MXPA99009765A - 1,3,8-triazaspiro[4.5]decanone compound as orl1-receptor agonist - Google Patents

Abstract

A compound of the formula:R<1>and R<2>are independently C1-C4 alkyl;or R<1>and R<2>, taken together with the carbon atom to which they are attached, form a mono-, bi-, tri- or spiro-cyclic group having 3 to 13 carbon atoms, wherein the cyclic group is optionally substituted by one to five substituents;A is (C1-C3)alkyl, phenyl, benzyl or the like;R is hydrogen, (C1-C3)alkyl, amino-(C1-C6)alkyl, heterocyclic-(C1-C3)alkyl wherein the heterocyclic is optionally substituted by amino, ((C1-C4)alkyl)-Z-(C1-C6)alkyl wherein Z is OC(=O) or the like;and X is (C1-C3)alkyl, phenyl or the like. These compounds are useful as ORL1-receptor agonists, and useful as analgesics or the like in mammalian subjects.

Description

COMPOUNDS OF 1, 3,8-TRIAZAESPIRO r4.51DECANONA AS AGRONISTS OF RECEIVER ORL1 TECHNICAL FIELD This invention relates to 1,3,8-triazaspiro [4,5.] Decanone compounds or their pharmaceutically acceptable salts, pharmaceutical compositions containing them, and their medical uses. The compounds of this invention have activity as ORL1 receptor agonists, and are useful as an analgesic, anti-inflammatory, diuretic, anesthetic, neuro-protective, anti-hypertensive or anti-anxiety agent, or as an appetite control or cholesterol regulation agent. ear.

ANTECEDENTS OF THE TECHNIQUE Despite their usefulness as analgesics, the use of opioids such as morphine and heroin is strictly limited. This is because such drugs induce side effects such as euphoria or respiratory failure. Additionally, multiple dosing of drugs causes addiction. Therefore, the need to provide less toxic analgesics has been felt for a long time. Considerable pharmacological and biochemical studies have been carried out to identify opioid receptors and their endogenous ligands, and peptide and non-peptide opioid ligands have been discovered. In recent years, amino acid sequences of mu (μ), delta (d) and kappa (K) opioid receptor subtypes have been identified and published.

Subsequently, a new receptor subtype was identified, which was designated ORL1 receptor, and Meunier, JC and others published the isolation and structure of the endogenous receptor agonist (Nature, Vol. 377, pp 532-535, 12 October 1995). It is suggested that the ORL1 receptor agonist is effective in neurogenic inflammation (Tips, Vol. 18, pp. 293-300, August 1997). It is also suggested that the agonist is a potent analgesic that produces fewer psychological side effects and less addiction (D. Julius, Nature, Vol. 377, p.476, October 12, 1995). European Patent Publication No. EP 856514 A1 discloses a series of 1,3-triazaspiro [4,5] -decan-4-one compounds substituted in position 8 as agonists and / or antagonists of the orphanin EQ receptor ( OFQ).

BRIEF DESCRPTION OF THE INVENTION The present invention provides a compound of the following formula: or its pharmaceutically acceptable salt, wherein R1 and R2 are independently C4 alkyl; or R1 and R2, taken together with the carbon atom to which they are attached, form a mono-, bi-, tri- or spiro-cyclic group having 3 to 13 carbon atoms, in which the cyclic group is substituted optionally with one to five substituents independently selected from halo, CrC alkyl, C2-C4 alkenyl, CrC4 alkoxy, hydroxy, oxo, = CH2, and = CH-C-? -C4 alkyl, with the proviso that the group bi- or tri -cyclic is not a benzocondensed ring; A is CrC7 alkyl, C2-C5 alkenyl, C2-Cs alkynyl, phenyl-C1-C5 alkyl, phenyl or heteroaryl selected from furyl, thienyl, pyrrolyl and pyridyl, in which phenyl and heteroaryl are optionally substituted with one to three substituents selected from halo, C1-C3 alkyl and C1-C3 alkoxy; R is hydrogen, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C1-C6 alkanoyl, (C4 alkyl) -Z-CrC6 alkyl, (C3-C cycloalkyl) -Z-Cyan alkyl Cß, Ci-Cß heterocycle, C-pC β phenyl, heterocycle- (CrCdJ alkyl-Z-Ci-Cß alkyl, phenyl- (CrC 6 alkyl) -Z-C-pCß alkyl, C-heterocycle-Z-alkyl? -C6, (C3-C cycloalkyl) -heterocycle-CrC6 alkyl, heterocycle-heterocycle-Z-alkyl CI-CT, in which the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclic groups are optionally substituted with one to three substituents selected from halo, hydroxy, amino, guanizino, carboxy, amidino, ureido, C1-C3 alkyl, C1-C3 alkoxy, and mono- or di-alkylamino CC, and in which Z is O, S, SO, S02, CO, C (= O) 0, OC (= 0), N (R), C (= 0) N (R) or N (R) CO (with R in Z preferably being hydrogen or C 4 alkyl); and X is phenyl, heterocycle, C-pCß alkyl, C2-C6 alkenyl, cycloalkyl, C3-C7, C2-C alkynyl, in which the phenyl, heterocyclic, alkyl, alkenyl, cycloalkyl and alkynyl groups are optionally substituted with one or three substituents selected from halo, alkyl C1-C3 and C1-C3 alkoxy. The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals, having straight, branched or cyclic moieties or combinations thereof. The term "alkoxy," as used herein, includes O-alkyl groups in which "alkyl" is as defined above. The term "halo", as used herein, refers to F, Cl, Br or I, preferably F or Cl. The term "cycloalkyl", as used herein, means a saturated carbocyclic radical with inclusion, but without limitation, of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and the like. The term "heterocyclic" means a saturated, partially saturated or fully unsaturated monocyclic or bicyclic hydrocarbon ring system having one or more heteroatoms in the ring, preferably having 4 to 10 carbon atoms and 1 to 3 heteroatoms A preferred heterocyclic group includes, but without limiting character, piperidino, piperidinyl, hexamethyleneimino, morpholino, thiamorpholino, pyrrolidino, pyrazolidino, pyrazolidin, pyrazolyl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, isoquinolyl, quinolyl , thiophenyl, pyrazinyl, pyridazinyl, aziridinyl and azetidinyl The term "mono-, bi- or tri-cyclic ring" means cyclic hydrocarbon groups of 3 to 13 carbon atoms, containing one to three rings, and optionally having one bond double, including, but not limited to, cycloalkyl, cycloalkenyl, decahydronaft aleno, bicyclo- [2.2.1] heptane, bicyclo [3.2.1] octane, bicyclo [3.3.1] nonane, adamantane and tricyclo [5.2.1.O2 f3] decane. The term "spirocyclic group" means a spirocyclic hydrocarbon group of 6 to 13 carbon atoms, including, but not limited to, spiro [5.5] undecanyl and spiro [4.5] decanyl. The term "treat", as used herein, refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which that term applies, or one or more symptoms of said disorder or condition. The term "treatment", as used herein, refers to treating, as "treating" is defined in the immediately preceding phrase. A preferred group of the compounds of the present invention includes the compounds of formula (I), wherein R 1 and R 2 are independently C C alkyl; or R1 and R2, taken together with the carbon atom to which they are attached, form a monocyclic group selected from C3-C13 cycloalkyl and C3-C3 cycloalkenyl) in which the monocyclic group is optionally substituted with one or two selected substituents independently of halo and CrC 4 alkyl; A is phenyl-C 1 -C 5 alkyl or phenyl optionally substituted with one or three substituents independently selected from halo, alkyl C1-C3 and C1-C3 alkoxy. R is hydrogen, C 1 -C 2 alkyl, C 2 -C 6 alkenyl, heterocycle alkyl C C6 or (C 1 -C 4 alkyl) -Z-CrC 6 alkyl, in which the alkyl, alkenyl, and heterocyclic groups are optionally substituted with one to three substituents selected from halo, hydroxy, amino, guanizine, carboxy, amidino, ureido, C1-C3 alkyl, C1-C3 alkoxy, mono- and dialkylamino C4; and X is phenyl, heterocycle, C?-C6 alkyl or C2-C6 alkenyl, in which the phenyl, heterocycle, alkyl and alkenyl groups are optionally substituted with one to three substituents selected from halo, alkyl Cr C3 and alkoxy C Cs.

