MXPA98000824A - Derivatives of 1,3,8-triaza-espiro [4.5] decan-4-ona 8-substitute - Google Patents

Abstract

The present invention relates to compounds of the formula (I), wherein R1 and R2 are, independently of each other, hydrogen, lower alkyl, lower alkoxy or halogen, R3 is phenyl, optionally substituted by lower alkyl, CF3, lower alkoxy or halogen, and R 4 is hydrogen, lower alkyl, lower alkenyl, -C (O) -lower alkyl, -C (O) -phenyl, lower alkyl-C (O) -phenyl, lower alkylene -C (O) O-alkyl lower, lower-di-C-alktriyl (O) O-lower alkyl, hydroxy-lower alkyl, lower-alkyl-O-lower alkyl, lower-alkyl-CH (OH) CF3, phenyl or benzyl, R5 and R6 are, independently of each other , hydrogen, phenyl, lower alkyl or lower di-lower alkyl or can together form a phenyl ring, and R5 and one of R1 or R2 can together form a saturated or unsaturated 6-membered ring, A is a saturated ring of 4-7 members which may contain a heteroatom such as O or S, and their pharmaceutically acceptable acid addition salts which are antagonists and / or antagonists of the O receptor

Description

DESCRIPTION OF THE INVENTION The present invention relates to compounds of the formula where I R! and R2 are, independently of each other, hydrogen, lower alkoyl, lower alkoxy or halogen; R3 is phenyl, optionally substituted by lower alkenyl, CF3, lower alkoxy or halogen; and R 4 is hydrogen, lower alkenyl, lower alkenyl, -C (O) -lower alkyl, -C (O) -phenyl, lower alkyl-C (0) -phenyl, to < lower-C (O) O-lower alkoyl, lower-lower-di-C-C (O) 0-lower alkyl, hydroxy-lower-guyl, lower-alkyl-0-lower alkyl, lower alkyl-CH (OH) CF3, phenyl or benzyl, R5 and R6 are, independently of each other, hydrogen, phenyl, lower alkyl or di-lower alkyl or can together form a phenyl ring, and R ^ and one of Rl OR R2 can form together a saturated or unsaturated 6-membered ring, A is a 4-7 membered saturated ring which may contain a heteroatom such as 0 or S, and its pharmaceutically acceptable acid addition salts. The compounds of formula I and their salts are distinguished by valuable therapeutic properties. Has been found, REF: 26654 surprisingly, that the compounds of the present invention are agonists and / or antagonists of the OFQ receptor. Therefore they will be useful in the treatment of psychiatric, neurobiological and physiological disorders, especially, but not limited to, in the improvement of anxiety symptoms and stress disorders, depression, trauma, memory loss due to Alzheimer's disease or other dementias, epilepsy. and seizures, states of acute and / or chronic pain, withdrawal symptoms of addiction drugs, water balance control, Na + excretion, arterial blood pressure disorders and nutritional disorders such as obesity. The FQ orphanin (OFQ), a peptide with a length of sixteen amino acids (FGGFTGARKSARKLANQ), has been isolated from the brain of the rat and is a natural binder for a G protein-coupled receptor (OFQ-R), found at high levels in the brain tissue. OFQ exhibits agonistic activity in the OFQ-R both in vitro and in vivo. Julius (Nature 377, 476, [1995] discusses the discovery of OFQ highlighting that this peptide shares the highest sequence similarity with dynorphin A, an endogenous ligand established for opioid receptors.) OFQ inhibits adenylate cyclase in CHO cells (LC 132 +) in culture and induces hyperalgesia when administered intra-cerebroventricularly to mice.The pattern of results indicates that this heptadecapeptide is an endogenous agonist of the LC 132 receptor and results to have pro-noceceptive properties.It was decoded that when injected intra-cerebroventricularly In mice, OFQ retards locromotor activity and induced hyperalgesia It was concluded that OFQ can act as a brain neurotransmitter to modulate nociceptive and locomotor behavior Objects of the present invention are compounds of formula I and their pharmaceutically acceptable addition salts, mixtures racemates and their corresponding enantiomers, the preparation of the compounds cited, medicines containing them and their preparation, as well as the use of the aforementioned compounds in the control or prevention of diseases, especially diseases and disorders of the type referred to above, or in the preparation of corresponding drugs. The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination. As used herein the term "lower alkyl" denotes a straight or branched chain alkyl group containing from 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2- butyl, t-butyl. The term "halogen" denotes chlorine, iodine, fluorine and bromine. The term "lower alkoxy" denotes a group wherein the alkyl radical is as defined above, and that is linked via an oxygen atom. The term "pharmaceutically acceptable acid addition salts" encompasses salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid , tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like. Preferred examples are compounds wherein R 1 and / or R 2 are hydrogen or chlorine, for example the following compounds: (-) -8- (5,8-dichloro-1,2,3,4-tetrahydro-naphthyl-2-) -1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one, 8 - (8-chloro-l, 2, 3, 4-tetrahydro-naphthyl-2) -1-phenyl-1,3,8-triazaes-pyro [4.5] decan-4-one, 1-phenyl-8- ( 1, 2,3, 4-tetrahydro-naphthyl-1) -1,3, 8-triazaspiro [4.5] -decan-4-one, 8-indan-2-yl-l-phenyl-l, 3, 8- triazaspiro [4.5] decan-4-one. Preferred examples are also compounds wherein R ^ and one of R ^ - or R2 together form a saturated 6-membered ring, for example the following compounds: (RS) -8- (acenaphthen-1-yl) -1-phenyl- l, 3, 8-triazaspiro [4.5] decan-4-one, (RS) -8- (acenaphthen-l-yl) -3-methyl-l-phenyl-1,3,8-triazaspiro [4.5] Decan-4-one, (RS) -8- (2, 3-dihydro-lH-phenalen-1-yl) -1-phenyl-1,3,8-triazaspiro- [4.5] decan-4-one , (R) -8- (acenaphthen-1-yl) -1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one, 8- (2, 3, 3a, 4, 5, 6 -hexahydro-lH-phenalen-l-yl) -1-phenyl-l, 3, 8- -triazaspiro [4.5] decan-4-one and (RS) -8- (5-methyl-1, 2, 3, 4-tetrahydro-naphthalen-1-yl) -1-phenyl-1,3,3-triazaspiro [4.5] decan-4-one.

The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, with procedures described below, comprising a) hydrogenating the double bond in a compound of formula wherein RÍ-R ^ have the above-indicated meaning and Af is a 5-7 membered unsaturated partial ring which may contain a heteroatom such as O or S to a compound of formula I, or b) alkylate, benzylate or acylate a compound of formula I, wherein R 4 is hydrogen, to a compound of formula I, wherein R 4 lower alkyl, lower alkenyl, -C (O) -low alkyl, -C (0) -phenyl, lower alkyl-C (O) -phenyl, lower alkylene-C (O) 0-lower alkyl, lower alcantriyl-di-C (O) O-lower alkyl, hydroxy-lower alkyl, lower alkyl-O-lower alkyl, lower alkyl-CH (OH) CF3, phenyl or benzyl, or c) reductively amines a compound of the formula with a compound of the formula IV to a compound of the formula where A and R! - R ^ have the meaning indicated above, or d) convert a racemic mixture into its enantiorneric components for the preparation of optically pure compounds, and e) if desired, convert the compound of formula I obtained into a pharmaceutically acceptable addition salt. acceptable According to variant a) of the process a compound of formula II can be hydrogenated in conventional manner, for example with metal hydrides, such as borohydride, sodium cyanoborohydride or with triethylsilane in protic solvents, for example methanol or ethanol, and / or in the presence of protic reagents such as trifluoroacetic acid in methylene chloride. This reaction is usually carried out at room temperature.

Another method is hydrogenation in the presence of at least one hydrogenation catalyst, such as palladium on carbon, platinum or ruthenium, in an inert solvent, for example methanol, ethanol or ethyl acetate or mixtures thereof. This reaction is carried out at a pressure of 1 to 1000 and at temperatures between 25 and 250 ° C. According to process variant b) a compound of formula I, wherein R 4 is hydrogen, can be alkylated, benzylated or acylated in conventional manner, for example in the presence of a corresponding alkyl-, benzyl- or acyl-halide, such as ethyliodide, allylbromide, benzyl bromide, ethyl bromide, acetylchloride, methylbromacetate and the like. This reaction is carried out in the presence of a metal hydride, such as sodium hydride at a temperature of about 60-100 ° C. The reductive amination of a keto compound of formula III with an amine of formula IV according to variant c) is carried out in conventional manner in a solvent, such as tetrahydrofuran (THF), methanol or ethanol, or in a mixture of THF with an appropriate alcohol, and in the presence of a reducing agent, such as Na-cyanoborohydride. Another method is described in J. Org. Chem., 55, 2552-54, 1990. According to this variant the reaction is carried out by reaction of an amine with a ketone in the presence of TI- (IV) -isopropoxide and Na-cyanoborohydride. The salt formation according to variant e) is carried out at room temperature in accordance with methods "which are known per se and which are familiar to any expert in the art. They come into consideration not only salts with inorganic acids, but also salts with organic acids. Examples of these salts are hydrochloride, hydrobromides, sulfates, nitrates, citrates, acetates, maleates, succinates, methansulphonates, p-toluenesulfonates and the like. The compounds "which are used as starting materials can be prepared, for example, in accordance with reaction schemes 1 and 2 and with examples aa-av. In addition, the starting materials of the compound described in Example 44 can be prepared according to J. Org. Chem., 1995, 60, 4324-4330 and with J. Med. Chem., 1996, 39, 3169. Scheme 1 wherein the substituents have the above mentioned indicated.

