or benzyl; R 4 is hydrogen or benzyl; n has a value of 0, 1 or 2; and its pharmaceutically available 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. Neurological and neuropsychiatric disorders. 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). The. 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.-Targe ts, 2001, 5 (4): 507-518; Nakazato A. and Okuyama, S., et al., 2000, Exp. Opiñ. Ther Paten ts, 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., B, J. Psychi a try, 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, psychomimetic action induced by PCP incorporates positive and negative symptoms as well as cognitive dysfunction resembling schizophrenia in patients (Javitt DC et al., 1999, Bi ol. Psychia try, 45: 668- 679 and references here). Furthermore, 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 in which the 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, Na ture, 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, Na ture: 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. It acts as an inhibitory amino acid, binding to strychnine-sensitive glycine receptors and also influences 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 the glycinergic actions postsynaptic and maintenance of a low concentration of glycine to reabsorb glycine in the presynaptic nerve terminals and the surrounding glial 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. Bi ol., 18: 13-20). Therefore, a strategy to enhance the The activity of the NMDA receptor is to generate the concentration of glycine in the local microenvironment of synaptic NMDA receptors by inhibiting the GlyT-1 transporter (Bergereon R. et al., 1998, Proc. Na ti. Acad. Sci., USA, 95: 15730-15734; Chen L. et al., -2003, J. Neurophysi ol., 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. Paten ts, 11 (4): 563-572) ,. psychotic mood disorders and severe major depressive disorders, mood disorders 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. Neurobi ol., 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.Parents, 11 (4): 563-572).

Therefore, the increase in the activation of NMDA receptors through the inhibition of GlyT-1 leads to the agents for the treatment against psychosis, schizophrenia, dementia and other diseases where cognitive processes such as disorders and deficits are diminished of attention in Alzheimer's disease. 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 the inhibition of GlyT-1, their preparation, medicines based on a compound according to the invention and its production as well as the use of a compound of 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 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 chain group containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, -butyl, t-butyl and the like. Preferred alkyl groups are groups with 1-4 carbon atoms. As used herein, the term "alkenyl" denotes a straight or branched unsaturated chain group containing 2 to 7 carbon atoms with at least one double bond The term "cycloalkyl" denotes a saturated or partially saturated ring it contains. 3 to 7 carbon atoms, for example cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl or cycloheptenyl 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 "roaryl" denotes a cyclic or aromatic hydrocarbon radical containing 1, 2 or 3 roatoms 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 isoxazolylb. 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. Especially preferred are those compounds of the formula I, where: A-B is -CH2-CH2_, -CH2-0-, -0-CH2, -S-CH2- or -N (R4) -CH2-; R1 is lower alkyl, lower alkenyl, cycloalkyl or phenyl, optionally substituted with one or two substitutes selected from the group comprising halogen, cyano, lower alkyl, CF3, OCF3 or lower alkoxy or is roaryl, optionally substituted by lower alkyl; R2 is lower alkyl or is phenyl, optionally substituted by a substitute selected from the group comprising halogen, lower alkyl, CF3, lower alkoxy or roaryl; R3 is hydrogen; R4 is benzyl; and n has a value of 1 or 2; and its pharmaceutically available salts. Even more preferred are compounds where -AB- is -CH2-CH2- and n has a value of 1. Of this group, compounds are particularly preferred where R1 and R2 are phenyl, optionally substituted by halogen or lower alkyl, for example following compounds: rac-4-phenyl-8- (1-phenyl-cyclohexyl) -2,8-diaza-spiro [4.5] decan-1-one, rac-4- (4-fluoro-phenyl) -8- [ 1- (4-fluoro-phenyl) -cyclohexyl] -2, 8-diaza-spiro [4.5] decan-1-one, or rac-8- [1- (4-fluoro-phenyl) -cyclohexyl] -4- p-tolyl-2, 8-diaza-spiro [4.5] decan-1-one, where R1 is thiophenyl and R2 is phenyl substituted by halogen, for example the following compounds: rac-4- (4-fluoro-phenyl) - 8- (l-thiophen-2-yl-cyclohexyl] -2, 8- diaza-spiro [4.5] decan-1-one or rac-4- (4-fluoro-phenyl) -8- (1-thiophen-3-yl-cyclohexyl] -2, 8-diaza-spiro [4.5] decan- 1-one, where R1 is phenyl optionally substituted by halogen and R2 is lower alkyl, for example the following compounds: rac-8- (1-phenyl-cyclohexyl) -4-propyl-2, 8-diaza-spiro [4.5] decan-1-one or rac-8- [1- (4-fluoro-phenyl) -cyclohexyl] -4-propyl-2, 8-diaza-spiro [.5] decan-1-one. compounds wherein -AB is -O-CH2-, -CH2O-, -S-CH2- or - (benzyl) -CH2- and n is 1. Another objective of the present invention are the compounds of the formula I, wherein n is a value of 2. An example of this group is the compound: rac-4- (4-fluoro-phenyl) -8- [1- (4-fluoro-phenyl) -cycloheptyl] -2,8-diaza-spiro [ 4.5] decan-1-one 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 and comprising den: a) reacting a compound of the formula with a compound of the formula in the presence of AcOii and TMSCN and then with a corresponding Grignard reagent of the formula R ^ -Mghal 9 to obtain a compound of the formula where the substitutes are as described above and hal is Cl, Br or I and b) if desired, separate the racemic forms obtained in their corresponding enantiomers, and if desired, convert the obtained compounds to their pharmaceutically acceptable acid addition salts. The acid addition salts of the basic compounds of the formula I can be converted into their corresponding free bases by treatment of at least one stoichiometric equivalent of a suitable base such as sodium or potassium hydroxide or potassium carbonate, sodium bicarbonate, ammonium and the similar. The compounds of the formula I can be prepared in accordance with the variant processes a) and b) and with the following Reaction Schemes 1 and 2. The raw material is commercially available or can be prepared according to known methods.

The following abbreviations have been used: LDA = lithiodiisopropylamide TMSCN = trimethylthiocyanate DCM = dichloromethane TFA = trifluoroacetic acid THF = tetrahydrofuran Starting with the appropriately 1-protected-piperidin-4-ethylcarboxylate 1, treatment with an appropriate base, usually LDA, followed by treatment with an appropriately substituted nitroalkene 2 results in the formation of a nitroalkane 3. 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 solvent, results in the formation of 4. The subsequent cyclization by heating in refluxing toluene provides the amide 5. 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 diazaspiropiperidines 6 (Reaction Scheme 1). Reaction Scheme 1 wherein R is an N-protecting group such as BOC or benzyl and the other substitutes are as described above. The compounds of formula 6 are subjected to treatment by Strecker reaction conditions, with a compound of formula 7 in the presence of AcOH and a cyanide source (preferably TMSCN) to produce a compound of formula 8 which is then subjected to to treatment, by Bruylant reaction conditions, with a corresponding Grignard reagent 9 to produce the compounds of formula 1 (Reaction Scheme 2). Strecker synthesis can also be carried out using cyanide reagents Suitable (KCN, acetocyanohydrin) according to known methods at temperature ranges ranging from 0 to 100 ° C with reaction times between 30 minutes and 7 days. The Bruylant reactions can be carried out using Grignard reagents which are prepared from Mg (0) or i-PrMgCl or other known reagents in a suitable solvent such as tetrahydrofuran (THF). Suitable Grignard reagents are represented by the formula R1-Mghal9.