A more preferred group of this invention includes the compounds of formula (I), in which R1 and R2, taken together with the carbon atom to which they are attached, form a monocyclic group selected from C5-C10 cycloalkyl and C5-C10 cycloalkenyl group , in which the monocyclic group is optionally substituted with one or two substituents independently selected from C1-C3 alkyl; A is phenyl or benzyl; R is hydrogen, C 1 -C 3 alkyl, C 1 -C 6 amino-alkyl, C 1 -C 3 heterocycle-alkyl in which the heterocyclic group is optionally substituted with amino or (CrC 4 alkyl) -Z-CrC 6 alkyl in which Z is OC (= O); and X is C1-C3 alkyl or phenyl. A still more preferred group of this invention includes the compounds of formula (I), in which R1 and R2, taken together with the carbon atom to which they are attached, form cyclohexyl, cycloheptyl, or cycloheptenyl; A is phenyl or benzyl (more preferably phenyl); R is hydrogen, amino-propyl, aminohexyl, piperidinylethyl, 4-aminopiperidinyl-ethyl or methoxy-carbonylmethyl; and X is phenyl. Particularly preferred individual compounds are: 3- (3-aminopropyl) -1-phenyl-8- (1-phenylcycloheptyl) -1,3,8-tri-azaspiro [4.5] decan-4-one; 8- (1-methylcycloheptyl) -1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one; and their pharmaceutically acceptable salts. This invention also relates to a pharmaceutical composition for the treatment of a disorder or condition mediated by the ORL1 receptor and its endogenous ligands in a mammal including a human, or for the anesthesia of a mammal including a human, comprising an effective amount of the compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. More specifically, this invention relates to a pharmaceutical composition for the treatment of a disorder or condition selected from the group consisting of inflammatory diseases, hyperalgesia related to inflammation, disorders of food intake, disorders of arterial blood pressure. , tolerance to narcotic analgesics, dependence on narcotic analgesics, anxiety, stress disorders, psychic trauma, schizophrenia, Parkinson's disease, chorea, depression, Alzheimer's disease, dementias, epilepsy and seizures, useful as an analgesic, anesthetic, neuroprotective agent or enhancer of analgesics, or useful for controlling water balance, regulating the ear, controlling excretion of sodium ion or improving brain function, comprising an amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, that is effective to treat such disorder or condition in u n mammal with inclusion of a human being, and a pharmaceutically acceptable vehicle. This invention relates to a method for treating a disorder or condition, or anesthetizing a mammal including a human, whose treatment and anesthesia can be effected or facilitated by activation of the ORL1 receptor in a mammal including a human being, comprising administering a mammal in need of such treatment an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. More specifically, this invention relates to a method for treating a disorder or condition in a mammal including a human being, in which the disorder or condition is selected from the group consisting of inflammatory diseases, hyperalgesia related to inflammation, disorders of food intake, arterial blood pressure disorders, tolerance to narcotic analgesics, dependence on narcotic analgesics, anxiety, stress disorders, psychic trauma, schizophrenia, Parkinson's disease, chorea, depression, Alzheimer's disease, dementias , epilepsy, and convulsions, or to anesthetize a mammal including a human being, or to relieve pain, produce a neuroprotective effect, intensify analgesics, control water balance, regulate the ear, control the excretion of sodium ion or improve brain function in a mammal including a human being, comprising admi administering to said mammal an effective amount and a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

DETAILED EXHIBITION OF THE INVENTION The following reaction schemes illustrate the preparation of the compounds of the present invention. Unless otherwise indicated, R1, R2, A, R and X in the reaction schemes and in the following discussion have been defined above. In the preparation methods described hereinafter, amino or carbonyl groups may be protected according to known procedures such as described in Protective Group in Organic Synthesis by T.W. Green and others. (John Wiley &Sons, 1991). Typical amino protecting groups include benzyl, ethoxycarbonyl, and t-butoxycarbonyl (abbreviated as t-Boc or Boc). The carbonyl groups can typically be protected as acetals, thioacetals, hydrazones, oximes and cyanohydrins, which can be easily removed by treatment in the presence of an acid or Lewis acid.