Scheme 2 wherein the substituents have the meaning indicated above. A compound of formula II is obtained by treating an appropriate ketone of formula III with an amine secondary to an enamine with loss of water. This reaction is reversible, so the water must be separated azeotropically or with a drying agent. This reaction is carried out in an inert solvent, such as benzene or toluene and in the presence of an acidic catalyst such as p-toluenesulfonic acid or sulfuric acid or, alternatively, with a drying agent, for example with molecular sieves at temperatures around 80-120 ° C. The aforementioned compounds of formula II can also be prepared by stirring components in an inert solvent, such as hexane, benzene or 1,2-dichloroethane at room temperature or elevated temperatures up to 80 ° C in the presence of, for example, titanium tetrachloride as Lewis acid. and drying agent. The compounds of formula I can then be obtained according to variant a) of the process. According to scheme 2, compounds of formula Iala are obtained. A compound of formula V is dissolved in an inert solvent, such as methanol, ethanol, water or mixtures thereof and refluxed with NH2OH and NaOAc. The obtained oxime is dissolved in an inert solvent such as diethyl ether. After a reaction with NaN02 in water in the presence of H2SO4 a compound of formula VI is obtained. This compound is dissolved in an inert solvent, such as acetonitrile and is stirred together with the corresponding compound of formula IV and molecular sieves to give a compound of formula lal. A compound of formula can then be obtained by hydrogenation according to variant a) of the process. The ketones or aldehydes of formulas III and V and the compounds of formula IV are known compounds or can be prepared according to methods known per se. As indicated above, the compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacodynamic properties. The compounds of the present invention have been found to be agonists and / or antagonists of the OFQ receptor and have effects in animal models of psychiatric, neurobiological and physiological disorders, such as anxiety, stress disorders, depression, trauma, memory loss due to Alzheimer's disease or other dementias, epilepsy and seizures, states of acute and / or chronic pain, withdrawal symptoms of addiction drugs, water balance control, Na + excretion, arterial blood pressure disorders and nutritional disorders such as obesity. The compounds were investigated according to the following tests: Binding Assay Methods OFQ-R Cell Culture HEK-293 cells adapted for suspension development (293s) were grown in HL medium plus 2% FBS. The cells were transfected with rat OFQ receptor cDNA (LC132), FEBS Lett. 347, 284-288, 1994, cloned into the pCEP4 expression vector (Invitrogen, SanDiego, CA, USA) using lipofectin (Life Technologies, Bethesda, MD, USA). The transfected cells were selected in the presence of hygromycin (1000 U / ml) (Calbiochem, SanDiego, CA, USA). A group of resistant cells was tested for OFQ-R expression by [3H] -0FQ binding (Amersham PLC, Buckinghamshire, England). These cells (293s-OFQ-R) were expanded for large-scale culture and membrane preparation. Membrane preparation 293s-OFQ-R cells were harvested by centrifugation, washed 3 times with phosphate buffered saline (PBS) before resuspension in 50 mM Tris-HCl buffer, pH 7.8, 5 mM MgCl2, 1 mM EGTA) and disruption with a tissue homogenizer (30 seconds, fixation 4, Pt 20, Kinematica, Griens-Lucern, Switzerland). A total membrane fraction was obtained by centrifugation at 49,000 x g at 4 ° C. This procedure was repeated twice and the pellet resuspended in buffer. Aliquots were stored at -70 ° C and protein concentrations were determined using BCA ™ Protein Assay Reagent (Pierce, Rockford, IL) following the manufacturer's recommendations. Binding assays [3H] -OFQ competition studies were carried out with 77 μg of membrane protein in a final assay volume of 0.5 ml of buffer A plus 0.1% BSA and 0.01% of bacitracin (Boehringer-Mannheim, Mannheim, Germany) for one hour at room temperature. 50 nM of OFQ was used without signaling to define the specific nq binding. The tests were terminated by filtration through Whatman GF / C filters (Unifilter-96, Canberra Packard SA, Zurich, Switzerland) pretreated with 0.3% poleitileni ina (Sigma, St. Louis, MO, USA) and 0, 1% BSA (Sigma) for 1 hour. The filters were washed 6 times with 1 ml of 50 mM Tris-HCl pH 7.5 cooled by ice. The radioactivity retained was counted on a Packard Top-Count microplate scintillation counter after the addition of 40 μl of Microscint 40 (Canberra Packard). The effects of the compounds were determined using at least 6 concentrations in triplicate and were determined twice. The IC50 values were determined by curve coupling and these values were converted to K-values with the method of Cheng and Prusoff, Biochem. Pharmacol., 22, 3099, 1973. The affinity to the OFQ receptor, given as pK-1, is within 6.6 to 9.6. For example, the values pKj_ of examples 8 and 15 are 7.9 and 8.0, respectively. 8 3-benzyl-8- (5,8-dichloro-1,2,3,4-tetrahydro-naphthyl-2) -1- phenyl-1,3,8-triaza-spiro [4, 5] decan- 4-one 15 3-acetyl-8- (5,8-dichloro-1,2,3,4-tetrahydro-naphthyl-2) -1- -phenyl-1, 3, 8-triaza-spiro [4, 5 ] decan-4-one The compounds of formula I, as well as their pharmaceutically usable acid addition salts 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, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be carried out rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions. The compounds of formula I and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert inorganic or organic excipients for the production of tablets, coated tablets, dragees and hard gelatine capsules. As excipients, for example for tablets, dragees and hard gelatin capsules, lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used. Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. Suitable excipients for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.

Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc. Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or illiquid polyols, etc. In addition, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances. The dose can vary within wide limits and will obviously conform to the individual requirements of each particular case. In general, in the case of oral administration, a daily dose of about 10 to 1000 mg per person of a compound of general formula I should be appropriate, although the above upper limit may also be exceeded when indicated. The following examples illustrate the present invention, but in no way are to be understood as limiting. All temperatures are expressed in degrees Celsius. EXAMPLE 1 8- (6-Chloro-1,2,3,4-tetrahydro-naphthyl-2) -1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one hydrochloride 6-chloro was dissolved -2-tetralone 22.7 mmol) in toluene (210 ml). 1-Phenyl-1,3,8-triaspiro [4.5. ] decan-4-one (22.7 mmol) and molecular sieves (10 g) and the mixture was refluxed for 6 hours. After cooling, the molecular sieves were separated by filtration and washed with methylene chloride. Evaporation of the filtrate gave a residue which was dissolved in THF (90 ml) and methanol (10 ml). Sodium cyanoborohydride (22.7 mmol) was added to the solution and the pH was adjusted to 4. The mixture was stirred for 4 hours at room temperature. Ethyl acetate was added and the organic phase was washed with 2N sodium hydroxide and brine. The organic phase was concentrated and chromatographed on silica gel (ethyl acetate). Addition of HCl in ethanol to a solution of the product in ethyl acetate / ethanol gave 8- (6-chloro-1,2,3,4-tetrahydro-naphthyl-2) -1-phenyl-1,3,8 hydrochloride. -triaza-spiro [4.5] decan-4-one (4.0 g, 41%) as a colorless solid, melting point 288-290 ° C. E «JEMPLO 2_ Hydrochloride of 8- (8-chloro-l, 2,3, 4-tetrahydro-naphthyl-2) -1-phenyl-1,3, 8-triazasp'iro [4,5] decan-4- The title compound, melting point 286-290 ° C, was prepared in accordance with the general method of example 1 from 8-chloro-2-tetralone and 1-phenyl-1,3,8-triazas-pyro. [4.5] decan-4-one. E «JEMPLO 3_ Hydrochloride of 8- (5, 8-dichloro-l, 2, 3, 4-tetrahydro-naphthyl-2) -1- phenyl-1,3,8-triazaspiro [4, 5] decan-4- The title compound, melting point s, was prepared. 290-293 ° C, in accordance with the general method of Example 1, starting from 5,8-dichloro-2-tetralone and 1-phenyl-1,3,8-triazas-piro [4.5] decan-4-one .