Reaction Scheme 2 All the compounds of the formulas I, 3, 4, 5, 6 and 8 can be prepared in their racemic forms following the procedures described below and separated into their non-racemic chiral enantiomers by preparative HPLC using either a column Chiralpak OD or AD (5 x 50 cm) at room temperature using a mobile phase ethanol: heptane with UV detection at 200 nM. The compounds of formula I and their pharmaceutically usable addition salts have pharmacological properties of value. Especially, it has been found that the compounds of the present invention are good inhibitors of glycine transporter I (GlyT-1). The compounds were investigated in accordance with 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), Glutamine 1 mM (Gibco life technologies). Absorption buffer (UB): 150 mM NaCl, 10 mM Hepes-Tris, pH 7., 1 mM CaCl2, 2.5 M KCl, 2.5 mM MgSO, 10 M (+) D-glucose. Flp-in ™ -CH0 (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, IC 50, the concentration of the competitor that inhibits the absorption of glycine 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 used with a scintillation fluid, shaken for 3 hours and the radioactivity of the cells was counted using a scintillation counter. The following activity could be demonstrated in the mouse and in human: 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. Medications that contain a compound of the Formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier is also an object of the present invention as also a process for its production, which comprises converting one or more of the compounds of the formula I and / or one of their 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, must be adjusted to the individual requirements in each particular case. In the case of oral administration, the dose for adults can 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 6 Rac-4-phenyl-2,8-diaza-spiro [4.5] decan-l-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 THF dry (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 a temperature of -60 ° C. -40 ° C for a period of one hour with which a solution of trans-beta-nitrostyrene (1.93 g, 13 mmol) in THF (8 ml) is added dropwise. 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-phenyl-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-phenyl-2, 8-diaza-spiro [4.5] decan-1-one c) A solution of ethyl ester of rac-4- (2) is heated under reflux for a period of 4 hours. -amino-l-phenyl-ethyl) -l-benzyl-piperidine-4-carboxylic acid (2.9 g, 8 nmol) in toluene (30 ml). After cooling to room temperature and evaporating, the mixture is purified by chromatography on silica gel eluting with DCM: MeOH: NHOH (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 [4.5] decan-1-one d) A suspension of rac-8-benzyl-4-phenyl-2, 8-diaza-spiro [4.5] decan- l-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 on 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). Reaction Scheme I, Step 1: Derivative-F of the protective group Boc Ras-4- (4-fluoro-phenyl) -2, 8-diaza-spiro [4.5] decan-1-one-tert-butyl ester of the 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 + NH4). 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-1,4-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-l-phenyl-ethyl) -1-tert-butyl-piperidin-1,4-dicarboxylic acid c) A solution of rac-1-tert-butyl ester of rac is hydrogenated -4- [1- (4-Fluoro-phenyl) 2-nitro-ethyl] -piperidin-1, -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) -1-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-l-phenyl-ethyl) -I-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 onto NaOH (3 N, 200 ml) and the product it 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).

(R) -4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one and (S) -4- (4-fluoro-phenyl) -2,8-diaza- spiro [4.5] decan-1-one Enantiomers of rac-4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one were separated using a Chiralpak AD column of 5 x 50 cm at room temperature using a mobile phase 15% ethanol: 85% heptane with UV detection at 220 nM. The less polar component (Peak 1) corresponds to the enantiomer- (R) (see below).

Elucidation of absolute stereochemistry: To a solution of 4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one (Peak A, 50 mg, 0.2 mmol) in methanol (10 ml ) IR- (-) - camphorsulfonic acid (46.8 mg, 0.2 mmol) is added and the solution is stirred for 10 minutes at room temperature. The resulting mixture is evaporated and the residue is crystallized from ethyl acetate. A single crystalline structural analysis by X-rays determined that the absolute configuration was (R) - as the salt of the IR- (-) - camphorsulfonic acid. Preparation of Structural Blocks 8 rac-1- (l-oxo-4-phenyl-2, 8-diaza-spiro [4.5] des-8-yl) cyclic exancarbonitrile To a mixture of rac-4-phenyl-, 8-diaza-spiro [4.5] decan-1-one (8.0 g, 34.7 mmol) in AcOH (80 ml) is added cyclohexanone (3-4 g, 34.7 mmol) followed by the dropwise addition of TMSCN (10.4 g, 104.2 mmol) and the resulting mixture is stirred at room temperature for 5 days. The resulting mixture is poured onto ice cold sodium hydroxide (25%, 200 ml) and the resulting white solid is filtered. The solid is dissolved in DCM (50 ml) and washed with water (40 ml) and dried over sodium sulfate. Filtration and evaporation afforded the title compound (7.25 g, 62%) as a white solid after purification by chromatography on silica gel eluting with DCM: MeOH (9: 1), MS: m / e = 338.3 ( M + H).

Ras-1- [4- (4-fluoro-phenyl) -l-oxo-2,8-diaza-spiro [4.5Jdec-8-yl] -cyclohexanecarbonitrile As described above, rac-4- (4-fluoro- phenyl) -2,8-diaza-spiro [4.5] decan-1-one (10.0 g, 40.3 mmol) is converted to the title compound (8.0 g, 56%) which is obtained as a white solid. MS: m / e = 356.5 (M + H).

(R) -1- [4- (4-Fluoro-phenyl) -l-oxo-2, 8-diaza-spiro [4.5] dec-8-yl] -cyclohexanecarbonitrile As described above, (R) -4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-l-one (Pico A, 150 mg, 0.4 mmol) is converted to the title compound (116 mg, 54%) obtained as a solid white color. MS: m / e = 356.5 (M + H).

(S) -1- [4- (4-fluoro-phenyl) -l-oxo-2, 8-diaza-spiro [4.5] dec-8-yl] -cyclohexanecarbonitrile As described above, (S) -4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one (Peak B, 150 mg, 0.4 mmol) is converted into the title compound (116 mg, 54%) obtained as a solid white color. MS: m / e = 356.5 (M + H).

Example 1 ras-4-l-phenyl-8- (1-phenyl-sislohexyl) -2,8-diaza-spiro [4.5] decan-1-one To a solution of rac-1- (l-oxo-4-) phenyl-2, 8-diaza-spiro [4.5] dec-8-yl) -cyclohexanecarbonitrile (400 mg, 1.2 mmol) in dry THF (12 ml) in an argon atmosphere at 0 ° C is added phenylmagnesium bromide ( 1 M in THF, 3.5 ml, 3.6 mmol) and the resulting mixture is warmed to room temperature overnight. The reaction is quenched by the addition of an aluminum chloride solution (saturated, ml) and the product is extracted with ethyl acetate (2 x 50 ml): The combined organic extracts are washed with brine (50 ml), dried over sodium sulfate, filtered and evaporated. The residue is purified by chromatography on silica gel eluting with DCM: MeOH: NH40H (95: 4.5: 0.5) to give the title compound (430 mg, 94%) as a white solid. MS: m / e = 389.3 (M + H). Example 2 Ras-4-phenyl-8- (1-p-tolyl-cyclohexyl) -2,8-diaza-spiro [4.5] decan-1-one As described for example 1, rac-1- (1- oxo-4-phenyl-2, 8-diaza-spiro [4.5] dec-8-yl) -cyclohexanecarbonitrile (200 mg, 0.6 mmol) is converted to the title compound (186 mg, 78%) (using p-tolylmagnesium bromide instead of phenylmagnesium bromide) which is obtained as a white solid. MS: m / e = 403.6 (M + H).

Example 3 Rac-4-phenyl-8- (1-m-tolyl-cyclohexyl) -2,8-diaza-spiro [4.5] desan-1-one To a solution of 3-iodotoluene (388 mg, 1.8 mmol) in Dry THF (6 ml) under an argon atmosphere at -60 ° C is added isopropylmagnesium chloride (2 M solution in THF, 977 uL, 2.0 mmol) and the resulting solution is heated at 0 ° C for one hour and then at room temperature for 10 minutes The resulting solution is added dropwise to a solution of rac-1- (l-oxo-4-phenyl-2, 8-diaza-spiro [.5] dec-8-yl) -cyclohexanecarbonitrile (200 mg, 0.6 mmol ) in dry THF (3 ml) and the solution is stirred overnight at room temperature. The reaction is quenched by the addition of an ammonium chloride solution (saturated, 10 ml) and the product is extracted with ethyl acetate (2 x 20 ml). The combined organic extracts are washed with brine (20 ml), dried over sodium sulfate, filtered and evaporated.

The residue is purified by chromatography on silica gel eluting with DCM: MeOH: NH4OH (95: 4.5: 0.5) to provide the title compound (170 mg, 71%) as a white solid. MS: m / e = 403.6 (M + H).

Example 4 rac-4-phenyl-8- (1-o-tolyl-cyclohexyl) -2,8-diaza-spiro [4.5] decan-1-one As described for example 3, rac-1- (l- oxo-4-phenyl-2, 8-diaza-spiro [4.5] dec-8-yl) -cyclohexanecarbonitrile (200 mg, 0.6 mmol) is converted to the title compound (11 mg, 5%) (using 2-iodotoluene instead of 3-iodotoluene) which is obtained as a white solid. MS: m / e = 403.6 (M + H).