General synthesis The ORL1 agonists of the formula (I) of this invention can be prepared according to the following methods. Reaction scheme 1 illustrates a method for the preparation of compound (I).

SCHEME 1 As shown in scheme 1, the compounds (I) can be obtained from a 1,3,8-triazaspiro [4.5] decanone (II) via the intermediate (IV). First, the compound (II) can be subjected to Strecker synthesis with the stoichiometric amount of the ketone (III). Secondly, the compound (IV) can be subjected to a Grignard reaction with a reagent represented by the formula AMgX '(X' is for example halo) to give the compounds (I). Strecker synthesis can be carried out using a suitable cyanide reaction agent according to known procedures published by A. Kalir et al., (J. Ed. Chem. 1969, 12 473). Suitable cyanide reaction agents include cyanide such as potassium cyanide (KNC). This reaction can be carried out at a pH of about 3 to 11, at a temperature of 0 to 50 ° C, preferably in ice water for 30 minutes to 7 days. The Grignard reaction can be carried out under anhydrous conditions according to known procedures (e.g., O.A. Al-Deeb, Arzneim.- Forsch./Drugs Res., 1994, 44, 1141). More specifically, this reaction can be carried out in a suitable solvent such as tetrahydrofuran (THF), at a temperature between about room temperature (e.g., 20 ° C) and the reflux temperature of the solvent for 30 minutes to 48 hours. The compounds (I) in which R1 and R2, taken together with the carbon atom to which they are attached, form a monocyclic, bicyclic, tricyclic, or spirocyclic ring, can also be prepared by subjecting an intermediate (II) to the reaction of Grignard according to procedures similar to that illustrated in scheme 1. Suitable Grignard reagents are those represented by the formula of R1R2ACMgX ', in which R1 and R2, taken together with the carbon atom to which they are attached, form the cyclic ring; and X'is halo. The compounds (I) can also be prepared by the methods illustrated in scheme 2.

SCHEME 2 As shown in scheme 2, the compounds (I) in which R is hydrogen can be prepared from a piperidine-4-one (V) through a compound (VI) according to known procedures as described in U.S. Pat. No. 3,238,216. First, the compound (V) can be reacted with a hydrochloric acid salt of an amino compound (VII) (i.e., XNH2) in the presence of a suitable cyanide reaction agent such as potassium cyanide (KNC) for give the compound (VI). This reaction can be carried out in a suitable solvent inert in the reaction, such as water at a temperature between 0 ° and 50 ° C for 30 minutes to 7 days. Then, the compound (VI) can be treated with sulfuric acid at a temperature comprised between 0 ° and 100 ° C for 30 min. To 10 hours, followed by reaction with formamide (HCONH2). The reaction with formamide can be carried out at a temperature between 150 ° and 250 ° C for 30 min to 20 hours. If a mixture of 1-phenyl-1, 3,8-triazaspiro [4.5] decan-4-one derivative and 1-phenyl-1,3,8-triazaspiro [4.5] dec-2-en-4 is obtained Under these reaction conditions, the mixture can be treated with a reducing agent such as sodium borohydride (NaBH4) to give the desired 1-phenyl-1, 3-8-triazaspiro [4.5] decan-4-one derivative. A compound of the formula (I) in which R is hydrogen obtained as above can be subjected to suitable reactions to replace R with other substituents. For example, the compound of formula (I) in which R is hydrogen can be subjected to necleophilic substitution reactions. Those skilled in the art should understand that nucleophilic substitution reactions can be conveniently carried out in the presence of a base. If desired, a phase transfer catalyst such as tetrabutylammonium hydrogensulfate (Bu NH-S04) can be used in the reactions. For example, a compound of formula (I) in which R is alkyl, substituted alkyl or the like can be prepared by reaction of a compound of formula (I) in which R is hydrogen with a suitable nucleophile. Suitable leaving groups in the nucleophiles include sulfonate such as mesylate and tosylate, and halo. Suitable bases used in the reactions include sodium hydride (NaH), sodium hydroxide and the like. The reactions can be carried out in an inert solvent in the reaction such as DMF and THF at a temperature between about 0 ° and 100 ° C for a period of time between about 0.5 and 24 hours. In the above reactions, the amino or hydroxy groups can be protected, and subsequently the protecting groups can be removed after the reactions according to procedure known to those skilled in the art. Removal of the amino protecting group can be conveniently carried out by treatment of the resulting amino-protected compound with an acid such as hydrochloride. The removal of the hydroxy protecting group can be conveniently carried out by treatment of the resulting hydroxy-protected compound with a reducing agent such as L-IAH.

The compounds of formula (I) thus obtained in which R is hydroxy-alkyl can be modified by inversion of the hydroxy group to give another substituent. This modification can be carried out in reactions comprising introduction of a functional group and subsequent nucleophilic substitution reaction. Suitable functional groups include sulfonate such as tosylate and mesylate, and halo. The introduction of the functional group can be carried out in the absence or presence of a base such as triethylemine in an inert solvent in the reaction such as ethanol, DMSO, cyclohexane, dichloromethane or the like. The nucleophilic substitution reaction can typically be carried out using an amino compound as a nucleophile. This reaction can be carried out in the presence of a base such as potassium carbonate or the like, in a reaction-inert solvent such as DMF or the like, at a temperature between about 0 ° and 100 ° C, and for a period of time comprised between approximately 0.5 and 24 hours. The intermediate compounds (V) can be prepared by the methods illustrated in scheme 3.