EXAMPLE 4 8- (6-Chloro-1,2,3,4-tetrahydro-naphthyl-2) -3-methyl-1-phenyl-1,3,8-triazaspiro [4, 5] decan-4- hydrochloride One suspension of 8- (6-chloro-1,2,3,4-tetrahydro-naphthyl-2) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one hydrochloride. 0.47 mmol) and sodium hydride (60 mg, 60%) in DMF was stirred for 30 minutes at 80 ° C. Methyl iodide (40 ml, 0.47 mmol) was added and stirring was continued for another 30 minutes. The mixture was cooled, ethyl acetate (100 ml) was added and washed with sodium bicarbonate solution and brine (50 ml each time). The aqueous phases were extracted with ethyl acetate, the organic phases were pooled, dried with sodium sulfate and evaporated. Addition of HCl in ethanol to a solution of the residue in ethyl acetate gave 8- (6-chloro-l, 2, 3, 4-tetrahydro-naphthyl-2) -3-methyl-1-phenyl-1 hydrochloride, 3, 8-triaza-spiro [4.5] -decan-4-one (0.17 g, 82%) as a colorless solid, melting point > 250 ° C MS: m / e = 410.2 (M + H) +). EXAMPLE 5 8- (8-Chloro-1,2,3,4-tetrahydro-naphthyl-2) -3-methyl-1-phenyl-1,3,8-triazaspiro [4, 5] decan-4- hydrochloride ona The title compound was prepared, melting point > 250 ° C and MS: m / e = 410.4 (M + H +) according to the general method of example 4 from 8- (8-chloro-1,2,3,4-tetrahydro-2-naphthyl) -l-phenyl-l, 3, 8-triaza-spiro [4.5] decan-4-one and metilyo-duro E. EXAMPLE 6 Hydrochloride of 8- (5,8-dichloro-l, 2, 3, 4- tetrahydro-naphthyl-2) -3-methyl-1-phenyl-1,3,8-triazaspiro [4,5] decan-4-one The title compound was prepared, melting point> 250 ° C and MS: m / e = 444.7, 446.6 (M + H +) according to the general method of Example 4 from 8- (5, 8-dichloro-1,2,3,4-tetrahydro-2-naphthyl) -l-phenyl-1, 3, 8-triaza-spiro [4.5] decan-4-one and methyloduro E «JEMPLO 1_ 3-allyl-8- (5,8-dichloro-l, 2, 3 hydrochloride, 4-tetrahydro-naphthyl-2) -1-phenyl-1,3,8-triazaspiro [4, 5] decan-4-one The title compound was prepared, melting point> 250 ° C and MS: m / e = 470.4, 472.4 (M + H +) according to the general method of Example 4 from 8- (5,8-dichloro-1,2,3,4-tetrahydro-2-naphthyl) 1-phenyl-l, 3, 8-triaza-spiro [4.5] deca n-4-one and allylbromide. EIJTEMPLQ _8 3-Benzyl-8- (5,8-dichloro-l, 2,3, 4-tetrahydro-naphthyl-2) -1-phenyl-1,3,8-triazaspiro hydrochloride [4,5] decan-4-one The title compound was prepared, melting point > 250 ° C and MS: m / e = 520.3, 522.3 (M + H +) according to the general method of Example 4 from 8- (5, 8-dichloro-l, 2, 3, 4 - tetrahydro-2-naphthyl-l-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one and benzylbromide E «JEMPLQ 9 8- (5,8-dichloro-l, 2-hydrochloride 3,4-tetrahydro-naphthyl-2) -3-ethyl-1-phenyl-1,3,8-triazaspiro [4, 5] decan-4-one - The title compound was prepared, melting point > 250 ° C and MS: m / e = 458.3, 460.3 (M + H +) according to the general method of example 4 from 8- (5, 8-dichloro-l, 2, 3, 4 -tetrahydro-2-naphthyl-l-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one and ethylbromide E-JTEMPLO 10. L-phenyl-8- hydrochloride (1, 2, 3 , 4-tetrahydro-naphthyl-2) -1, 3, 8-triazaspiro [4, 5] decan-4-one The title compound was prepared, melting point> 250 ° C and MS: m / e = 362 , 3, (M + H +) according to the general method of example 1 from 2-tetralone and l-phenyl-1,3, 8-triazaspiro [4.5] decan-4-one. l-phenyl-8- (1,2,3,4-tetrahydro-naphthyl-1) -1,3,8-triazaspiro [4, 5] decan-4-one 3,4-dihydro-2H-naphthyl was dissolved -l-oxime (2.98 mmol) in ether (6 ml) and a solution of sodium nitrite (5 mmol) was added in 2.5 ml of the solution.The solution was stirred for 1 hour under an inert atmosphere (Ar). Then H 2 SO 4 (5 ml) was added and the solution was stirred for 3 hours, the organic phase was separated and washed with water. times with 5 ml of NaHC 3 - The aqueous phase was washed with 5 ml of ether. Evaporation of the pooled organic phases gave a residue which was dissolved in acetonitrile (10 ml) and to this solution a suspension of 1-phenyl-1,3,8-triaza-spiro [4.5] -decan- was added at 0 ° C. 4-one (11.9 mmol) in acetonitrile (30 ml). The mixture and molecular sieves (10 g) were stirred for about 40 hours at room temperature under an inert atmosphere (Ar). The organic phase was concentrated and washed twice with acetonitrile (20 ml). After evaporation of the filtrate the residue was dissolved in THF (90 ml) and ethanol (10 ml).

Sodium cyanoborohydride (190 mg) was added to the solution and the pH was adjusted to 4 (HCl / EtOH). The mixture was stirred for 105 minutes at room temperature. Evaporation and purification (described in Example 1) gave l-phenyl-8- (1, 2, 3, 4-tetrahydro-l-naphthyl) -1,3,8-triazaspiro [4.5] decan-4-one hydrochloride, fusion > 250 ° C and MS: m / e = 361 (M +). EXAMPLE 12 8- (7-Chloro-1,2,3,4-tetrahydro-naphthyl-2) -1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one hydrochloride The compound of epigraph, melting point > 250 ° C and MS: m / e = 396.2, 398.2 (M + H +) according to the general method of Example 1 from 7-chloro-2-tetralone and 1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one. EIJEMPLQ 13 8- (5-Chloro-1,2,3,4-tetrahydro-naphthyl-2) -1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one hydrochloride The compound of epigraph, melting point > 250 ° C and MS: m / e = 396.2, 398.4 (M + H +) according to the general method of example 1 from 5-chloro-2-tetralone and 1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one. E «JEMPLO 14 Hydrochloride of 8- (5,7-dimethyl-l, 2,3,4-tetrahydro-naphthyl-2) -1- phenyl-1,3,8-triazaspiro [4.5] decan-4-one Se prepared the compound of the epigraph, melting point > 250 ° C and MS: m / e = 389 (M +) according to the general method of Example 1 starting from 5,7-dimethyl-2-tetralone and 1-phenyl-1,3,8-triaza-spiro [ 4.5] decan-4-one.

EXAMPLE 15 3-Acetyl-8- (5,8-dichloro-l, 2, 3, 4-tetrahydro-naphthyl-2) -1-phenyl-1,3,8-triazaspiro [4,5] decan-4- hydrochloride Ona The title compound, melting point > 250 ° C and MS: m / e = 472.3, 474.4 (M + H +) according to the general method of Example 4 from 8- (5, 8-dichloro-l, 2, 3, 4 -tetrahydro-2-naphthyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one and acetylchloride. EXAMPLE 16 [8- (5,8-Dichloro-l, 2, 3, 4-tetrahydro-naphthyl-2) -4-oxo-l-phenyl-1,3,8-triazaspiro acid methyl ester hydrochloride [4.5 ] dec-3-yl] acetic The title compound was prepared, melting point 185-187_ ° C in accordance with the general method of Example 4 from 8- (5,8-dichloro-1,2,3,4-tetrahydro-2-naphthyl) -1-phenyl-1, 3, 8 -triaza-spiro [4.5] decan-4-one and methyl bromoacetate.

E «JEMPLO 17 (-) -8- (5, 8-dichloro-l, 2, 3, 4-tetrahydro-naphthyl-2) -1-phenyl-1,3,8-triazaspiro [4,5] decan- 4-one - The title compound was prepared, melting point > 250 ° C and MS: me = 430.5, 432.5 (M + H +) and [alpha] 20D = -54.9 from 8- (5, 8-dichloro-l, 2, 3, 4- tetrahydro-2-naphthyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one by co-crystallization with (+) -2, 2 '- (1,1' -bubfthyl) - phosphoric. EXAMPLE "'18 (+) - 8- (5,8-dichloro-l, 2,3,4-tetrahydro-naphthyl-2) -1-phenyl-1,3,8-triazaspiro [4,5] decan- 4-one The title compound was prepared, melting point> 250 ° C and MS: m / e = 430.5, 432.5 (M + H +) and [alpha] 20D = -53.2 from 8- (5,8-dichloro-1,2,3,4-tetrahydro-2-naphthyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one by co-crystallization with acid ( -) -2, 2 '- (1, 1-binaphthyl) -phosphoric EXAMPLE 19 (RS) -3-Benzoyl-8- (5,8-dichloro-l, 2, 3, 4-tetrahydroxyhydrochloride) naphthalen-2-yl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one (1: 1) The title compound, melting point 220 ° C, was prepared, in accordance with the general method of Example 4, from 8- (5,8-dichloro-1,2,3,4-tetrahydro-2-hydrochloride. naphthyl) -1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one and benzoyl-chloride. EXAMPLE 20 Dimethyl ester hydrochloride of (RS) -2- [8- (5,8-dichloro-1,2,3,4-tetrahydro-naphthalen-2-yl) -4-oxo-l-phenyl-1 , 3, 8-triaza-spiro [4.5] dec-3-yl] -malonic (1: 1) The title compound was prepared, melting point 191-192 ° C dec., In accordance with the general method of the example 4, from 8- (5,8-dichloro-l, 2, 3, 4-tetrahydro-2-naphthyl) -1-phenyl-1,3,8-triazaspiro hydrochloride [4.5. ] decan-4-one and dimethyl bromomalonate. EXAMPLE 21 (RS) -8- (8-Chloro-1,2,3,4-tetrahydro-naphthalen-2-yl) -3- (2-oxo-2-phenyl-ethyl) -1-phenyl- hydrochloride 1, 3, 8-triaza-spiro [4.5] decan-4-one (1: 1) The title compound was prepared, melting point > 250 ° C and MS: m / e = 514.3 (M + H +), in accordance with the general method of Example 4, from 8- (8-chloro-1,2,3,4-tetrahydrohydrochloride -2-naph il) -1-phenyl-1,3,8-triazaspiro [4.5] de-can-4-one and phenacylbromide. ErJEMPLO 22 Hydrochloride of (RS) -8- (5,8-dimethyl-l, 2, 3, 4-tetrahydro-naphthalen-2-yl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one (1: 1) The title compound, melting point > 250 ° C and MS: m / e = 390.5 (M + H +), in accordance with the general method of example 1, from 3,4-dihydro-5,8-dimethyl-1 (2H) -naphthalenone and 1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one. EXAMPLE 23 Hydrochloride of (RS) -8- (8-chloro-l, 2, 3, 4-tetrahydro-naphthalen-2-yl) -3- (2-hydroxy-ethyl) -1-phenyl-1,3,8-triaza-spiro [4.5. ] decan-4-one (1: 1) The title compound was prepared, melting point 244 ° C, dec. and MS: m / e = 439 (M "1"), in accordance with the general method of Example 4, from 8- (8-chloro-1,2,3,4-tetrahydro-2-naphthyl hydrochloride ) -1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one and 2-chloroethoxytrimethylsilane (deprotection in situ). ErMEMPLO 24 (RS) -8- (8-chloro-l, 2, 3, 4-tetrahydro-naphthalen-2-yl) -3-methoxymethyl-l-phenyl-1,3,8-triaza-spiro hydrochloride 4.5. ] decan-4-one (1: 1) The title compound was prepared, melting point >; 227-229 ° C, dec. and MS: m / e = 440.6 (M + H +), in accordance with the general method of Example 4, from 8- (8-chloro-l, 2, 3, 4-tetrahydro-2-hydrochloride naphthyl) -1-phenyl-1,3,8-triaza-spiro [4.5] de-can-4-one and chloromethyl-methyl ether.