Example 5 Ras-8- [1- (3-fluoro-phenyl) -cyclohexyl] -4-phenyl-2,8-diaza-spiro [4.5] decan-1-one As described for Example 3, rac-1 - (l-oxo-4-phenyl-2, 8-diaza-spiro [4.5] dec-8-yl) -cyclohexanecarbonitrile (200 mg, 0.6 mmol) is converted to the title compound (146 mg, 61%) (using 1-fluoro-3-iodobenzene instead of 3-iodotoluene) which is obtained as a white solid. MS: m / e = 407.5 (M + H). Example 6 rac-8- [1- (3,4-difluoro-phenyl) -cyclohexyl] -4-phenyl-2,8-diaza-spiro [4.5] decan-1-one As described for example 3, rac -1- (L-oxo-4-phenyl-2, 8-diaza-spiro [4.5] dec-8-yl) -cyclohexanecarbonitrile (200 mg, 0.6 mmol) is converted to the title compound (96 mg, 38% ) (using 1,2-difluoro-4-iodobenzene instead of 3-iodotoluene) which is obtained as a white solid. MS: m / e = 425.6 (M + H).

Example 7 rac-8- [1- (4-chloro-phenyl) -cyclohexyl] -4-phenyl-2, 8-diaza-spiro [.5] esan-1-one As described for example 3, rac- 1- (1-oxo-4-phenyl-2, 8-diaza-spiro [4.5] dec-8-yl) -cyclohexanecarbonitrile (200 mg, 0. 6 mmol) is converted to the title compound (96 mg, 38%) (using l-chloro-4-iodobenzene instead of 3-iodotoluene) which is It gets like a solid white color. MS: m / e = 423.4 (M).

Example 8 rac-4-phenyl-8- [1- (4-trifluoromethyl-phenyl) -cyclohexyl] -2,8-diaza-spiro [4.5] decan-l-one As described for example 3, rac-1 - (1-oxo-4-phenyl-2, 8-diaza-spiro [4.5] dec-8-yl) -cyclohexanecarbonitrile (200 mg, 0.6 mmol) is converted to the title compound (169 mg, 63%) ( using 4-iodobenzotrifluoride instead of 3-iodotoluene) which is obtained as a white solid. MS: m / e = 457.6 (M + H).

Example 9 rac-4- [l- (l-oxo-4-phenyl-2,8-diaza-spiro [4.5] dec-8-yl) -benzonitrile. As described for example 3, rac-1- (l-oxo-4-phenyl-2, 8-diaza-spiro [4.5] dec-8-yl) -cyclohexanecarbonitrile (200 mg, 0. 6 mmol) is converted to the title compound (81 mg, 33%) (using 4-iodobenzonitrile instead of 3-iodotoluene) which is obtained as a white solid. MS: m / e = 414.5 (M + H).

Example 10 rac-3- [l- (l-oxo-4-phenyl-2,8-diaza-spiro [4.5] dec-8-yl) -cyclohexyl] -benzonitrile As described for example 3, rac-1 - (l-oxo-4-phenyl- 2, 8-diaza-spiro [4.5] dec-8-yl) -cyclohexanecarbonitrile (200 mg, 0.6 mmol) is converted to the title compound (77 mg, 31%) (using 3-iodobenzonitrile instead of 3-iodotoluene) ) which is obtained as a solid white color. MS: m / e = 414.5 (M + H).

Example 11 rac-8- [1- (4-methoxy-phenyl) -cyclohexyl] -4-phenyl-2, 8-diaza-spiro [.5] decan-1-one As described for example 1, rac- 1- (l-oxo-4-phenyl-2, 8-diaza-spiro [4.5] dec-8-yl) -cyclohexanecarbonitrile (200 mg, 0.6 mmol) is converted to the title compound (68 mg, 27%) (using 4-methoxyphenylmagnesium bromide instead of phenylmagnesium bromide) which is obtained as a white solid. MS: m / e = 437.5 (M + H).

Example 12 rac-8- [1- (3-methoxy-phenyl) -cyclohexyl] -4-phenyl-2, 8-diaza-spiro [4.5] decan-1-one As described for example 3, rac-1 - (l-oxo-4-phenyl-2, 8-diaza-spiro [4.5] dec-8-yl) -cyclohexanecarbonitrile (200 mg, 0.6 mmol) is converted to the title compound (150 mg, 61%) (using 3-iodoanisole instead of 3-iodotoluene) which is obtained as a white solid. MS: m / e = 419.5 (M + H).

Example 13 rac-8- [1- (2-methoxy-phenyl) -cyclohexyl] -4-phenyl-2, 8-diaza-spiro [4.5] decan-1-one As described for example 3, rac-1 - (l-oxo-4-phenyl-2, 8-diaza-spiro [4.5] dec-8-yl) -cyclohexanecarbonitrile (200 mg, 0.6 mmol) is converted to the title compound (37 mg, 15%) (using 2-iodoanisole instead of 3-iodotoluene) which is obtained as a white solid. MS: m / e = 419.5 (M + H).

Example 4 rac-4-phenyl-8- [1- (4-trifluoromethoxy-phenyl) -cyclohexyl] -2,8-diaza-spiro [4.5] decan-l-one As described for example 3 ,. rac-1- (1-oxo-4-phenyl-2, 8-diaza-spiro [4.5] dec-8-yl) -cyclohexanecarbonitrile (200 mg, 0.6 mmol) is converted to the title compound (19 m 7% ) (using l-bromo-4- (trifluoromethoxy) benzene instead of 3-iodotoluene) which is obtained as a white solid. MS: m / e = 473.5 (M + H).

Example 15 rac-4-phenyl-8- [1- (3-trifluoromethoxy-phenyl) -cyclohexyl] -2,8-diaza-spiro [4.5] decan-1-one As described for example 3, rac-1 - (1-oxo-4-phenyl-2, 8-diaza-spiro [4.5] dec-8-yl) -cyclohexanecarbonitrile (200 mg, 0.6 mmol) is converted to the title compound (115 mg, 41%) (using 3- (trifluoromethoxy) iodobenzene instead of 3-iodotoluene) which is obtained as a white solid. MS: m / e = 437.5 (M + H) '. Example 16 rac-4-phenyl-8- (1-thiophen-3-yl-cyclo-exyl) -2,8-diaza-spiro [. 5] decan-1-one As described for example 3, rac-1 - (L-Oxo-4-phenyl-2, 8-diaza-spiro [4.5] ec-8-yl) -cyclohexanecarbonitrile (300 mg, 0.9 mmol) is converted to the title compound (77 mg, 22%) ( using 3-bromothiophene instead of 3-iodotoluene) which is obtained as a white solid. MS: m / e = 395.4 (M + H).

Example 17 rac-8-bisislohexyl-l-yl-4-phenyl-2, 8-diaza-spiro [4.5] desan-1-one As described for example 1, rac-1- (l-oxo-4-) phenyl-2, 8-diaza-spiro [4.5] dec-8-yl) -cyclohexanecarbonitrile (160 mg, 0.5 mmol) is converted to the title compound (26 mg, 14%) (using cyclohexylmagnesium chloride instead of bromide of phenylmagnesium) which is obtained as a white solid. MS: m / e = 395.4 (M + H).