SCHEME 3 Route 1: Route 3: (XIII) (v) Route 1 illustrates a preparation of compound (V) from the known 4- piperidinol (VIII) according to the procedures published by A. Kalir et al., J. Med. Chem., 1969, 12, 473. First, the compound (VIII) can be condensed with the compound (III) and reacted with cyanide to give the compound (IX). Second, the compound (IX) obtained can be subjected to the Grignard reaction with AMgX 'in which formula X' is halo, to give the compound (X). Subsequently, the compound (X) can be oxidized to give the compound (V). Route 2 illustrates a preparation of compound (V) from an initial amine (XI) comprising the condensation of (XI) with 3,3-ethylenedioxypentane-1,5-diol dimethanesulfonate (XII) followed by deprotection. This reaction can be carried out under known conditions (e.g., B. De Costa, et al., J. Chem. Soc, Perkin Trans., I, 1992, 1671). Route 3 illustrates a preparation of compound (V) from a known 4-piperidone-ethylene-ketal (XIV). This preparation comprises (a) condensation of (XIV) with (lll), (b) cyanide reaction, (c) the reaction of Grignard and (d) deprotection. These reactions can be carried out under the same conditions described in scheme 1. As shown in route 4, compound (V) can be prepared directly from an initial amine (XI) using N-ethyl- iodide. N-methyl-4-oxopiperidinium according to the DM procedure Tschaen et al. (J. Org. Chem. 1995, 60, 4324). The starting amines (XI) can be easily prepared by methods known to those skilled in the art (eg, J. Weinstock, et al., OS IV 910, eg Cone, et al., J. Med. Chem., 1981, 24 , 1429, and the reaction of Ritter described in Org. React, 1969, 17, 313). Unless otherwise indicated, the actual pressure at which the above reactions are performed is not critical. Generally, the reactions will be conducted at a pressure of about one to about three atmospheres, preferably at ambient pressure (about one atmosphere). The compounds of formula (I) of this invention are basic, whereby they will form acid addition salts. All of said salts are within the scope of this invention. However, it is necessary to use an acid addition salt that is pharmaceutically acceptable for administration to a mammal. The acid addition salts can be prepared by standard methods. For example, salts can be prepared by contacting the basic compounds with an acid in substantially equivalent proportions in water or in an organic solvent such as methanol or ethanol, or a mixture thereof. The salts can be isolated by crystallization or evaporation of the solvent. Typical salts that can be formed are hydrochloride, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succyanate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, p-toluenesulfonate, oxalate and pamoate (1,1'-methylene-bis- (2 -hydroxy-3-naphthoate) It has been found that the compounds of the formula (I) possess selective affinity for the ORL1 receptors and ORL-1 receptor agonist activity.Thus, these compounds are useful as an analgesic, anti-inflammatory agent , diuretic, anesthetic, neuroprotective, antihypertensive or anti-anxiety, or as an appetite control or ear regulation agent, in mammals, especially humans, that are in need of said agents. treatment of other psychiatric, neurological and physiological disorders such as depression, trauma, memory loss due to Alzheimer's disease and other dementias, epilepsy, and seizures, withdrawal symptoms It gives addiction drugs, water balance control, sodium excretion, and arterial blood pressure disorders. These compounds are particularly useful as analgesics, anti-inflammatories, diuretics or anesthetics. The present invention also includes isotope-labeled compounds, which are identical to those indicated in formula (I), except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the mass atomic or mass number that is usually found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 32P, 35S, 8F, and 36CI, respectively. The compounds of the present invention, their prodrugs, and the pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms, are within the scope of this invention. Certain compounds of the present invention labeled with isotopes, for example those in which radioactive isotopes such as 3H and 14C are incorporated, are useful in the assay of distribution of drugs and / or substrates in tissues. Particularly preferred are isotopes of tritium, ie, 3H, and carbon 14, ie 14C, for their ease of presentation and susceptibility to detection. Additionally, substitution with heavier isotopes such as deuterium, i.e. H may provide therapeutic benefits resulting from increased metabolic stability, for example increased half-life in vivo or reduced dosage requirement, and, therefore, may be preferred in certain circumstances . The compounds of formula (I) labeled with isotopes of this invention and their prodrugs can generally be prepared by performing the procedure described in the schemes set forth above and / or the following examples and preparations, employing an easily available isotopically-labeled reagent instead of a reagent not labeled with isotopes. Affinity, agonist activities and analgesic activity can be demonstrated by the following trials, respectively.

Selective affinity for ORL1 receptors: Affinity for the QRL1 receptor: The binding affinity to the ORL1 receptor of the compounds of this invention is determined by the following procedures. Membranes of HEK-293 cells transfected with the human ORL1 receptor and SPA beads coated with wheat germ agglutinin are combined with 0.4 nM [3 H] nociceptin and the unlabeled test compounds in 200 μl of 50 mM Hepes buffer pH 7.4 which It contains 10 mM MgCl2 and 1 mM EDTA.

This mixture is incubated at room temperature (abbreviated as ta) during min to 60 min. Nonspecific binding is determined by the addition of 1 μM nociceptin. Reactivity is counted in a Wallac 1450 device MicroBeta.

Affinity for the μ receptor: The binding affinity to the mu opioid receptor (μ) of the compounds of this invention is determined by the following procedures. Membranes of CHO-K1 cells transfected with the human mu opioid receptor and SPA beads coated with wheat germ aglatanin are combined with [3 H] DAMGO 1.0 nM and the unlabeled test compounds in 200 μl of 50 mM Hepes buffer pH 7.4 containing 10 mM MgCl 2 and 1 mM EDTA. This mixture is incubated at rt for 30 min to 60 min. Non-specific binding is determined by the addition of 1 μM DAMGO. The reactivity is counted on a Wallac 1450 MicroBeta team.