EXAMPLE 25 Mixture of l-phenyl-8- [(R) - and - [(S) -l, 2,3,4-tetrahydro-naphthalen-2-yl] -3- [(S) -4 hydrochloride, 4, 4-trifluoro-5-hydroxy-butyl] -!, 3, 8-triaza-spiro [4, 5] decan-4-one (1: 1) The title compound was prepared, melting point > 245 ° C, dec. and MS: m / e = 488.5 (M + H +), in accordance with the general method of Example 4, from 8- (1,2,3,4-tetrahydro-2-naphthyl) -1 hydrochloride phenyl-1,3,8-triaza-spiro [4.5] -decan-4-one and (S) -1- (4-methylbenzenesulfonate) -4,4, 4-trifluoro-1,3-butanediol. E. EXAMPLE 26 (RS) -8-Indan-l-yl-phenyl-1,3,8-triaza-spiro [4.5] -decan-4-one (1: 1) Hydrochloride The title compound was prepared, melting point > 250 ° C and MS: m / e = 348.4 (M + H +) according to the general method of example 11, starting from 2,3-dihydro-lH-inden-1-one oxime and 1-phenyl- l, 3, 8-triazaspiro [4.5] decan-4-one. EXAMPLE 27 Mixture of l-phenyl-8- [(R) - and - [(S) -l, 2,3,4-tetrahydro-naphthalen-2-yl] -3- [(R) - hydrochloride] 4,4, 4-trifluoro-3-hydroxybutyl] -1,3,8-triaza-spiro [4, 5] decan-4-one (1: 1) The title compound was prepared, melting point > 246 ° C, dec. and MS: m / e = 488.5 (M + H +), in accordance with the general method of Example 4, from 8- (1, 2, 3, 4-tetrahydro-2-naphthyl) -1 hydrochloride phenyl-1,3,8-triaza-spiro [4.5] -decan-4-one and (R) -1- (4-methylbenzenesulfonate) -4,4,4-trifluoro-1,3-butanediol.

EXAMPLE 28 (RS) - (2,3-Dihydro-benzofuran-3-yl) -1-phenyl-1,3,8-triaza-spiro [4.5] -decan-4-one (1: 1) Hydrochloride prepared the title compound, melting point > 235 ° C desc. and MS: m / e = 350.4 (M + H +) according to the general method of Example 1, starting from 3 (2H) -benzofuranone and 1-phenyl-1,3,8-triazaspiro [4.5] decan -4-one. E «JEMPLO 29 (RS) -8-bromo-l, 2, 3, 4-tetrahydro-naphthalen-2-yl) -1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one hydrochloride (1: 1) The title compound was prepared, melting point > 250 ° C desc. and MS: m / e = 440.4, 442.4 (M + H +) according to the general method of example 1, from 8-bromo-3,4-dihydro-2 (1H) -naphthalenone and 1 phenyl-l, 3, 8-triazaspiro [4.5] decan-4-one. EXAMPLE 30 Mixture of (1RS, 3RS) - and (1RS, 3RS) -l-phenyl-8- (3-phenyl-indan-1-yl) -1, 3, 8-triaza-spiro hydrochloride [4, 5] ] decan-4-one (1: 1) The title compound was prepared, melting point > 250 ° C and MS: m / e = 424.4 (M + H +) according to the general method of example 1, starting from 2,3-dihydro-3-phenyl-lH-inden-1-one and phenyl-l, 3, 8-triazaspiro [4.5] decan-4-one. EXAMPLE 31 Mixture of (1RS, 3RS) - and (1RS, 3RS) -8- (3-menyl-indan-1-yl) -1-phenyl-1,3,8-triaza-spiro hydrochloride [4, 5] ] decan-4-one (1: 1) The title compound was prepared, melting point > 244-246 ° C and MS: m / e = 361 (M + H +) according to the general method of example 1, starting from 2,3-dihydro-3-menyl-lH-inden-1-one and 1 phenyl-l, 3, 8-triazaspiro [4.5] decan-4-one. EXAMPLE 32_ - Hydrochloride of 8-indan-2-yl-l-phenyl-1,3,8-triaza-spiro [4.5] -decan-4-one (1: 1) The title compound was prepared, melting point > 250 ° C and MS: m / e = 348.4 (M + H +) according to the general method of Example 1, starting with 1,3-dihydro-2H-inden-2-one and 1-phenyl-1 , 3, 8-triazaspiro [4.5] decan-4-one. E. EXAMPLE 33 (RS) -l-phenyl-8- (3,3,6-trimethyl-indan-1-yl) -1,3,8-triaza-spiro [4.5] decan-4-one methansulfonate ( 1: 1) The title compound was prepared, melting point 250 ° C and MS: m / e = 390.2 (M + H +) according to the general method of Example 1, starting with 2, 3-dihydro 3, 3, 6-trimethyl-lH-inden-1-one and 1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one. EXAMPLE 34 (RS) -l-phenyl-8- (6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl) -1,3,8-triaza-spiro [4,5] decan- 4-one (1: 1) 6, 7, 8, 9-tetrahydro-5H-benzocyclohepten-5-one was dissolved (3.1 mmol) in THF (10 ml). 1-Phenyl-1,3,8-triazaspiro [4.5] decan-4-one (3.1 mmol) and tetraisopropyl-orthotitanate (3.1 mmol) were added and the mixture was stirred for 22 hours at room temperature. Evaporation gave a residue which was dissolved in ethanol (5 ml). Sodium cyanoborohydride (2) was added to the solution, 1 mmol) and the mixture was stirred for 2 d at room temperature. Water was added, the precipitate was separated by filtration through Celite® and washed with ethanol. The filtrate was dried with N 2 S 4 and concentrated. Chromatography on silica gel (ethyl acetate / hexane, 50:50) gave the desired product which crystallized as its HCl salt from methylene chloride / ethanol. 0.1 g (8%) of (RS) -l-phenyl-8- (6,7,8,9-tetrahydro-5H-benzocyl-clohepten-5-yl) -l, 3,8-triazaspiro hydrochloride [4.5] decan-4-one (1: 1) as a colorless solid, melting point >; 250 ° C and MS: m / e = 376.4 (M + H +). EXAMPLE 35 (RS) -8- (5-Chloro-1,2,3,4-tetrahydro-naphthalen-1-yl) -1-phenyl-1,3,8-triaza-spiro [4,5] decan- 4-one (1: 1) The title compound, melting point > 250 ° C and MS: m / e = 396.2 (M + H +), in conformance with the general method of example 11, from 5-chloro-3,4-dihydro-l (2H) -naphthalenone oxime and 1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one. EXAMPLE 36 (RS) -8- (7-Fluoro-1,2,3,4-tetrahydro-naphthalen-1-yl) -1-phenyl-1,3,8-triaza-spiro [4,5] decan- 4-one (1: 1) The title compound, melting point > 250 ° C and MS: m / e = 380.3 (M + H +), according to the general method of Example 11, from 7-fluoro-3,4-dihydro-l (2H) -naphthalenone oxime and 1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one. EXAMPLE 37 (RS) -8- (5-Chloro-indan-1-yl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one (1: 1) Hydrochloride Was prepared the compound of the epigraph, melting point > 250 ° C and MS: m / e = 382.2 (M + H +) according to the general method of Example 34, starting from 5-chloro-2,3-dihydro-lH-en-1-one and 1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one. EXAMPLE 38 (RS) -8- (7-Chloro-5-fluoro-l, 2, 3, 4-tetrahydro-naphthalen-1-yl) -1-phenyl-1,3,8-triaza-spiro hydrochloride. { 4.5] decan-4-one (1: 1) The title compound was prepared, melting point > 250 ° C and MS: m / e = 414.2 (M + H +) according to the general method of example 11, from 7-chloro-5-fluoro-3,4-dihydro-1 (2H) - Naphthalenone oxime and 1-phenyl-1,3,8-triaza-spiro- [4.5] decan-4-one. EXAMPLE 39 (RS) -8- (4-Methyl-indan-1-yl) -1-phenyl-1,3,8-triaza-spiro (4.5) decan-4-one (1: 1) Hydrochloride Was prepared the title compound, melting point> 250 ° C and MS: m / e = 362.2 (M + H +) according to the general method of example 34, starting from 2,3-dihydro-4-methyl -lH-inden-1-one and 1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one EXAMPLE 40 8-Indan-2-yl-3-methyl-1-phenyl-1-hydrochloride , 3, 8-triaza-spiro { 4.5] decan-4-one (1: 1) The title compound was prepared, melting point > 250 ° C and MS: m / e = 362.2 (M + H +) according to the general method of Example 4, starting from 8-indan-2-yl-l-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one (1: 1) and methyl iodide EXAMPLE 41 (RS) -8- (7-chloro-l, 2, 3, 4-tetrahydro-naphthalene-l-11) -1-pheny1-1, 3, 8-triaza hydrochloride -spiro [4.5] decan-4-one (1: 1) The title compound was prepared, melting point> 250 ° C and MS: m / e = 396.2 (M + H +) according to the method general example or 11, from 7-chloro-3,4-dihydro-l (2H) -naphthalenone oxime and 1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one. EXAMPLE 42 (RS) -3-Methyl-l-phenyl-8-l, 2,3, 4-tetrahydro-naphtha-len-l-yl) -1-phenyl-1,3,8-triaza-spiro hydrochloride . { 4.5] decan-4-one (1: 1) The title compound, melting point 232-234 ° C according to the general method of Example 4, was prepared from l-phenyl-8- hydrochloride (1: 1). , 2, 3, 4-tetrahydro-naphthyl-1) -1, 3, 8-triaza-spiro [4.5] decan-4-one (1: 1) and methyl iodide. EXAMPLE 43 (RS) -8-Indan-l-yl-3-methyl-l-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one hydrochloride (1: 1) The compound was prepared of the epigraph, melting point 200-203 ° C and MS: m / e = 362.2 (M + H +) according to the general method of Example 4, from (RS) -8-indan-1-yl-1-phenyl hydrochloride -l, 3, 8-triaza-spiro [4.5] decan-4-one (1: 1) and methyl iodide. EXAMPLE 44 (R) -8-Indan-l-yl-l-phenyl-1,3,8-triaza-spiro- [4.5] decan-4-one (1: 1) Hydrochloride Was stirred for 2 hours at 200 ° C, (R) -l-indan-1-yl-4-phenylamino-piperidine-4-carboxylic acid amide (2.9 mmol) suspended in formamide (15 ml). The mixture was cooled, poured into cold water (150 ml) and extracted with ethyl chloride. The organic phases were pooled, dried with sodium sulfate and concentrated, which gave a mixture of (R) -8-indan-1-yl-1-phenyl-1, 3, -criaza-spiro [4.5] decan- 4-one and (R) -8-indan-1-yl-1-phenyl-1, 3, 8-triaza-spiro [4.5] dec-2-en-4-one. This mixture was dissolved in methanol (60 ml) and sodium borohydride (4.2 mmol) was added. The mixture was stirred for 1 hour at 60 ° C, cooled and concentrated. Saturated ammonium chloride solution and methylene chloride were added to the residue. The aqueous phase was extracted with methylene chloride. The organic phases were combined, dried with sodium sulfate and concentrated. Chromatography on silica gel (methylene chloride / methanol, 98: 2) gave the desired product. This was crystallized as its HCl salt in ethyl acetate / ethanol. 0.27 g (24%) of (R) -8-indan-1-yl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one hydrochloride (1: 1), melting point > 250 ° C and MS: m / e = 348.4 (M + H +). E «EXAMPLE 45 (RS) -8- (6-Chloro-thiochroman-4-yl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one The title compound was prepared, melting point 164-166 ° C, dec. and MS: m / e = 414.2 (M + H +), in accordance with the general method of Example 11, from 6-chloro-2,3-dihydro-4H-1-benzothiopyran-4-one oxime and 1-phenyl-1,3,8-triaza-spiro- [4.5] decan-4-one. EXAMPLE 46 (RS) -8- (6-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl) -1-phenyl-1,3,8-triaza-spiro [4,5] decan- 4-one (1: 1) The title compound was prepared, melting point 235-236 ° C and MS: m / e = 392.2 (M + H +) according to the general method of example 11 from 3,4-dihydro-6-methoxy-l (2H) -naphthalenone oxime and 1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one.