Example 18 rac-8- (l-cislopentyl-cyclohexyl) -4-phenyl-2,8-diaza-spiro [4.5] decan-1-one. As described for example 1, rac-1- (l-oxo- 4-faith? Il- 2, 8-diaza-spiro [4.5] dec-8-yl) -cyclohexanecarbonitrile (160 mg, 0. 5 mmol) is converted to the title compound (46 mg, 26%) (using cyclopentylmagnesium chloride instead of phenylmagnesium bromide) which is obtained as a white solid. MS: m / e = 381.5 (M + H). Example 19 rac-8- (1-cyclopropyl-cyclohexyl) -4-phenyl-2, 8-diaza-spiro [4.5] desan-1-one. As described for example 1, rac-1- (l-oxo- 4-phenyl-2,8-diaza-spiro [4.5] dec-8-yl) -cyclohexanedcarbonitrile (150 mg, 0.44 mmol) is converted to the title compound (21 mg, 12%) (using cyclopropylmagnesium bromide instead of phenylmagnesium bromide) which is obtained as a white solid. MS: m / e = 353.4 (M + H). EXAMPLE 20 rac-8- (1-isopropyl-cyclohexyl) -4-phenyl-2,8-diaza-spiro [4.5] decan-l-one As described for example 14, rac-1- (l-pxo- 4-phenyl-2,8-diaza-spiro [4.5] dec-8-yl) -cyclohexanecarbonitrile (200 mg, 0.6 mmol) is converted to the title compound (22 mg, 6%) which is obtained as a color solid White. MS: m / e = 355.5 (M + H). EXAMPLE 21 Ras-8- [1- (2-methyl-propenyl) -cyclohexyl] -4-phenyl-2,8-dxaza-spiro [4.5] decan-1-one As described for example 1, rac-1 - (l-oxo-4-phenyl-2,8-diaza-spiro [4.5] dec-8-yl) -cyclohexanecarbonitrile (160 mg, 0.47 mmol) it is converted to the title compound (55 mg, 32%) (using 2-methyl-1-propenylmagnesium bromide instead of phenylmagnesium bromide) which is obtained as a white solid. MS: m / e = 367.3 (M + H).

EXAMPLE 22 Ras-4- (4-fluoro-phenyl) -8- (1-p-tolyl-cyclohexyl) -2,8-diaza-spiro [4.5] decan-1-one As described for example 2, rac -4- (4-fl'uoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one (200 mg, 0.6 mol) is converted into the title compound (173 mg, 73%) which It is obtained as a solid white color. MS: m / e = 421.4 (M + H).

Example 23 Ras-4- (4-fluoro-phenyl) -8- (1-m-tolyl-cyclohexyl) -2,8-diaza-spiro [4.5] decan-l-one As described for Example 3, rac -4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one (200 mg, 0.6 mmol) is converted to the title compound (100 mg, 42%) obtained as a solid white color. MS: m / e = 421.5 (M + H).

Example 24 rac-4- (4-fluoro-phenyl) -8- (1-o-tolyl-cyclohexyl) -2,8-diaza-spiro [4.5] decan-l-one As described for example 4, rac -4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one (200 mg, 0.6 mmol) was convert the title compound (36mg, 15%) obtained as a white solid. MS: m / e = 421.5 (M + H).

Example 25 rac-4- (4-f luoro-phenyl) -8- [1- (4-f luoro-phenyl) -cyclohexyl) -2,8-diaza-spiro [.5] decan-1-one As described for example 1, rac-4- (4-f luoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one (1.0 g, 2.8 mmol) is converted to the title compound (891 mg, 75%) (using '4-fluorophenylmagnesium bromide instead of phenylmagnesium bromide) which is obtained as a white solid. MS: m / e = 425.5 (M + H).

(R) -4- (4-fluoro-phenyl) -8- [1- (4-f luoro-phenyl) -cyclohexyl] -2,8-diaza-spiro [4.5] decan-1-one As described for Example 24-rac, (R) -4- (4-f luoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one (103 mg, 0.3 mmol) is converted to the title compound (29 mg, 24%) which is obtained as a white solid. MS: m / e = 425.5 (M + H). (S) -4- (4-fluoro-phenyl) -8- [1- (4-f luoro-phenyl) -cyclohexyl] -, 28-diaza-spiro [4.5] decan-1-one As described for Example 24-rac, (S) -4- (4-f luoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one (97 mg, 0.3 mmol) is converted into the title compound ( 35 mg, 30%) which is obtained as a white solid. MS: m / e = 425.5 (M + H).

Example 26 rac-4- (4-fluoro-phenyl) -8- [1- (3-fluoro-phenyl) -cyclohexyl] -2,8-diaza-spiro [4.5] decan-1-one As described for Example 5, rac-4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one (200 mg, 0.6 mmol) is converted to the title compound (180 g, 75 %) that is obtained as a solid white color. MS: m / e = 425.4 (M + H).

Example 27 rac-8- [1- (3,4-difluoro-phenyl) -cyclohexyl] -4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one As described for example 6, rac-4- (4-fluoro-phenyl) -2,8-diaza-spiro [.5] decan-1-one (200 mg, 0.6 mmol) is converted to the title compound (85 mg , 34%) that is obtained as a solid white color. MS: m / e = 443.5 (M + H). Example 28 Ras-8- [1- (4-Chloro-phenyl) -cyclohexyl] -4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one As described for Example 7, rac-4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one (200 mg, 0.6 mmol) is converted to the title compound (12 mg, 5%). ) That It gets like a solid white color. MS: m / e = 441.5 (M).

Example 29 rac-4- (4-fluoro-phenyl) -8- [1- (4-trifluoromethyl-phenyl) -islohexyl] -2,8-diaza-spiro [4.5] desan-l-one As described for Example 8, rac-4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one (200 mg, 0.6 mmol) is converted to the title compound (114 mg, 42% ) which is obtained as a solid white color. MS: m / e = 475.6 (M + H).

Example 30 Rac-4-. { 1- [4- (4-fluoro-phenyl) -l-oxo-2, 8-diaza-spiro [.5] dec-8-yl] -cyclohexyl} -benzonitrile As described for example 9, rac-4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one (200 mg, 0.6 mmol) is converted to the compound of title (88 mg, 36%) which is obtained as a white solid. MS: m / e = 432.6 (M + H). Example 31 rac-3-. { l- [4- (4-Fluoro-phenyl) -l-oxo-2, 8-diaza-spiro [4.5] dec-8-yl] -sislohexyl} -benzonitrile As described for example 10, rac-4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one (200 mg, 0.6 mmol) is converted to the compound of title (16 mg, 7%) that It gets like a solid white color. MS: m / e = 432.3 (M + H).

Example 32 rac-4- (4-fluoro-phenyl) -8- [1- (4-methoxy-phenyl) -cyclohexyl] -2,8-diaza-spiro [4.5] decan-1-one As described for Example 11, rac-4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one (250 mg, 0.7 mmol) is converted into the title compound (95 mg, 31% ) which is obtained as a solid white color. MS: m / e = 437.5 (M + H).

Example 33 rac-4- (4-fluoro-phenyl) -8- [1- (3-methoxy-phenyl) -cyclohexyl] -2,8-diaza-spiro [4.5] decan-1-one As described for Example 12, rac-4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one (250 mg, 0.7 mmol) is converted to the title compound (95 mg, 39%). ) which is obtained as a solid white color. MS: m / e = 437.5 (M + H). Example 34 rac-4- (4-fluoro-phenyl) -8- [1- (4-trifluoromethoxy-phenyl) -cyclohexyl] -2,8-diaza-spiro [4.5] decan-1-one As described for Example 14, rac-4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one (200 mg, 0.6 mmol) is convert to the title compound (10 mg, 4%) which is obtained as a white solid. MS: m / e = 491.5 (M + H).

Example 35 rac-4- (4-fluoro-phenyl) -8- [1- (3-trifluoromethoxy-phenyl) -cyclohexyl] -2,8-diaza-spiro [4.5] decan-1-one As described for Example 15, rac-4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one (200 mg, 0.6 mmol) is converted to the title compound (88 mg, 32%). ) which is obtained as a solid white color. MS: m / e = 491.5 (M + H).

Example 36 rac-4- (4-fluoro-phenyl) -8- (1-thiophen-2-yl-cyclohexyl) -2,8-diaza-spiro [4.5] ecan-1-one As described for example 3 , rac-4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one (150 mg, 0.4 mmol) is converted to the title compound (93 mg, 53%) ( using 2-iodothiophene instead of 3-iodotoluene) which is obtained as a white solid. MS: m / e = 413.4 (M + H).

Example 37 rac-4- (4-fluoro-phenyl) -8- [1- (5-methyl-thiophen-2-yl) -cyclohexyl] -2,8-diaza-spiro [4.5] decan-1-one As described for example 3, rac-4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one (100 mg, 0.28 mmol) it is converted to the title compound (50 mg, 42%) (using 2-bromo-5-methylthiophene instead of 3-iodotoluene) which is obtained as a white solid. MS: m / e = 427.6 (M + H).