Affinity for the K receptor: The binding affinity to the kappa opioid receptor (K) of the compounds of this invention is determined by the following procedures. Membranes of CHO-K1 cells transfected with the human kappa opioid receptor and SPA beads coated with wheat germ agglutinin are combined with 0.5 nM [3H] CI-977 and unlabelled test compounds in 200 μl of 50 mM Hepes buffer pH 7.4 containing 10 mM MgCl2 and EDTA 1 mM. This mixture is incubated at rt for 30 min to 60 min. Nonspecific binding is determined by the addition of 1 μM CI-977. Radioactivity is counted in the Wallac 14501 MicroBeta equipment.

Affinity for the receptor d The binding affinity to the delta opioid receptor (d) of the compounds of this invention is determined by the following procedures. Membranes of CHO-K1 cells transfected with the human delta opioid receptor and SPA beads coated with wheat germ agglutinin are combined with 2.0 nM [3H] DPDPE and the unlabeled test compounds in 200 μl of 50 mM Hepes pH buffer 7.4 containing 10 mM MgCl 2 and 1 mM EDTA. The test mixture is incubated at room temperature for 30 min to 60 min. The specific binding is determined by the addition of 1 μM concentrations of each of the unlabeled ligands. The radioactivity is counted on the equipment Wallac 1450 MicroBeta. Each of the non-specific binding percentages thus obtained is plotted according to the concentration of the compound. A sigmoidal curve is used to determine the IC50 values. All compounds of Examples 1 to 8 were tested by the above procedures and demonstrated satisfactory affinity for ORL1 receptors. In this test, the above-mentioned particularly preferred compounds demonstrated higher affinity for the receptors ORL1 that for the mu receptors (ie, the IC50 ratios for the ORL1 / IC50 receptors for the mu receptors were less than 1.0).

Functional assay: The functional activity of the compounds of this invention in each opioid receptor can be determined in the 35S-GTP? S fixation system according to the procedures published by L.J. Sim, R. Xiao and S. Childers, Neuroreort Vol. 7, pp. 729-733, 1996. Membranes of CHO-K1 or HEK cells transfected each are used with the human ORL1, mu, kappa, and delta receptors. The membranes are suspended in ice-cold 20 mM HEPES buffer, pH 7.4 containing 100 mM NaCl, 10 mM MgCl 2 and 1 mM EDTA. 0.17 mg / ml dithiothreitol (DTT) is added to this buffer before use. The membranes are incubated at 25 ° C for 30 minutes with the appropriate concentration of the test compounds in the presence of 5 μM GDP, 0.4 nM concentration of 35S-GTPγS and SPA beads coated with wheat germ agglutinin (WGA) ( 1.5 mg) in a total volume of 0.2 ml. The basal fixation is evaluated in the absence of agonist, and the specific binding is determined with 10 μM GTPγS. The radioactivity is counted on the equipment Wallac 1450 MicroBeta.

Analgesic tests: Tail shaking test: Male ICR mice, 4 weeks old and weighing 19-25 g are used. Training sessions are performed until the mice can shake their tails within 4.0 s using the MK-330A analgesic meter (Muromachi Kikai, Japan). Selected mice are used in this experiment. The latency time is recorded twice after 0.5, 1.0 and 2.0 h after the administration of the compound. The beam intensity is set to 80. Cutting time is set to 8.0 s. A compound of this invention is administered subcutaneously 30 min before the assay. The DE5o value is observed in the control group, defined as the dose of the tested compounds that halves the tail shaking.

Acetic acid contortion test: ICR male mice, 4 weeks old and weighing 21-26 g, are used. They are left fasting the day before use. Acetic acid is diluted with saline at a concentration of 0.7% (volume / volume) and injected intraperitoneally (0.2 ml / 10 g of body weight) into the mice with a 26 gauge needle. A compound of this invention is dissolved. in methylcellulose (MC) at 0.1% saline solution and administered subcutaneously to the mice 0.5 h before the injection of acetic acid. After the injection of acetic acid, each animal is placed in a 1 L hot filtration cup and recorded with a video tape recorder. Count the number of contortions from 5 to min after the injection of acetic acid. The ED50 value is observed in the control group, defined as the dose of the compounds tested that reduces contortions by half. Some compounds of this invention demonstrated satisfactory analgesic activity in this assay (ie, ED50 value from 0.02 mg / kg to 1 mg / kg).

Formalin lick assay: Male SD rats (80-100 g) are injected subcutaneously with a test compound dissolved in 0.1% methylcellulose (MC) -salt or vehicle solution. After 30 min, 50 μl of 2% formalin is injected into a hind paw. The number of licks of the injected paw is counted for each observation period 15 to 30 min after the formalin injection and expressed as% inhibition compared to the respective vehicle group. This test method is described, for example, in (1) R.L. Follenfant, et al., Br. J. Pharmacol. 93, 85-92 (1988); (2) H. Rogers, et al., Br. J. Pharmacol. 106, 783-789 (1992); and (3) H. Wheeler-Aceto, et al., Psychopharmacology, 104, 35-44 (1991). The compounds of the formula (I) of this invention can be administered by the conventional pharmaceutical technique orally, parentally or topically to mammals, for the treatment of the indicated diseases. For administration to a human patient by any route, the dose is in the range of about 0.01 mg / kg to about 3000 mg / kg of body weight of the patient per day, preferably about 0.01 mg / kg to about 1000 mg /. kg of body weight per day, and more preferably about 0.1 mg / kg to about 100 mg / kg of body weight per day administered once or in the form of divided doses. However, variations will necessarily occur depending on the weight and conditions of the individual subjected to the treatment, the compound employed, the disease state in question and the particular route of administration selected. The compounds of the present invention can be administered alone or in combination with pharmaceutically acceptable carriers by any of the above routes indicated above, and such administration can be carried out in single or multiple doses. Generally, the compounds can be combined with various pharmaceutically acceptable carriers in the form of tablets, powders, capsules, splints, troches, hard candies., powders, sprays, creams, ointments, suppositories, jellies, gels, pastes, lotions, ointments, suspensions, solutions, elixirs, syrups or the like. Such pharmaceutical carriers include solvents, excipients, coating agents, bases, binders, lubricants, disintegrators, solubilizing agents, suspending agents, emulsifying agents, stabilizers, buffering agents, tonicity agents, preservatives, flavoring agents, aromatics, coloring agents. and analogues.