EXAMPLE _47 (RS) -8- Hydrochloride (5-methoxy-1,2,3,4-tetrahydro-naphthalene-1-yl) -1-phen? Ll, 3,8-triaza-spiro [4.5] decan-4-one (1: 1) The title compound, melting point > 250 ° C and MS: m / e = 392.3 (M + H +) according to the general method of example 11 from 3,4-dihydro-5-methoxy-l (2H) -naphthalenone oxime and l- phenyl-1,3, 8-triaza-spiro [4.5] decan-4-one. EXAMPLE 48 (S) -8-Indan-l-yl-l-phenyl-1,3,8-triaza-spiro- [4.5] decan-4-one hydrochloride (1: 1) The title compound was prepared, melting point > 250 ° C, dec., And MS: m / e = 348.4 (M + H +) according to the general method of example 44, from (S) -1-indan-1-i1- acid amide 4-phenylamino-piperidine-4-carboxylic acid. EXAMPLE 49 Hydrochloride of (RS) -8- (6-chloro-1,2,3,4-tetrahydro-naphthalen-1-yl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan- 4-one (1: 1) The title compound was prepared, melting point > 250 ° C and MS: m / e = 396.2 (M + H +) according to the general method of example 11 from 6-chloro-3,4-dihydro-l (2H) -naphthalenone oxime and 1- phenyl-l, 3, 8-triaza-spiro [4.5] decan-4-one.

EXAMPLE 50 l-Phenyl-8- (6,7,8,8-tetrahydro-5H-benzocyclohepten-7-yl) -1,3,8-triaza-spiro [4.5] decan-4-one hydrochloride ( 1: 1) The title compound was prepared, melting point > 250 ° C and MS: m / e = 376.3 (M + H +) according to the general method of Example 1 starting from 5, 6, 8, 9-tetrahydro-7H-benzocyclohepten-7-one and 1- phenyl-l, 3, 8-triaza-spiro [4.5] decna-4-one. EXAMPLE 51 (RS) -8- (6-Fluoro-chroman-4-yl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one (1: 1) Hydrochloride Was prepared the compound of the epigraph, melting point > 250 ° C and MS: m / e = 382.2 (M + H +) according to the general method of example 11, starting from 6-fluoro-2,3-dihydro-4H-l-benzopyran-4-one oxime and 1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one. EXAMPLE 52 (RS) -8- (6-Chloro-chroman-4-yl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one (1: 1) Hydrochloride Was prepared the compound of the epigraph, melting point >; 250 ° C and MS: m / e = 398.2 (M + H +) according to the general method of example 11, starting from 6-chloro-2,3-dihydro-4H-l-benzopyran-4- ona oxime and 1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one. EXAMPLE 53 (R) -l-phenyl-8- (1, 2, 3, 4-tetrahydro-naphthalen-1-yl) -1,3,8-riaza-spiro [4.5] decan-4-one hydrochloride ( 1: 1) The title compound was prepared, melting point > 250 ° C and MS: m / e = 362.2 (M + H +) according to the general method of example 44, starting from (R) -4-phenylamino-1- (1,2,3) acid amide , 4-tetrahydro-naphthalen-1-yl) -piperidine-4-carboxylic acid.