Example 38 Ras-4- (4-fluoro-phenyl) -8- (1-thiophen-3-yl-cyclohexyl) -2,8-diaza-spiro [4.5] decan-1-one As described for Example 16 , rac-4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one (150 mg, 0.4 mmol) is converted into the title compound (108 mg, 62%) which It is obtained as a solid white color. MS: m / e = 413.4 (M + H).

Example 39 rac-4- (4-fluoro-phenyl) -8- (l-thiazol-2-yl-cyclo-exyl) -2,8-diaza-spiro [4.5] decan-l-one As described for the example 3, rac-4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one (100 mg, 0.28 mmol) is converted to the title compound (26 mg, 15%) (using 2-bromothiazole instead of 3-iodotoluene) which is obtained as a white solid. MS: m / e = 414.4 (M + H). Example 40 Ras-8- (1-cislopropyl-cyclohexyl) -4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one As described for example 19, rac-4 - (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one (125 mg, 0.35 mmol) it is converted to the title compound (11 mg, 8%) which is obtained as a light yellow solid. MS: m / e = 371.3 (M + H). Example 41 rac-8- (1-cyclopropyl-cislohexyl) -4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] desan-1-one As described for example 34, rac-4 - (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one (200 mg, 0.6 mmol) is converted to the title compound (13 mg, 6%) which is obtained as a Solid white color. MS: m / e = 373.6 (M + H). Example 42 Ras-8- (1-ethyl-cyclohexyl) -4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one As described for Example 3, rac-4 - (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one (200 mg, 0.6 mmol) is converted to the title compound (29 mg, 14%) (using 2-iodopyridine and ethylmagnesium bromide instead of 3- iodotoluene and isopropylmagnesium chloride) which is obtained as a light brown solid. MS: m / e = 359.3 (M + H). Example 43 Ras-4-phenyl-8- (4-phenyl-tetrahydro-pyran-4-yl) -2,8-diaza-spiro [4.5] esan-1-one rac-4- (l-oxo-4-) phenyl-2, 8-diaza-spiro [4.5] dec-8-yl) -tetrahydro-pyran-4-carbonitrile • a) As described for Structural Block 8, rac-4- phenyl-2, 8-diaza-spiro [4.5] decan-1-one (150 mg, 0.65 mmol) is converted to the title compound (70 mg, 32%) (using tetrahydro-4H-pyran-4-one in instead of cyclohexanone) that is obtained as a yellow foam. MS: m / e = 340.3 (M + H). rac-4-phenyl-8- (4-phenyl-tetrahydro-pyran-4-yl) -2,8-diaza-spiro [4.5] decan-1-one b) As described for example 1, rac-4 - (1-oxo-4-phenyl-2, 8-diaza-spiro [4.5] dec-8-yl) -tetrahydro-pyran-4-carbonitrile (70 mg, 0.2 mmol) is converted to the title compound (24 mg, 30%) which is obtained as an orange solid. MS: m / e = 391.3 (M + H).

Example 44 4-phenyl-8- (3-phenyl-tetrahxdro-pyran-3-yl) -2, 8-diaza-spiro [4.5] decan-1-one rac-3- (l-oxo-4-phenyl- 2, 8-diaza-spiro [4.5] dec-8-yl) -tetrahydro-pyran-3-carbonitrile a) As described for Example 43a, rac-4-phenyl-2, 8-diaza-spiro [4.5] decan-1-one (150 mg, 0.65 mmol) is converted to the title compound (55 mg, 25%) (using dihydro-pyran-3-one instead of tetrahydro-4H-pyran-4-one) which is It gets like a solid white color. MS: m / e = 340.3 (M + H). rac-4-phenyl-8- (3-phenyl-tetrahydro-pyran-3-yl) -1, 8-diaza-spiro [4-, 53 decan-1-one b) As described for example 1, rac-3- (l-oxo-4-phenyl-2, 8-diaza-spiro [4.5] dec -8-yl) -tetrahydro-pyran-3-carbonitrile (54 mg, 0.16 mmol) is converted to the title compound (20 mg, 30%) which is obtained as an orange solid. MS: m / e = 391.3 (M + H). Example 45 Rac-4- (4-fluoro-phenyl) -8- (4-phenyl-tetrahydro-thiopyran-4-yl) -2,8-diaza-spiro [4.5] decan-1-one Rac-4- [4- (4-fluoro-phenyl) -l-oxo-2, 8-diaza-spiro [4.5] dec-8-yl] -terahydro-thiopyran-4-carbonitrile a) To a stirring mixture of rac-4- hydrochloride (4-fluoro-phenyl) -2,8-diaza-spiro [.5] decan-1-one (500 mg, 2.0 mmol) and tetrahydro-Ef-thiopyran-4-one (300 mg, 2.6 mmol) add a solution of KCN (168 mg, 2.6 mmol) in water (30 ml). The resulting mixture is stirred vigorously at room temperature overnight and the resulting precipitate is filtered, washed with water and hexane and dried to yield the title compound (424 mg, 44%). MS: m / e = 374.5 (M + H). rac-4- (4-f uoro-phenyl) -8- (4-phenyl-tetrahydro-thiopian-4-yl) -2, 8-diaza-spiro [4.5] decan-1-one b) As described for Example 1, rac-4- [4- (4-fluoro-phenyl) -l-oxo-2, 8-diaza-spiro [4.5] dec-8-yl] - tetrahydro-thiopyran-4-carbonitrile (150 mg, 0.4 mmol) is converted to the title compound (50 mg, 29%) which is obtained as a white solid. MS: m / e = 425.5 (M + H). Example 46 Rac-4- (4-fluoro-phenyl) -8- [4- (4-fluoro-phenyl) -tetrahydro-thiopyran-4-yl] -2,8-diaza-spiro [4.5] decan-l- ona As described for Example 25, rac-4- [4- (4-fluoro-phenyl) -l-oxo-2, 8-diaza-spiro [4.5] dec-8-yl] -tetrahydro-thiopyran-4 -carbonitrile (520 mg, 1.4 mmol) is converted to the title compound (94 mg, 15%) which is obtained as a white solid. MS: m / e = 443.5 (M + H). Example 47 Ras-8- [1-benzyl-4- (4-fluoro-phenyl) -piperidin-4-yl] -4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan- 1-one rac-l-benzyl-4- [4- (4-fluoro-phenyl) -l-oxo-2, 8-diaza-spiro [4.5] dec-8-yl] -piperidine-4-carbonitrile a) As described for Example 43a, rac-4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-1-one (300 mg, 1.6 mmol) is converted to the title compound ( 650 mg, 92%) (using l-benzyl-4-piperidone instead of cyclohexanone) which is obtained as a white solid. MS: m / e = 447.6 (M + H). rac-8- [l-benzyl-4- (4-fluoro-phenyl) -piperidin-4-yl] -4- (4-fluoro-phenyl) -2,8-diaza-spiro [4.5] decan-l- ona b) As described for example 25, rac-l-benzyl-4- [4- (4-fluoro-phenyl) -l-oxo-2, 8-diaza-spiro [4.5] dec-8-yl] - piperidine-4-carbonitrile (500 mg, 1.1 mmol) is converted to the title compound (33 mg, 6%) which is obtained as a white solid. MS: m / e = 516.5 (M + H). Example 48 Ras-4-phenyl-8- (4-phenyl-sylcophenyl) -2,8-diaza-spiro [4.5] decan-1-one rac-1- [4- (phenyl) -l-oxo-2, 8-diaza-spiro [4.5] dec-8-yl] -cycloheptanecarbonitrile a) As described for example 45a, rac-4-phenyl-2, 8-diaza-spiro [4.5] decan-1-one (60 mg , 0.5 mmol) is converted to the title compound (120 mg, 64%) (using cycloheptanone instead of cyclohexanone) which is obtained as a white solid. MS; m / e = 352.1 (M + H). rac-4-phenyl-8- (1-phenyl-cycloheptyl) -2,8-diaza-spiro [4.5] decan-1-one b) As described for example 1, rac-1- [4- (phenyl) ) -1-oxo-2, 8-diaza-spiro [4.5] dec-8-yl] -cycloheptanecarbonitrile (100 mg, 0.28 mmol) is converted to the title compound (41 mg, 36%) which is obtained as a Solid white color. MS: m / e = 403.6 (M + H). Example 49 Ras-4- (4-fluoro-phenyl) -8- (1-phenyl-cycloheptyl) -2,8-diaza-spiro [4.5] decan-1-one rac-1- [4- (4-fluoro phenyl) -l-oxo-2, 8-diaza-spiro [4.5] dec-8-yl] -cycloheptanecarbonitrile a) As described for example 48a, rac-4- (4-fluoro- phenyl-2, 8-diaza-spiro [4.5] decan-1-one (300 mg, 2.7 mmol) is converted to the title compound (488 mg, 49%) which is obtained as a white solid. MS: m / e = 370.4 (M + H). rac-4- (4-fluoro-phenyl) -8- (1-phenyl-cycloheptyl) -2,8-diaza-spiro [.5] decan-1-one b) As described for Example 1, rac- 1- [4- (4-Fluoro-phenyl) -l-oxo-2,8-diaza-spiro [4.5] dec-8-yl] -cycloheptanecarbonitrile (200 g, 0.54 mmol) is converted to the title compound ( 110 mg, 48%) which is obtained as a white solid. MS: m / e = 421.5 (M + H).