For example, the tablets may contain various excipients such as starch, lactose, glucose, microcrystalline cellulose, calcium sulfate, calcium carbonate, talc, titanium oxide and the like, coating agents such as gelatin, hydroxypropylcellulose and the like, binding agents such such as gelatin, gum arabic, methylcellulose and the like, and disintegrating agents such as starch, agar, gelatin, sodium hydrogencarbonate and the like. Additionally, lubricating agents such as magnesium stearate and talc are often very useful for tablet manufacturing purposes. Solid compositions of a similar type can also be used as fillers in gelatin capsules; Preferred materials in this context also include lactose as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matters or dyes, and, if desired, also emulsifying and / or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and various analogous combinations thereof. In general, the therapeutically effective compounds of this invention are present in said oral dosage forms at concentration levels between 5% and 70% by weight, preferably 10% to 50% by weight. The compounds of the present invention in solution form can be injected parenterally such as intradermally, subcutaneously, intravenously or intramuscularly. For example, the solutions are aqueous solutions, aqueous suspensions and solutions in edible oils, all of them sterile. The aqueous solutions may be suitably buffered (preferably pH> 8), and may contain sufficient amounts of salts or glucose to make the solution isotonic with the blood. The aqueous solutions are suitable for intravenous injection purposes. The aqueous suspensions may contain a suitable dispersing or suspending agent such as sodium carboxymethyl cellulose, methyl cellulose, polyvinyl pyrrolidone or gelatin. Aqueous suspensions can be used for subcutaneous or intramuscular injections. Edible oil, such as cottonseed oil, sesame oil, coconut oil or peanut oil can be used for solutions in edible oil. Oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection. The preparation of all these solutions under sterile conditions is easily accomplished by standard pharmaceutical methods well known to those skilled in the art. It is also possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin, and this can preferably be done by means of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.

EXAMPLES AND PREPARATION The present invention is illustrated by the following examples and preparations. However, it should be understood that the invention is not limited to the specific details of these examples and preparations. The melting points were determined with a Buchi melting point apparatus on a micro scale, and are not corrected. The infrared (IR) absorption spectra were measured with a Shimadzu infrared spectrometer (IR-470). The 1H and 13C nuclear magnetic resonance (NMR) spectra were measured in CDCI3 with a JEOL NMR spectrometer (JNM-GX270, 270 MHz) unless otherwise indicated, and the positions of the peaks are expressed in parts per million ( ppm) in descending field, referred to tetramethylsilane. The shapes of the peaks are designated as follows: s, singlet, d, doublet; t, triplet, m, multiplet, br, wide.

PREPARATION 1 1 - (4-Oxo-l-phenyl-1,3,8-triazaspiror-4,51dec-8-yl) cycloheptane-carbonitrile To a stirred mixture of 1- (4-oxo-1-phenyl-1, 3,8-triazaspiro [4.5] decane hydrochloride (578.8 mg, 2.16 mmol) and cycloheptanone (304 μl, 2. 59 mmol) was added a solution of KCN (169 mg, 2.59 mmol) in water (1 ml) at room temperature. The reaction mixture was stirred vigorously at room temperature for 20 h. The precipitated white solid was collected by filtration, washed with water and hexane, and dried under vacuum at 50 ° C for 1 h to provide 323 mg (42.4%) of white powder. 1 H NMR (270 MHz, CDCl 3) d 7.58 (1 H, br.s), 7.32-7.26 (2 H, m), 6. 93-6.84 (3H, m), 4.76 (2H, s), 3.00-2.96 (4H, m), 2.72-2.61 (2H, m), 2.20-2.15 (2H, m), 2.01-1.67 (12H, m ).

EXAMPLE 1 1 -Fenil-8- (1-phenylcycloheptiD-1, 3,8-triazaspirof4.51decan-4-one) To a stirred solution of 1- (4-oxo-1-phenyl-1, 3,8-triazaspiro [4.5] dec-8-yl) cycloheptane-carbonitrile (323 mg, 0.916 mmol) in THF (6 mL) was added phenylmagnesium bromide (3 M solution in diethyl ether, 3.05 ml, 9.16 mmol) at room temperature. The reaction mixture was then stirred at room temperature for 24 h. The reaction mixture was poured into ice water, and then extracted with CH2Cl2. The combined extracts were dried (Na2SO4), filtered, and concentrated. The residue was purified by preparative thin layer chromatography (TLC) (CH2Cl2 / MeOH: 10/1) to give 70.5 mg (19.1%) of the title compound. MS (mass spectroscopy, from Mass Spectroscopy) m / z [The Electron Impact (direct electron impact)]: 403 (M +), 375, 347, 325, 228, 172, 127. 1 H NMR (270 MHz, CDCl 3) d 7.70-7.50 (2H, m), 7.40-7.15 (5H, m), 7.05-6.80 (4H, m), 4.70 (2H, s), 2.95-2.70 (4H, m ), 2.65-2.47 (2H, m), 2. 20-200 (4H, m), 1.90-1.40 (10H, m). This free amine was converted to the addition salt of HCl by treatment with HCl solution in methanol. After evaporation of the solvent, the resulting white amorphous solid was collected by filtration to provide an amorphous solid. IR (KBr): 3400, 1709 cm 1 Analysis, calculated for C26H33N3O HCM H20: C, 68.18; H, 7.92; n, 9.17. Found: C, 68.29; H, 7.76; N, 9.23.