EXAMPLE 54 (S) -l-phenyl-8- (1, 2, 3, 4-tetrahydro-naphthalen-1-yl) -1,3,8-triaza-spiro [4.5] decan-4-one hydrochloride ( 1: 1) The title compound, melting point > 250 ° C and MS: m / e = 362.2 (M + H +) according to the general method of Example 44, starting from (S) -4-phenylamino-1- (1,2,3) -amide , 4-tetrahydro-naphthalen-1-yl) -piperidine-4-carboxylic acid. E. EXAMPLE 55 (RS) -8- (4-Chloro-indan-1-yl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one (1: 1) hydrochloride The title compound, white solid, melting point > 230 ° C and MS: m / e = 382.2 (M + H +) according to the general method of example 34 from 4-chloro-indan-1-one and 1-phenyl-1,3,8- triaza-spiro [4.5] decna-4-one. E «JEMPLO 56 (RS) -8- (Chroman-4-yl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one (1: 1) Hydrochloride Was prepared the title compound, white solid, melting point 240 ° C (dec.) and MS: m / e = 363 (M +) according to the general method of example 11, from 4- cro anona oxime and 1- phenyl-1,3,8-triazaspiro [4.5] decan-4-one. EXAMPLE 57 Hydrochloride of (RS) -8- (5-methoxy-indan-1-yl) -1-phenyl-1,3,8-triaza-spiro [4.5] ecan-4-one (1: 1) prepared the title compound, white solid, melting point > 220 ° C and MS: m / e = 378.3 (M + H +) according to the general method of Example 34, from 5-methoxy-indan-1-one and 1-phenyl-1,3,8. -triazaspiro [4.5] decan-4-one. EXAMPLE 58_ (RS) -8- (4-Methoxy-indan-l-yl) -1-phenyl-1,3,8-tri-aza-spiro-1,4-decan-4-one hydrochloride (1: 1) ) The title compound, light yellow solid, melting point > 220 ° C and MS: m / e = 378.3 (M + H +) according to the general method of Example 34, from 4-methoxy-indan-1-one and 1-phenyl-1,3,8. -triazaspiro [4.5] decan-4-one. EXAMPLE 59 (RS) -8- (Acenaphthen-1-yl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one (1: 1) Hydrochloride The title compound was prepared , light yellow solid, melting point > 220 ° C and MS: m / e = 384.3 (M + H +) according to the general method of Example 34, starting from 2H-acenaphthylene-l-one and 1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one. EXAMPLE 60 (RS) -8- (5-methoxy-indan-1-yl) -1-phenyl-1,3,8-triazine-spiro [4.5] decan-4-one (1: 1) hydrochloride The title compound, light yellow solid, melting point > 220 ° C and MS: m / e = 378.3 (M + H +) according to the general method of Example 34, from 5-methoxy-indan-1-one and 1-phenyl-1,3,8. -triazaspiro [4.5] decan-4-one. EXAMPLE 61 (RS) -8- (5-Iso-propyl-indan-1-yl) -I-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one (1: 1) hydrochloride The title compound, white, faded solid, melting point > 220 ° C and MS: m / e = 390.2 (M + H +) according to the general method of example 34, starting with 5-iso-propyl-mdan-1-one and 1-phenyl-1,3. , 8-triaza-spiro [4.5] decan-4-one. EXAMPLE 62 8- (3-Phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl-1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one hydrochloride (1: 1) ) (mixture of racemates diast.) The title compound was prepared, white solid, melting point 203 ° C and MS: m / e = 438.3 (M + H +) according to the general method of example 11, a from 3-phenyl-3,4-dihydro-1 (2H) -naphthalenone oxime and 1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one EXAMPLE 63 Hydrochloride (RS) ) -8- (7-methoxy-1,2,3,4-tetrahydro-naphthalene-1-yl) -1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one (1: 1) The title compound was prepared, white solid, melting point> 220 ° C and MS: m / e = 392.2 (M + H +) according to the general method of example 11, starting from 7-methoxy- 3, 4-dihydro-1 (2H) -naphthalenone oxime and 1-phenyl-1,3,8-triaza-spiro- [4.5] decan-4-one EXAMPLE 64 (RS) -8- (acenaphthalene) hydrochloride 1-yl) -3-methyl-l-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one (1: 1) The title compound was prepared Faith, solid light brown, melting point >; 185 ° C (dec.) And MS: m / e = 398.3 (M + H +), according to the general method of Example 4, from (RS) -8- hydrochloride (acenaphthen-1 il) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one (1: 1) and methyl iodide. EXAMPLE 65 Clorhdirate of 8- (6,7-dihydro-5H-dibenzo [a, c] cyclohepten-6-yl) -1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one (1: 1) The title compound, white solid, melting point > 220 ° C and MS: m / e = 424.3 (M + H +) according to the general method of Example 1, starting from 5,7-dihydro-dibenzo [a, c] cyclohepten-6-one and 1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one. EXAMPLE 66 8- (1, 2, 2a, 3, 4, 5-hexahydro-acenaphthylene-1-yl) -1- phenyl-1,3,8-triaza-spiro [4.5] decan-4-one hydrochloride 1: 1) (mixture of racemates diast.) The title compound was prepared, light brown solid, melting point 293 ° C (dec.) And MS: m / e = 388.2 (M + H +), in accordance with the general method of Example 34, starting with 2a, 3, 4, 5-tetrahydro-2H-acenaphthylene-l-one and 1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one . EXAMPLE 67 (RS) -8- (2,3-Dihydro-lH-phenalen-1-yl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one hydrochloride (1: 1) The title compound was prepared, light brown solid, melting point 251 ° C and MS: m / e = 398.3 (M + H +), conforarity with the general methods of example aa and 44 from 4 phenylamino-l- (2, 3-dihydro-lH-phenalen-1-yl) -piperidin-4-carbonitrile without isolation of the intermediate amide.

EXAMPLE 68"(S) -8- (Acenaphthen-1-yl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one hydrochloride (1: 1) The compound of epigraph, light brown solid, melting point 253 ° C and MS: m / e = 384.3 (M + H +) according to the general methods of example aa and 44 from (S) -4-phenylamino-l - (acenaphthen-1-yl) -piperidine-4-carbo-nitrile without isolation of the intermediate amide EXAMPLE 69 Hydrochloride of (R) -8- (acenaphthen-1-yl) -1-phenyl-1,3,8 -triaza-spiro [4.5] decan-4-one (1: 1) The title compound was prepared, white solid, melting point 270 ° C and MS: m / e = 384.3 (M + H +) in accordance with the general methods of examples aa and 44, starting from (R) -4-phenylamino-1- (acenaphthen-1-yl) -piperidine-4-carbonitrile without isolation of the intermediate amide EXAMPLE 70 Hydrochloride of 8- (2, 3, 3a, 4, 5, 6-hexahydro-lH-phenalen-l-yl) -1- phenyl-1,3,8-triaza-spiro [4.5] decan-4-one (1: 1) The title compound was prepared, white solid, melting point n 246 ° C and MS: m / e = 402.4 (M + H +) according to the general method of example 11, starting from 2, 3, 3a, 4, 5, 6-hexahydro-phenalen-1 ona oxime and 1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one. EXAMPLE 71 8- (Fluoren-9-yl) 1-phenyl-1,3,8-triaza-spiro [4.5] -decan-4-one (1: 1) hydrochloride The title compound, white solid, was prepared. mp 285 ° C and MS: m / e = 396.1 (M + H +) according to the general methods of examples aa and 44, starting from 4-phenylamino-1- (flñuoren-9-il) -piperidine-4-carbonitrile without isolation of the intermediate amide. ETEMPLO 72 (RS) -8- (5-Methyl-1,2,3,4-tetrahydro-naphthalen-1-yl) -lfenyl-1,3,8-triazaspiro [4.5] decan-4-one hydrochloride ( 1: 1) The title compound, melting point > 250 ° C and MS: m / e = 376.3 (M + H +) according to the general method of example 11, starting with 5-methyl-3,4-dihydro-l (2H) -naphthalenone oxime and 1 phenyl-l, 3, 8-triazaspiro [4.5] decan-4-one. EXAMPLE 73 (RS) -8- (Acenaphthen-1-yl) -1- (3-chloro-phenyl) -1,3,8-triaza-spiro [4.5] decan-4-one (1: 1) hydrochloride The title compound was prepared, white solid, melting point 272 ° C and MS: m / e = 418.2 (M + H +) according to the general methods of examples aa and 44, from (RS) 1- (Acenaphthen-1-yl) -4- (3-chloro-phenylamino) -piperidine-4-carbonitrile without isolation of the intermediate amide. EXAMPLE 74 (RS) -8- (Acenaphthel-yl) -1- (ra-tolyl) -1,3,8-triaza-spiro [4.5] decan-4-one (1: 1) Hydrochloride The compound was prepared of the heading, white solid, melting point 268 ° C and MS: m / e = 398.3 (M + H +) according to the general methods of examples aa and 44, from 'RS) 1- (acenaphthalene) -l-il) -4- (m-tolylamino) -piperidin-4-carbonitrile without isolation of the intermediate amide.

EXAMPLE 75 (RS) -8- (Acenaphthen-1-yl) -1- (p-tolyl) -1,3,8-triaza-spiro [4.5] decan-4-one (1: 1) Hydrochloride Was prepared the title compound, white solid, melting point 266 ° C and MS: m / e = 398.3 (M + H +) according to the general methods of examples aa and 44, from (RS) 1- (acenaphthen-1-yl) -A- (p-tolylamino) -piperidine-4-carbonitrile without isolation of the intermediate amide. EXAMPLE 76 (RS) -8- (Acenaphthenl-yl) 1- (3-methoxy-phenyl) -1,3,8-triaza-spiro [4.5] decan-4-one (1: 1) hydrochloride The preparation was prepared compound of heading, white solid, melting point 274 ° C and MS: m / e = 414.2 (M + H +) according to the general methods of examples aa and 44, from (RS) 1- ( acenaphthen-1-yl) -A- (3-methoxy-phenylamino) -piperidine-4-carbonitrile without isolation of the intermediate amide. EXAMPLE 77 (RS) -8- (Acenaphthel-yl) 1- (4-methoxy-phenyl) -1,3,8-triaza-spiro [4.5] decan-4-one (1: 1) hydrochloride The compound of heading, white solid, melting point 262 ° C and MS: m / e = 414.2 (M + H +) according to the general methods of examples aa and 44, from (RS) 1- ( acenaphthen-1-yl) - (4-methoxy-phenylamino) -piperidine-4-carbonitrile without isolation of the intermediate amide. SYNTHESIS OF INTERMEDIATES E «3EMPLO aa (S) -l-indan-l-yl-4-phenylamino-piperidin-4-carboxylic acid amide was added dropwise, at room temperature, (S) -l-? r, dan-l-yl-4-phenylamino-piperidine-4-carbonitrile (27 mmol) to a mixture of acetic anhydride and formic acid (40 ml each). The mixture was stirred for 16 hours at room temperature. Sodium hydroxide solution (pH = 7) was added and the mixture was extracted with ethyl acetate. The organic phases were combined, dried with sodium sulfate and concentrated. Chromatography on silica gel (ethyl acetate) gave the formylated amine which was dissolved in t-butanol (60 ml). Ammonia (28%, 10 ml), water (10 ml) and hydrogen peroxide solution (33% in water, 5 ml) were added. The mixture was stirred for 2 1/2 hours at room temperature, cooled with cold water (50 ml) and extracted with methylene chloride. The organic phases were combined, dried with sodium sulfate and concentrated. Chromatography on silica gel (methylene chloride / methanol, 98: 2) gave the desired product as a solid. 1.0 g (11%) of (S) -l-indan-l-yl-4-phenylamino-piperidine-4-carboxylic acid amide, melting point 194-195 ° C and MS: m / e = 336 , 2 (M + H +). E-JEMPLO ab (S) -l-indan-l-yl-4-phenylamino-piperidin-4-carbonitrile (S) -l-indan-l-yl-piperidin-4-one (31 mmol) was dissolved in acid acetic acid (28 ml). Aniline (33 mmol) and tri-ethylsilylcyanide (31 mmol) were added and the mixture was stirred for 45 minutes at room temperature. The reaction mixture was poured into cold ammonia solution (water / 28% ammonia, 50 ml / 30 ml). The solution was adjusted to pH 10 and extracted with methylene chloride. The organic phases were combined, dried with sodium sulfate and concentrated. Crystallization from diethyl ether gave the desired product as a solid. 8.1 g (80%) of (S) -l-indan-l-yl-4-phenylamino-piperidin-4-carbonitrile, melting point 157-160 ° C and MS: m / e = 318.3 ( M + H +). EXAMPLE a (S) -l-indan-l-yl-piperidin-4-one [S] -1-aminoindan (37 mmol) was dissolved in ethanol (65 ml). Potassium carbonate (3.7 mmol) and 1-ethyl-1-methyl-4-oxo-piperidinium iodide (56 mmol) dissolved in water (30 ml) were added and the mixture was refluxed for 30 minutes. Water was added, ethanol was removed in vacuo and the residue was extracted with ethyl acetate. The organic phases were combined, dried with sodium sulfate and concentrated. Chromatography on silica gel (ethyl acetate) gave the desired product as an oil. 7.1 g (90%) of (S) -l-indan-l-yl-piperidin-4-one, MS: m / e = 216.4 (M + H +). E 'JEMPLO ad Amide of (R) -l-indan-l-yl-4-phenylamino-piperidine-4-carboxylic acid The title compound was prepared, melting point 193-195 ° C and MS: m / e = 336.2 (M + H +) according to the general method of Example aa from (R) -l-indan-l-yl-4-phenylamino-piperidine-4-carbonitrile. EXAMPLE af (R) -l-indan-l-yl-4-phenylamino-piperidin-4-carbonitrile The heading was prepared, melting point 158-159 ° C and MS: m / e = 318.3 (M + H +) according to the general method of example ab from (R) -l-indan-l-yl-piperidin-4-one, aniline and trimethylsilicyanide.