Example 50 rac-4- (4-fluoro-phenyl) -8- [1- (4-fluoro-phenyl) -cycloheptyl] -2,8-diaza-spiro [4.5] decan-1-one As described for Example 25, rac-1- [4- (4-fluoro-phenyl) -l-oxo-2,8-diaza-spiro [4.5] dec-8-yl] -cycloheptanecarbonitrile (300 mg, 0.7 mmol) is converted to the title compound (182 mg, 77%) which is obtained as a white solid. MS: m / e = 439.5 (M + H).

Example 51 rac-8- (l-phenyl-sislo-exyl) -4-p-tolyl-2,8-diaza-spiro [4.5] desan-1-one 1-tert-butyl ester of rac-4- (2 -nitro-lp-tolyl-ethyl) -piperidin-1,4-dicarboxylic ester and 4-ethyl ester a) As described for Structural Block 7, the 1-tert-butyl ester of piperidin-1,4-diicarboxylic acid and 4-ethyl ester (3.15 g, 12.3 mmol) is converted to the title compound (4.86 g, 94%) (using trans-4-methyl-beta-nitrostyrene instead of 4-fluoro-trans-beta- nitrostyrene) which is obtained as a light brown foam. MS: m / e = 419.4 (M-H). tert-butyl ester of rac-l-oxo-4-p-tolyl-2, 8-diaza-spiro [4.5] decan-8-carboxylic acid b) As described for Structural Block 7, the 1-ter- butyl of rac-4- (2-nitro-lp-tolyl-ethyl) -piperidin-1,4-dicarboxylic acid and 4-ethyl ester (4.85 g, 11.5 mmol) is converted to the title compound (2.46 g, 62%) ) after the procedure in two steps of hydrogenation. Ra-Ni and heating under reflux in toluene solution. The title compound is obtained as a white solid after triturating from pentane. MS: m / e = 345.4 (M + H). rae 4-p-tolyl-2, 8-diaza-spiro [4.5] decan-1-one c) As described for Structural Block 7, the tert-butyl ester of rac-l-oxo-4-p-acid tolyl-2, 8-diaza-spiro [4.5] decan-8-carboxylic acid (2.45 g, 7.1 mmol) is converted to the title compound (1.1 g, 63%), after treatment with TFA in DCM, where it is obtained a solid coffee color. MS: m / e = 245.5 (M + H). rac-8- (1-phenyl-cyclohexyl) -4-p-tolyl-2, 8-diaza-spiro [4.5] decan-1-one d) As described for Structural Block 7, rac-4-p- tolyl-2,8-diaza-spiro [4.5] decan-l-one (350 mg, 0.1 mmol) is converted to the title compound (68 mg, 17%) which is obtained as an off-white solid. MS: m / e = 403.5 (M + H) after the two-step procedure involving Strecker and Bruylant reactions.

Example 52 rac-8- [1- (4-fluoro-phenyl) -islohexyl] -4-p-tolyl-2,8-diaza-spiro [4.5] decan-1-one As described for Example 51, , rac-4-p-tolyl-2, 8-diaza-spiro [4.5] decan-l-one (350 mg, 0.1 mmol) is converted to the title compound (93 mg, 22%) which is obtained as a whitish solid. MS: m / e = 421.3 (M + H) after the two-step procedure involving the Strecker and Bruylant reactions (using 4-fluorophenylmagnesium bromide instead of phenylmagnesium bromide).

Example 53 rac-8- [1- (4-fluoro-phenyl) -cyclohexyl] -4- (4-trifluoromethyl-methyl-phenyl) -2,8-diaza-spiro [4.5] ecan-1-one ester 1- tert-butyl of rac-4- [2-nitro-l- (4-trifluoromethyl-phenyl) -ethyl] -piperidine-1,4-dicarboxylic acid and 4-ethyl ester a) As described for example 51a, the 1-tert-butyl ester of piperidin-1,4-dicarboxylic acid and 4-ethyl ester (1.71 g, 6.6 mmol) is converted to the title compound (2.05 g, 65%) (using trans-4-trifluoromethyl- beta-nitrostyrene instead of 4-fluoro-trans-beta-nitrostyrene) which is obtained as a yellow oil. tert-butyl ester of rac-l-oxo-4- (4-trifluoromethyl-phenyl) -2,8-diaza-spiro [4.5] decan-8-carboxylic acid b) As described for example 51b, ester 1 butyl of rac-4- [2-nitro-l- (4-trifluoromethyl-phenyl) -ethyl] piperidin-1,4-dicarboxylic ester and 4-ethyl ester (2.04 g, 4.3 mmol) becomes the title compound (1.22 g, 71%) after the two-pass Ra-Ni hydrogenation process and heating under reflux in toluene solution containing triethylamine. The title compound is obtained as a white foam. MS: m / e = 399.3 (M + H). rac-4- (4-trifluoromethyl-phenyl) -2,8-diaza-spiro [4.5] decan-l-one 1: 1 hydrochloride c) tert-butyl ester of rac-l-oxo-4- (4) acid -trifluoromethyl-phenyl) -2,8-diaza-spiro [4.5] decan-8-carboxylic acid (1.22 g, 3.1 mmol) is converted into the title compound (1.03 g, 100%). After treatment with HCl in dioxane, where a white solid is obtained. MS: m / e = 299.3 (M + H). rac-1- [l-oxo-4- (4-trifluoromethyl-phenyl) -2,8-diaza-spiro [4.5] dec-8-yl] -cyclohexanecarbonitrile d) As described for example 45a, 4- ( 4-trifluoromethyl-phenyl) -2,8-diaza-spiro [4.5] decan-1-one 1: 1 hydrochloride (974 g, -2.9 mmol) is converted into the title compound (863 mg, 73%) which is It gets like a solid white color. MS: m / e = 406.3 (M + H). rac-8- [1- (4-fluoro-phenyl) -cyclohexyl] -4- (4-trifluoromethyl-phenyl) -2,8-diaza-spiro [4.5] decan-1-one e) As described for Example 25, 7, rac-1- [1-oxo-4- (4-trifluoromethyl-phenyl) -2,8-diaza-spiro [4.5] dec-8-yl] -cyclohexanecarbonitrile (250 mg, 0.62 mmol) is convert to the title compound (34 mg, 12%) which is obtained as a white solid. MS: m / e = 475.1 (M + H).