EXAMPLE 2 3- (3-Aminopropyl) -1-phenyl-8- (1-phenylcycloheptyl) -1, 3,8-triazaspirof4.51decan-4-one This compound was prepared according to the procedure of A. Petric et al (Bioorg, Med Chem. Lett, 1998, 8, 1455). To a stirred solution of 1-phenyl-8- (1-phenylcycloheptyl) -1, 3,8-triazaspiro [4.5] decan-4-one (54.3 mg, 0.135 mmol in toluene (0.3 ml) was added a solution of NaOH (23.8 mg, 0.595 mmol) in water (0.5 ml), n-Bu4NHSO4 (70.8 mg, 0.209 mmol), and a solution of N- (t-butoxycarbonyl) -3-bromo-propylamine (65.3 mg, 0.274 mmol, procedure which was published by BH Lee and others J. Org. Chem. 1983, 48, 24) in toluene (0.7 ml) at room temperature.The reaction mixture was stirred at room temperature for 18 h, and then a 90 ° C for 2 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with CH2Cl2. The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by preparative TLC (1 mm x 2 plate, CH 2 Cl 2 / -MeOH: 95/5, developed twice) to provide 54.2 mg (71.8%) of a colorless solid. 1 H NMR (270 MHz, CDCl 3) d 7.55-7.52 (2H, m), 7.33-7.15 (5H, m), 6.94-6.82 (3H, m), 5.22 (1 H, br.s), 4.64 (2H, s), 3.49-3.43 (2H, m), 3.17- 3.08 (2H, m), 2.93-2.84 (2H, m), 2.76-2.49 (2H, m), 2.18-2.01 (4H, m), 1.78- 1.51 (14H, m), 1.43 (9H, s). A solution of this Boc derivative (54.2 mg) in solution HCl in MeOH (2 mL) was stirred at room temperature for 15 h. Evaporation of the solvent gave a solid which was dried under vacuum at 45 ° C to give mg of solid, m.p. 150-154 ° C as an addition salt of HCl. 1H NMR (270 MHz, DMSO-d6) d 10.45-10.30 (1 H, m), 7.90 (3H, br.s), 7.72-7.69 (2H, m), 7.45-7.30 (14H, m), 7.20- 7.05 (4H, m), 6.75-6.63 (1 H, m), 4.57 (2H, s), 3.55-3.13 (8H, m), 3.05-2.85 (2H, m), 2.80-2.55 (4H, m) , 2. 45-2.30 (1 H, m), 1.85-1.00 (10H, m). IR (KBr): 3400, 1686 cm "1 MS (ESI positive) m / z: 461 (M + H) +. Analysis, calculated for C29H40N4O-2HCI-2.5H2O: C, 60.20; H, 8. 19; N, 9.68. Found: C, 60.45; H, 8.22; N, 9.47.

EXAMPLE 3 1-Phenyl-8- (1-phenylcycloheptyl) -3-r2- (1-piperidininetill-1, 3.8-triazaspirof4.51decan-4-one) This compound was prepared according to the procedure described in Example 2, using 1- (2-chloroethyl) piperidine hydrochloride in place of N- (1-butoxycarbonyl) -3-bromopropylamine and 90 ° C for 23 h instead of the room temperature for 18 h, then at 90 ° C for 2 h to give the addition salt of HCl, mp 174-178 ° C. The yield was 31%. IR (KBR): 3400, 1693 crn "1 • MS m / z (The direct): 514 (M +), 457, 341, 325, 286, 237, 172, 98. Analysis calculated for C33H46N4O-2HCI-3H2O: C , 61.77; H, 8.48; N, 8.73, Found: C, 61.74; H, 8.72; N, 8.49, A portion of this hydrochloride salt was converted to free amine, 1 H NMR (270 MHz, CDCl 3) d 7.60-7.48. 2H, m), 7.40-7.15 (5H, m), 7.00-6.80 (3H, m), 4.70 (2H, s), 3.51 (2H, t, J = 6.5 Hz), 3.00-2.30 (12H, m) , 2.20-1.95 (4H, m), 1.90-1.35 (16H, m).

EXAMPLE 4 8- (1 -Methylcycloheptyl) -1-phenyl-1,3,8-triazaspiror-4,11decan-4-one This compound was prepared according to the procedure described in Example 1, using methylmagnesium bromide in place of phenylmagnesium bromide. The yield was 30%. 1 H NMR (270 MHz, DMSO-d 6) d 10.11-9.96 (1 H, m), 9.02 (1 H, s), 7.26-7.11 (5H, m), 6.83-6.76 (1H, m), 4.62 (2H , s), 3.86-3.66 (2H, m), 3.11-2.92 (2H, m), 2.16-2.06 (2H, m), 1.91-1.46 (14H, m), 1.45 (3H, s). IR (KBr): 1711 cm'1 MS (ESI positive) m / z: 342 (M + H) +. Analysis, calculated for C21H3? N3O-2HCI 0.3H2O: C, 60.08; H, 8.07; N, 10.01. Found: C, 60.26; H, 8.26; N, 10.00 EXAMPLE 5 8- (1 -MethylcycloheptiD-1-phenyl-3-r2- (1-piperidine-Dethyl), 3,8-triazaspiror-4,11-decan-4-one This compound was prepared according to the procedure described in Example 3 using 8- (1-methylcycloheptyl) -1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one instead of 1-phenyl-8. - (1-phenylcycloheptyl) -1,8,8-triazaspiro [4.5] decan-4-one to give the addition salt of HCl, mp 50-53 ° C. The yield was 39%.

MS m / z (The direct): 452 (M +), 437, 395, 341, 285, 236, 98. Analysis, calculated for C28H44N40-2HCI-3.5H20: C, 57.13; H, 9.07; N, 9.52 Found: C, 57.46; H, 9.19; N, 9.10. A part of this hydrochloride salt was converted to free amine. 1 H NMR (270 MHz, CDCl 3) d 7.35-7.23 (2H, m), 7.05-6.80 (3H, m), 4.75 (2H, s), 3.53 (2H, t, J = 6.5 Hz), 3.00-2.60 ( 4H, m), 2.54 (2H, t, J = 6.5 Hz), 2.50-2.38 (4H, m), 2.00-1.22 (22H, m), 0.95 (3H, s).