EXAMPLE ag (P) -l-indan-l-yl-piperidin-4-one The title compound was prepared, MS: m / e = 216.4 v'M + H "") in accordance with the general method of example ac from (R) -1-aminoindane and l-ethyl-l-methyl-4-oxo-piperidinium iodide. EXAMPLE H (R) -4-phenylamino-1- (1, 2, 3, 4-tetrahydro-naphthalen-1-yl-piperidine-4-carboxylic acid amide The title compound, melting point 182-184 ° C and MS: m / e = 350.3 (M + H +) according to the general method of example aa from (R) -4-phenylamino-1- (1, 2, 3, 4 - tetrahydro-naphthalen-1-yl) -piperidine-4-carbonitrile. EXAMPLE ai (R) -4-phenylamino-l- (1, 2, 3, 4-tetrahydro-naphthalen-l-yl) -piperidin-4-carbonitrile It was dissolved (R) -1, 2, 3, 4-tetrahdiro -l-naphthylamine (16 mmol) in ethanol (30 ml). Potassium carbonate (9.3 mmol) and l-ethyl-1-methyl-4-oxo-piperidinium iodide (23 mmol) dissolved in water (30 ml) were added and the mixture was refluxed for 1 hour. Water was added, ethanol was removed in vacuo and the residue was extracted with ethyl acetate. The organic phases were combined, dried with sodium sulfate and concentrated. Chromatography on silica gel (ethyl acetate) gave (R) -1- (1,2,3,4-tetrahydro-naphthalen-1-yl) -piperidin-4-one which was dissolved in acetic acid (11 ml ). Aniline (14 mmol) and trimethylsilylcyanide (13 mmol) were added and the mixture was stirred for 1.5 hours at room temperature. The reaction mixture was poured into cold ammonia solution (water / 28% ammonia, 70 ml / 30 ml). The solution was adjusted to pH 10 and extracted with methylene chloride. The organic phases were combined, dried with sodium sulfate and concentrated. Crystallization from diethyl ether gave the desired product as a solid. 8.1 g (80%) of (R) -4-phenylamino-1- (1,2,3,4-tetrahydro-naphthalen-1-yl) -piperidine-4-carbonitrile, melting point 152-153 ° C and MS: m / e = 332.3 (M + H +). EXAMPLE II (S) -4-Phenylamino-1- (1, 2, 3, 4-tetrahydro-naphthalen-1-yl) -piperidine-4-carboxylic acid amide. The title compound was prepared, melting point. 186-187 ° C and MS: m / e = 350.3 (M + H +) according to the general method of example aa from (S) -4-phenylamino-1- (1, 2, 3, 4 - tetrahydro-naphthalen-1-yl) -piperidine-4-carbonitrile. EXAMPLE ak (S) -4-phenylamino-1- (1,2,3,4-tetrahydro-naphthalen-1-yl) -piperidine-4-carbonitrile The title compound was prepared, melting point 152-153 ° C. and MS: m / e = 332.3 (M + H +) according to the general method of example ai from (S) - (1, 2, 3, 4-tetrahydro-1-naphthalamine.) EXAMPLE a (RS ) -2, 3-dihydro-lH-phenalen-1-yl-amine To a stirred mixture of 2,3-dihydrophenone-1-one hydrochloride (1.32 g, 7.24 mmol), hydroxylamine hydrochloride (0.85 g, 12.2 mmol) and water (6 mL) was added dropwise at 75 ° C MeOH (7.5 mL) and then a solution of sodium acetate (2.58 g, 19.0 mmol) in water (4 ml) - Stirring was continued for a period of 1 hour and a half, water (20 ml) was added and after cooling (ice bath) the solid was collected by filtration. The crude product was dissolved in Nrl ^ / MeOH 3.5 N (100 ml) and hydrogenated over Raney Nickel (0.5 g, washed with MeOH) at room temperature for 17 hours. and the catalyst was filtered off, the solution was evaporated in vacuo and the residue was purified by column chromatography on silica gel (dichloromethane / MeOH 9: 1), which gave (RS) -2, 3-dihydro -lH-phenalen-1-yl-amine (0.95 g) in the form of a brown oil. E. EXAMPLE am (RS) -1- (2, 3-dihydro-lH-phenalen-1-yl) -piperidin-4-one The title compound, brown oil, was prepared according to the general method of the ac example from iodide of (RS) -2, 3-dihydro-lH-phenalen-1-yl-amine and 1-ethyl-1-methyl-4-oxo-piperidinium iodide. EXAMPLE an (RS) -4-phenylamino-1- (2,3-dihydro-lH-phenalen-1-yl) -piperidine-4-carbonitrile The title compound was prepared, pale brown oil, in accordance with the general method of example ab, from (RS) -1- (2,3-dihydro-lH-phenalen-1-yl) -piperidin-4-one. EXAMPLE ao (R) -acenaften-1-yl-amine To a cooled (0 ° C) stirred solution of (S) -acenaphthenol (1.74 g, 102 mmol) and diphenyl-phosphorylazide in toluene (17.5 ml) ) DBU (1.86 ml, 12.3 mmol) was added and stirring was continued at room temperature for a period of 20 hours. The reaction mixture was extracted with toluene (2 x 50 ml), the combined organic phases were washed with water, dried (MgSO 4) and evaporated in vacuo. The crude product was dissolved in EtOH ("120 ml) and hydrogenated at room temperature over Pt 2 (0.24 g). The catalyst was filtered off, the solution was evaporated in vacuo and the residue was purified by flash chromatography. column over silica gel (dichloromethane / MeOH 9: 1), which gave (R) -acenaften-1-yl-amine (1.56 g) as a pink oil, MS: m / e = 169 ( M "). EXAMPLE a £ (S) -acenaften-1-yl-amine The title compound was prepared, pale yellow oil, MS: m / e = 169 (M +) in accordance with the general method of example a or from (R) -acenaftenol. EXAMPLE aq (R) -1- (acenaphthen-1-yl) -piperidin-4-one The title compound was prepared, red brown oil, MS: m / e = 252.2 (M + H +) in accordance with general method of example ac from (R) -acenaften-1-yl-amine and 1-ethyl-1-methyl-4-oxo-piperidinium iodide. EXAMPLE ar (S) -1- (acenaphthen-l-yl) -piperidin-4-one The title compound was prepared, red brown oil, MS: m / e = 252.2 (M + H +) in accordance with general method of example ac from (S) -acenaften-1-yl-amine and 1-ethyl-1-methyl-4-oxo-piperidinium iodide.