Example 54 Ras-8- [1- (4-fluoro-phenyl) -cislohexyl] -4- (4-methoxy-phenyl) -2,8-diaza-spiro [4.5] desan-1-one ester 1-ter- butyl of rac-4- [1- (4-methoxy-phenyl) -2-nitro-ethyl] -piperidin-1,4-dicarboxylic acid and 4-ethyl ester a) As described for example 51a, ester 1 -butyl ester of piperidin-1, 4-dicarboxylic acid and 4-ethyl ester (2.87 g, 78 mmol) is converted into the title compound (3.8 g, 78%) (using 1- (4-methoxyphenyl) -2 -nitroetene instead of 4-fluoro-trans-beta-nitrostyrene) which is obtained as a light brown foam. MS: m / e = 437.6 (M + H). tert-butyl ester of rac-4- (4-methoxy-phenyl) -l-oxo-2, 8-diaza-spiro [4.5] decan-8-carboxylic acid b) As described for example 51b, ester 1 4- [1- (4-methoxy-phenyl) -2-nitro-ethyl] -piperidine-1,4-carboxylic acid ester and 4-ethyl ester (3.8 g, 8.7 mmol) is converted into the compound of title (750 mg, 21%) after the two-stage Ra-Ni hydrogenation process and heating under reflux in toluene solution containing triethylamine. The title compound is obtained as a white foam. MS: m / e = 361.6 (M + H). rac-4- (4-methoxy-phenyl) -2,8-diaza-spiro [4.5] decan-1-one c) As described for example 51c, the tert-butyl ester of rac-4- (4 -methoxy-phenyl) -l-oxo-2, 8-diaza-spiro [4.5] decan- 8-carboxylic acid (0.74 g, 2.1 mmol) is converted to the title compound (328 mg, 61%), after treatment with TFA in DCM, where a white solid is obtained. MS: m / e = 261.3 (M + H). rac-1- [4- (4-methoxy-phenyl) -l-oxo-2, 8-diaza-spiro [4.5] dec-8-yl] -cyclohexanecarbonitrile d) As described for Example 45a, 4- ( 4-methoxy-phenyl) -2,8-diaza-spiro [4.5] decan-l-one (300 mg, 1.2 mmol) is converted to the title compound (270 mg, 64%) which is obtained as a color solid White. MS: m / e = 368.4 (M + H). rac-8- [1- (4-fluoro-phenyl) -cyclohexyl] -4- (4-methoxy-phenyl) -2,8-diaza-spiro [4.5] decan-1-one e) As described for Example 25, rac-1- [4- (4-methoxy-phenyl) -l-oxo-2, 8-diaza-spiro [4.5] dec-8-yl] -cyclohexanecarbonitrile (250 mg, 0. 68 mmol) is converted to the title compound (104 mg, 35%) which is obtained as a white solid. MS: m / e = 437.4 (M + H).

EXAMPLE 55 Rac-8- (1-phenyl-scylohexyl) -4-thiophen-2-yl-2,8-diaza-spiro [4.5] decan-1-ana-1-tert-butyl ester of rac-4- acid ( 2-nitro-l-thiophen-2-yl-ethyl) -piperidin-1,4-dicarboxylic ester and 4-ethyl ester a) As described in Example 51a, the 1-tert-butyl ester of piperidin-1 acid, 4-dicarboxylic and 4-ethyl ester (1.66 g, 10.7 mmol) it is converted to the title compound (1.62 g, 61%) (using 2- (2-nitrovinyl) thiofen instead of 4-fluoro-trans-beta-nitrostyrene) which is obtained as a dark brown solid. MS: m / e = 413.4 (M + H). 1-tert-butyl ester of rac-4- (2-amino-1-thiophen-2-yl-ethyl) -piperidine-1,4-dicarboxylic acid and 4-ethyl ester b) To a 1-ester ester solution 4-ethyl 4- (2-nitro-1-thiophen-2-yl-ethyl) -piperidine-1,4-dicarboxylic acid butyl ester and 4-ethyl ester (1.5 g, 3.6 mmol) in acetic acid ml) zinc dust (2 g, 30.6 mmol) is added and the resulting mixture is stirred at room temperature for 3 hours. The mixture is diluted with water and basified with sodium carbonate. The product is extracted with ethyl acetate and 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 (98: 2) gives the title compound (403 mg, 29%) as a light brown foam. MS; m / e = 399.5 (M + NH4). rac-8- (1-phenyl-cyclohexyl) -4-thiophen-2-yl-2, 8-diaza-spiro [4.5] decan-1-one c) A mixture of 1-tert-butyl ester of acid and ester 4-ethyl 4- (2-amino-1-thiophen-2-yl-ethyl) -piperidine-1,4-dicarboxylic acid (400 mg, 0.97 mmol) in toluene (3 ml) It contains triethylamine (0.2 ml) and is heated under reflux for 5 hours. After cooling to room temperature the mixture is evaporated to yield the cyclic amide [MS: m / e = 337.3 (M + H)] which is then dissolved in dichloromethane (4 ml) and trifluoroacetic acid (0.8 ml) is added, 1.1 mmol) and the resulting mixture is stirred at room temperature for 30 minutes. The mixture is basified with NaOH (2 N) dn and the product is extracted with dichloromethane to give the amine (76 mg, 30%) as a brown foam. This product is then subjected to treatment in a manner analogous to Example 45a to provide the Strecker product (75 mg, 69%) as a brown oil. MS: m / e = 344.3 (M + H). Then this product is subjected to treatment as described for example 1 to provide the title compound (42 mg, 52%) which is obtained as a light yellow oil. MS: m / e = 395.3 (M + H).

Example 56 Rac-8- (l-phenyl-cislohexyl) -4-propyl-2,8-diaza-spiro [4.5] decan-1-one 1-nitro-pent-l-ene a) To a solution of butyraldehyde ( 90.1 ml, 1 mol) in NaHS03 (38%, 207.5 ml, 1 mole) and water (293 ml) is added a solution of nitromethane (54.1 ml, 1 mole) dissolved in NaOH (2 N, 150 ml, 300 mmol) and water (50 ml) and the resulting mixture stir at 43 ° C for 3 hours and then heat at reflux for 30 minutes. The mixture is cooled to room temperature overnight and adjusted to a pH of about 4 with HCl (6 N). The product is extracted with diethyl ether (3 x 500 ml) and the combined organic layers are washed with H0 and brine, dried over sodium sulfate and evaporated to yield a brown liquid (37.6 g, 282 mmol). The product is then dissolved in chloroform (100 ml) and subjected to treatment with acetyl chloride, and the resulting mixture is stirred at room temperature for 3 hours and heated under reflux for 30 minutes. After cooling to room temperature the mixture is poured onto ice and neutralized with solid NaHCO 3. The product is extracted with chloroform (2 x 200 ml) and the combined organic layers are washed with H20 and brine and dried over sodium sulfate and evaporated to leave a brown liquid (46.1 g, 263 mmol). This product is dissolved in ethyl acetate (1 L) and then sodium acetate (69.1 g, 842 mmol) is added and the resulting mixture is stirred at room temperature for 48 hours. The mixture is filtered and the solution evaporated. The residue is divided into diethyl ether and water and the water layer is extracted with diethyl ether. The combined organic layers are washed with H20 and brine, dried over sodium sulfate and evaporated to leave a brown liquid (46 g). The title compound (6.8 g, 23%) is purified by steam distillation (bp 70 ° C in 8 torr). 1-tert-butyl ester of 4- (l-nitromethyl-butyl) -piperidine-1,4-dicarboxylic acid ester and 4-ethyl ester b) As described for Structural Block 7, 1-tert-butyl ester piperidin-1,4-dicarboxylic acid and 4-ethyl ester (15.3 g, 59 mmol) is converted to the title compound (21.2 g, 96%) (using 1-nitro-1-pentyl-ene instead of 4-fluoro-traps-beta-nitrostyrene) which is obtained as a yellow oil. MS: m / e = 371.2 (M-H). tert-butyl ester of rac-l-oxo-4-propyl-2, 8-diaza-spiro [4.5] decan-8-carboxylic acid c) As described for Structural Block 7, 1-tert-butyl acid ester rac-4- (1-Nitromethyl-butyl) -piperidin-1,4-dicarboxylic acid and 4-ethyl ester (21.2 g, 57 mmol) is converted to the title compound (11.2 g, 66%) after a procedure in two steps of hydrogenation using Ra-Ni and heating under reflux in a toluene solution. The title compound is obtained as a white solid after being triturated from hot pentane. MS: m / e = 297.5 (M + H). rac-4-propyl-2, 8-diaza-spiro [4.5] decan-1-one d) As described in Structural Block 7, tert-butyl ester of l-oxo-4-propyl-2, 8- diaza-spiro [4.5] decan-8- carboxylic acid (11.2 g, 38 mmol) is converted to the title compound (6.3 g, 85%) which is obtained as a light yellow liquid. MS: m / e = 197.4 (M + H). rac-1- (1-oxo-4-propyl-2, 8-diaza-spiro [4.5] dec-8-yl) -cyclohexanecarbonitrile e) As described in Structural Block 8, rac-4-propyl-2, 8-diaza-spiro [4.5] decan-1-one (4.0 g, mmol) is converted to the title compound (718 mg, 12%) which is obtained as a white solid.

MS: m / e = 304.4 (M + H). rac-8- (1-phenyl-cyclohexyl) -4-propyl-2, 8-diazaspiro [4.5] decan-1-one As described for example 1, l- (l-oxo-4-propyl-2, 8-diaza-spiro [4.5] dec-8-yl) -cyclohexancarboni trile (200 mg, 0.66 mmol) is converted to the title compound (122 mg, 52%) which is obtained as a white solid. MS: m / e = 355.5 (M + H).

Example 57 rac-8- [1- (4-luoro-phenyl) -cislohexyl] -4-propyl-2, 8-diaza-spiro [4.5] desan-1-one As described for example 25, rac-1 - (1-oxo-4-propyl-2, 8-diaza-spiro [4.5] dec-8-il) - Cyclohexanecarbonitrile (200 mg, 0.66 mmol) is converted to the title compound (87 mg, 35%) which is obtained as a white solid. MS: m / e = 373.5 (M + H).

Example 58 Ras-4-propyl-8- (1-thio-en-2-yl-cyclohexyl) -2,8-dxaza-spiro [. 5] decan-1-one As described for Example 36, rac-1 - (l-Oxo-4-propyl-2,8-diaza-spiro [4.5] dec-8-yl) -cyclohexanecarbonyl trile (75 mg, 0.3 mmol) is converted into the title compound (40 mg, 45%) which is obtained as a solid white color. MS: m / e = 361.5 (M + H). Example 59 Rac-8- [1- (5-methyl-thiophen-2-yl) -cyclohexyl] -4-propyl-2, 8-diaza-spiro [4.5] desan-l-one As described for example 37 , rac-1- (1-oxo-4-propyl-2, 8-diaza-spiro [4.5] dec-8-yl) -cyclohexanecarbonitrile (77 mg, 0.3 mmol) is converted to the title compound (29 mg, 31%) that is obtained as a solid white color. MS: m / e = 375.4 (M + H).

Formulation of Tablet (Wet granulation) Product Ingredients mg / tablet 5mg 25mg lOOmg 500mg Compound of formula I 25 100 500 2 . Lactose anhydrous DTG 125 105 30 150 3 . Sta-Rx 1500 30 Four . Cellulose 30 30 30 150 microcrystalline Magnesium stearate 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. 4. Add product 5 and mix for a period of three minutes; Compress in a suitable press. Capsule Formulation Product Ingredients mg / capsule 5mg 25mg lO Omg 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 by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates.

Claims (22)

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: AB is CH2-CH2, -CH2-0-, -0-CH2_, -CH2-S-, -S-CH2-, -CH2-C (O) -, -C (0) -CH2-, -N (R4) -CH2- or -CH2-N (R4) -; R1 is lower alkyl, lower alkenyl, cycloalkyl or is aryl, optionally substituted with one or two substitutes selected from the group comprising halogen, cyano, lower alkyl, CF3, OCF3 or lower alkoxy or is heteroaryl, optionally substituted with one or two selected substitutes of the group comprising halogen, lower alkyl CF3, lower alkoxy, or R2 is lower alkyl, cycloalkyl or aryl optionally substituted by one or two substitutes selected from the group comprising halogen, lower alkyl, CF3 or lower alkoxy or R3 is hydrogen, lower alkyl or benzyl; R 4 is hydrogen or benzyl; n has a value of 0, 1 or 2; and its pharmaceutically available salts.
2. 2. The compounds of the formula I according to claim 1 characterized in that: A-B is -CH2-CH2_, -CH-0-, -0-CH2, -S-CH2- or -N (R) -CH2-; R1 is lower alkyl, lower alkenyl, cycloalkyl or phenyl, optionally substituted with one or two substitutes selected from the group comprising halogen, cyano, lower alkyl, CF3, OCF3 or lower alkoxy or is heteroaryl, optionally substituted by lower alkyl; R2 is lower alkyl or is phenyl, optionally substituted by a substitute selected from the group comprising halogen, lower alkyl, CF3, lower alkoxy or heteroaryl; R3 is hydrogen; R4 is benzyl; and n has a value of 1 or 2; and its pharmaceutically available salts.
3. 3. The compounds of the formula I according to claim 2, characterized in that n is 1.
4. 4. The compounds of the formula I according to claim 3, characterized in that -A-B- is -CH2-CH2-. .
5. 5. The compounds of the formula I according to claim 4, characterized in that R1 and R2 are phenyl, optionally substituted by halogen or lower alkyl.
6. 6. The compounds of the formula I according to claim 5, characterized in that they are: rac-4-phenyl-8- (1-phenyl-cyclohexyl) -2, 8-diaza-spiro [4.5] decan-1-one , rac-4- (4-fluoro-phenyl) -8- [1- (4-fluoro-phenyl) -cyclohexyl] -2,8-diaza-spiro [4.5] decan-1-one or rac-8- [ 1- (4-fluoro-phenyl) -cyclohexyl] -4-p-tolyl-2, 8-diaza-spiro [4.5] decan-1-one.
7. 7. The compounds of the formula I according to claim 4, characterized in that R1 is thiophenyl and R2 is phenyl, substituted with halogen.
8. 8. The compounds of formula I according to claim 7, characterized in that they are: rac-4- (4-fluoro-phenyl) -8- (1-thiophen-2-yl-cyclohexyl) -2,8-diaza -spiro [4.5] decan-l-one or rac-4- (4-fluoro-phenyl) -8- (l-thiophen-3-yl-cyclohexyl] -2,8-diaza-spiro [4.5] decan-1 9.
9. The compounds of the formula I according to claim 4, characterized in that R1 is phenyl, optionally substituted by halogen and R2 is lower alkyl 10.
10. The compounds of the formula I according to claim 9, characterized because they are: rac-8- (1-phenyl-cyclohexyl) -4-propyl-2, 8-diaza-spiro [4.5] decan-1-one or rac-8- [1- (4-fluoro-phenyl) -cyclohexyl] - 4-propyl-2, 8-diaza-spiro [4.5] decan-1-one 11.
11. The compounds of the formula I according to claim 3, characterized in that -AB- is -0-CH2-.
12. Compounds of the formula I according to claim 3, characterized in that -AB- is -CH2-0- 13.
13. The compounds of the formula I according to claim 3, characterized in that -AB- is -S-CH2- 14.
14. The compounds of formula I according to claim 3, characterized in that -AB- is -N (benzyl) -CH2- 15.
15. The compounds of formula I according to claim 2, characterized in that n is 2.
16. The compounds of the formula I according to claim 15, characterized in that the compound is rac-4- (4-fluoro-phenyl) -8- [1- (4-fluoro-phenyl) -cycloheptyl] - 2, 8-diaza-spiro [4.5] decan-l-one
17. 17. The process for prep of the compounds of the formula I and their pharmaceutically acceptable salts, characterized in that it comprises: a) reacting a compound of the formula with a compound of the formula in the presence of AcOH and TMSCN and then with a corresponding Grignard reagent of the formula R1Mghal 9 in a compound of the formula where the substitutes are as described above and hal is Cl, Br or I and b) if desired, separate the racemic forms obtained in their corresponding enantiomers and if desired, convert the obtained compounds to their pharmaceutically acceptable acid addition salts.
18. 18. A compound according to claim 1, characterized in that it is prepared by a process according to claim 17 or by an equivalent method.
19. 19. A medicament characterized in that it contains one or more compounds according to claim 1 and its pharmaceutically acceptable excipients.
20. 20. A medicine according to claim 19, characterized in that it is for the treatment against diseases based on the glycine absorption inhibitor.
21. 21. A medicine according to claims 19 and 20, characterized in that the diseases are psychosis, pain, memory dysfunction and learning, schizophrenia, dementia and other diseases where cognitive processes such as attention deficit disorders or Alzheimer's disease are impaired.
22. 22. The use of a compound according to claim 1 for the preparation of medicaments for the treatment against psychosis, pain, neurodegenerative dysfunction of memory and learning, schizophrenia, dementia and other diseases where cognitive processes deteriorate as disorders of attention deficit or Alzheimer's disease.