EXAMPLE as (R) -4-phenylamino-1- (acenaphthen-1-yl) -piperidine-4-carbonitrile The title compound was prepared, light yellow foam, MS: m / e = 354.3 (M + H +) according to the general method of example ab from (R) -1- (acenaphthen-1-yl) -piperidin-4-one. EXAMPLE at (S) -4-phenylamino-1- (acenaphthen-1-yl) -piperidine-4-carbonitrile The title compound was prepared, pale yellow oil, MS: m / e = 354.3 (M + H) + of compliance with the general method of example ab, from (S) -1- (acenaphthen-1-yl) -piperidin-4-one. EXAMPLE au 1- (fluoren-9-yl) -piperidin-4-one The title compound was prepared, reddish brown solid, melting point 135 ° C, MS: m / e = 263 (M +) according to the method of ac example from fluoren-9-yl-amine and l-ethyl-l-methyl-4-oxo-piperidinium iodide. EXAMPLE av 4-phenylamino-1- (fluoren-9-yl) -piperidine-4-carbonitrile The title compound was prepared, white solid, melting point 165 ° C, MS: m / e = 366.1 (M + H +) according to the general method of example ab from 1- (fluoren-9-yl) -piperidin-4-one. EXAMPLE aw (RS) -1- (acenaphthen-l-yl) -4- (3-chloro-phenylamino) -piperidin-4-carbonylpyl The title compound was prepared, pale brown foam, MS: m / e = 388 , 1 (M + H +) according to the general method of example ab from 3-chloroaniline and (RS) -1- (acenaphthen-1-yl) -piperidin-4-one. EXAMPLE ax (RS) -1- (acenaphthen-1-yl) -A- (m-tolylaminopiperidin-4-carbonyltrile) The title compound was prepared, pale brown foam, MS: m / e = 368.2 (M + H +) in accordance with the general method of the example ab from m-toluidine and (RS) -l- (acenaphthen-l-yl) -piperidin-4-one EXAMPLE a (RS) -1- (acenaphthen-1) -yl) -4- (3-methoxy-phenylamino) -piperidine-4-carbonitrile The title compound was prepared, pale brown foam, MS: m / e = 384.2 (M + H +) according to the method Example of ab from 3-methoxy-aniline and (RS) -1- (acenaphthen-1-yl) -piperidin-4-one E «JEMPL0 az (RS) -1- (acenaphthen-l-il) -A- (4-methoxy-phenylamino) -piperidin-4- -carbonitrile The title compound was prepared, pale brown foam, MS: m / e = 384.2 (M + H +) according to the general method of the example ab from 3-methoxy-aniline and (RS) -l- (acenaphthen-1-yl) -piperidin-4-one EXAMPLE ba (RS) -1- (acenaphthen-1-yl) -A- (p -tolylamino) -piperidin-4- -carbonitrile It is prep the title compound was added, pale brown foam, MS: m / e = 368.2 (M + H +) according to the general method of example ab from p-toluidine and (RS) -l- (cenaften-1). -yl) -piperidin-4-one. EXAMPLE A In the usual manner, tablets of the following composition are prepared: pig / tablet Active substance 5 Lactose 45 Corn starch 15 Microcrystalline cellulose 34 Magnesium stearate 1 Tablet weight 100- EXAMPLE B - Capsules of the following composition are prepared: mg / capsule Active substance 10 Lactose 155 Corn starch 30 Talc 5 Weight of filled capsule 200 The active substance, lactose and corn starch are first mixed in a mixer. The mixture is returned to the mixer, the talc is added and mixed thoroughly. The mixture is machine-packed in hard gelatin capsules.

E «JEMPLO C Suppositories of the following composition are prepared: mg / suppositories. Active substance 15 Suppository mass 1285 Total 1300 The suppository mass is melted in a glass or steel container, mixed thoroughly and cooled to 45 ° C. The finely powdered active substance is then added and stirred until it has completely dispersed. The mixture is poured into suppository molds of appropriate size, allowed to cool, suppositories are removed from the molds and individually packaged in wax paper or metal foil.

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. Having described the invention as above, property is claimed as contained in the following:

Claims (1)

1. CLAIMS 1. - Compue s of the general formula characterized because R1 and R2 are, independently of each other, hydrogen, lower alkyl, lower alkoxy or halogen; R3 is phenyl, optionally substituted by lower alkyl, CF3, lower alkoxy or halogen; and R 4 is hydrogen, lower alkyl, lower alkenyl, -C (O) -lower alkyl, -C (O) -phenyl, lower alkyl-C (O) -phenyl, lower alkylene-C (O) O-alkyl lower, lower-di-C-alktriol (O) -O-lower alkyl, hydroxy-lower alkyl, lower-alkyl- -O-lower-alkyl, lower-alkyl-CH (OH) CF3, phenyl or benzyl, R5 and R5 are, independently yes, hydrogen, phenyl, lower alkyl or lower di-lower alkyl or can together form a phenyl ring, and R5 and one of RI or R2 can together form a saturated or unsaturated 6-membered ring, A is a saturated ring of 4 - 7 members which may contain a heteroatom such as O or S, and their pharmaceutically acceptable acid addition salts. 2 • ~ A compound, in accordance with claim 1, characterized by: mmp R1 and R2 are halogen. . - A compound according to claim 2, characterized by the fact that R - * - and R2 are chlorine. 4. A compound according to claim 3 (-) -8- (5,8-dichloro-1,2,3,4-tetrahydro-naphyl-2) -1- phenyl-1,3,8- triaza-spiro [4.5] decan-4-one. 5. A compound according to claim 1, characterized in that one of RI and R2 is hydrogen and the other is halogen. 6. - a compound, according to claim 5, characterized in that R-- or R2 is chlorine. 7. A compound according to claim 6 8- (8-chloro-l, 2, 3, 4-tetrahydro-naphtyl-2) -1-phenyl-1,3,8-triaza-spiro [4.5 ] decan- 4 -ona. 8. A compound, according to claim 1, are hydrogen- 9. A compound according to claim 8, l-phenyl-8- (1,2,3,4-tetrahydro-napht-1). -1, 3, 8-triaza-spiro [4.5] decan-4-one and 8-indan-l-yl-l-phenyl-l, 3", 8 -triaza-spiro [4.5] decan-4 -one. 10. A compound, according to claim 1, character ±> park R ^ and one of RÍ or R ^ together form a saturated 6-membered ring 11.- A compound, according to claim 10 , chosen from the following group (RS) -3- (acenaphthen-1-? l) -1-phenyl-l, 3, 8-triaza-spiro [4.5] decan-4-one (RS) -8- (acenaften -1-yl) -3-methyl-l-phenyl-l, 3, 8-triaza-spiro- [4.5] -decan-4-one (RS) -8- (2,3-dihydro-lH-phenalen- 1-yl) -2-phenyl-1,3,8-triaza-is-pyro [4.5] decan-4-one (R) -8- (acenaphthen-1-yl) -1-phenyl-1,3, 8-triaza-spiro [4.5] decan-4-one 8- (2, 3, 3a, 4, 5, 6-hexahydro-lH-phenalen-1-yl) -1-phenyl-1,3,8- -triaza-spiro [4.5] decan-4-one and (RS) -8- (5-methyl-l, 2, 3,4-tetrahydro-naphthalen-1-yl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one. 12 - The reagent, characterized for the UP or P or P or R CET of any of claims 1 to 11 or a respective pharmaceutically acceptable salt for the treatment of diseases. 13. A medication, according to claim 12, for the treatment of diseases related to the orphanin FQ receptor (OFQ), which includes psychiatric, neurobiological and physiological disorders, such as anxiety and stress disorders, depression, trauma, memory loss due to Alzheimer's disease or other dementias, epilepsy and seizures, acute and / or chronic pain states, and withdrawal symptoms of addiction drugs, water balance control, Na + excretion, arterial blood pressure disorders and disorders nutritional factors such as obesity. 14. - A process for the preparation of a compound of formula I as defined in claim 1, characterized in that it comprises a) hydrogenating the double bond in a compound of formula wherein R ^ -R ^ have the above meaning and A 'is a 5-7 membered unsaturated partial ring which may contain a heteroatom such as 0 or S to a compound of formula I, or b) alkylate, benzylate or acylate a compound of formula I, wherein R 4 is hydrogen, to a compound of formula I, wherein R 4 lower alkyl, lower alkenyl, -C (0) -low alkyl, -C (0) -phenyl, lower alkyl-C (0) -phenyl, lower alkyl-Cι) O-lower alkyl, lower alkathiyl-di-C (0) -loweralkyl, hydroxy-lower alkyl, lower alkyl- O-lower alkyl, lower alkyl-CH (OH) CF3, phenyl or benzyl, or c) reductively a compound of the formula with a compound of the formula TV to a compound of the formula wherein A and R1-R ^ have the meaning indicated in claim 1, or d) convert a racemic mixture into its enantiomeric components for the preparation of optically pure compounds, and e) if desired, convert the compound of formula I obtained in a pharmaceutically acceptable acid addition salt. 15. A compound, according to any of claims 1-11, provided that they are prepared with a process according to claim 13, or by an equivalent method. 16. The use of a compound according to any of claims 1-11 for the treatment of diseases based on therapeutic indications for the orphanin FQ receptor (OFQ), which includes psychiatric, neurobiological and physiological disorders, such as anxiety and stress disorders, depression, trauma, memory loss due to Alzheimer's disease or other dementias, epilepsy and seizures, acute and / or chronic pain states, and withdrawal symptoms of addiction drugs, water balance control, excretion of Na +, blood pressure disorders and nutritional disorders such as obesity. SUMMARY OF THE INVENTION The present invention relates to compounds of the formula wherein R ^ and R2 are, independently from each other, hydrogen, lower alkyl, lower alkoxy or halogen; R3 is phenyl, optionally substituted by lower alkyl, CF3, lower alkoxy or halogen; and R 4 is hydrogen, lower alkyl, lower alkenyl, -C (O) -lower alkyl, -C (0) -phenyl, lower alkyl-C (O) -phenyl, lower alkylene-C (0) O-alkyl lower, lower-di-C-alktriyl (0) O-lower alkyl, hydroxy-lower alkyl, "lower-alkyl-" -O-lower alkyl, lower-alkyl-CH (OH) CF3, phenyl or benzyl, R5 and Rd are, independently of one another, hydrogen, phenyl, lower alkyl or lower di-lower alkyl or can together form a phenyl ring, and R ~ and one of R ^ or R2 can together form a saturated or unsaturated 6-membered ring, A is a ring saturated 4-7 member which may contain a heteroatom such as 0 or S, and pharmaceutically acceptable acid addition salts thereof which are agonists and / or antagonists of the OFQ receptor.