PREPARATION 2 1 - (4-Oxo-l-phenyl-1, 3,8-triazaspirof4.51dec-8-yl) -4-cycloheptene-1-carbonitrile This compound was prepared according to the procedure described in Preparation 1 using 4-cycloheptenone (J.A. Marshall and others J. Org. Chem. 1982, 47, 693) in place of cycloheptanone. The yield was 65%. 1 H NMR (270 MHz, CDCl 3) d 7.40 (1 H, br.s), 7.35-7.23 (2H, m), 7.00-6.83 (3H, m), 5.85-5.70 (2H, m), 4.76 (2H, s), 3.10-2.95 (4H, m), 2.70-2.30 (4H, m), 2.25-2.00 (4H, m), 1.95-1.70 (4H, m).

EXAMPLE 6 8- (1 -Methyl-4-cyclohepten-1H) -1-phenyl-1,3,8-triazaspiror4.51decanone This compound was prepared according to the procedure described in Example 4 using 1- (4-oxo-1-phenyl-1,3,8-triazaspiro [4.5] dec-8-yl) -4-cycloheptene-1-carbonitrile instead of 1- (4-oxo-1-phenyl-1, 3,8-triazaspiro [4.5] dec-8-yl) cycloheptanecarbonitrile. The yield was 16%. 1 H NMR (270 MHz, CDCl 3) d 7.36-7.23 (3H, m), 6.98-6.78 (3H, m), 5.83-5.70 (2H, m), 4.75 (2H, s), 3.02-2.60 (6H, m ), 2.50-2.35 (2H, m), 2.05-1.65 (6H, m), 1.50-1.35 (2H, m), 0.95 (3H, s). This free amine was converted to the hydrochloride salt, m.p. 251-254 ° C. IR (KBr): 3400, 1713 cm-1 MS (ESI positive) m / z: 340 (M + H) + Analysis, calculated for C2? H29N3O-2HCI 0.5H2O: C, 59.85; H, 7. 65; N, 9.97. Found: C, 59.91; H, 7.99; N, 9.63.

PREPARATION 3 1 - (4-Oxo-l-phenyl-1,3,8-triazaspiror-4,51dec-8-yl) cyclohexane-carbonitrile This compound was prepared according to the procedure described in Preparation 1 using 4-cyclohexanone instead of cycloheptanone. The yield was 81%. 1 H NMR (270 MHz, CDCl 3) d 7.40 (1 H, br.s), 7.34-7.25 (2 H, m), .02-6.86 (4 H, m), 4.75 (2 H, s), 3.06-2.98 (4 H , m), 2.64-2.50 (2H, m), 2.22- .06 (2H, m), 1.90-1.50 (10H, m).

EXAMPLE 7 8- (1-Benzylcycloheptyl-1-phenyl-1,3,8-triazaspirof4.51decan-4-one) This compound was prepared according to the procedure described in Example 1 using 1- (4-oxo-1-phenyl-1,3,8-triazaspiro [4.5] dec-8-yl) cyclohexanecarbonitrile instead of 1- (4 -oxo-1-phenyl-1,3,8-triazaspiro [4.5] dec-8-yl) cycloheptanecarbonitrile and benzylmagnesium bromide in place of phenylmagnesium bromide. The yield was 54%. 1 H NMR (270 MHz, CDCl 3) d 7.39-7.10 (7H, m), 7.00-6.94 (2H, m), 6.87-6.79 (1 H, m), 6.42 (1 H, br.s), 4.76 (2H , s), 3.10-2.90 (4H, m), 2.80-2.69 (2H, m), 2.68 (2H, s), 1.92-1.00 (12H, m). This free amine was converted to the hydrochloride salt, m.p. 237-241 ° C. IR (KBr): 1709 cm "1 Analysis, calc'd for C26H33N3O HCI-H2O: C, 68.18; H, 7.92; N, 9.17. Found: C, 68.06; H, 7.60; N, 8.87.

EXAMPLE 8 3- (3-Aminopropyl) -8- (1-methylcycloheptyl) -1-phenyl-1,3,8-triazaspirof4.51decan-4-one This compound was prepared according to the procedure described in Example 2 using 8- (1-methylcycloheptyl) -1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one instead of 1-phenyl-8 - (1-phenylcycloheptyl) -1, 3,8-triazaspiro [4.5] decan-4-one. The yield was 57%. The Boc group was then removed by treatment with HCl solution in methanol to give the title compound as HCl addition salt, m.p. 216-220 ° C. 1 H NMR (270 MHz, DMSO-d 6) d 10.35-10.20 (1 H, m), 7.93 (3 H, br.s), 7.20-7.05 (4H, m), 6.75-6.65 (1 H, m), 4.63 (2H, s), 3.70-3.50 (4H, m), 3.10-2.90 (4H, m), 2.75-2.60 (4H, m), 2.10-1.40 (14H, m), 1.35 (3H, s). IR (KBr): 3400, 1695 crn "1 MS (ESI positive) m / z: 399 (M + H) +. Analysis, calculated for C 24 H 38 N 4 O 2 HCl 0.5 CH 2 Cl 2: C, 57.25; H, 8.04; N, 10.90. Found: C, 57.39; H, 7.89; N, 11.01.

EXAMPLE 9 3- (6-Aminohexyl) -8- (1-phenylcycloheptiP-1-phenyl-1,3,8-triazaspirof4.51decan-4-one) This compound was prepared according to the procedure described in Example 2, using 8- (1-phenylcycloheptyl) -1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one and 6-t-mesylate butoxycarbonylaminohexyl in place of 3-butoxycarbonylaminopropyl bromide. The yield was 73%. The Boc group was then removed by treatment with HCl solution in methanol to give the title compound as an addition salt of HCl. • 1H NMR (270 MHz, DMSO-d6) d 10.45 (1 H, br.s), 7.94 (3H, br.s), 7.86-7.78 (2H, m), 7.53-7.43 (3H, m), 7.22 -7.17 (4H, m), 6.81-6.73 (1 H, m), 4. 64 (2H, s), 3.70-3.50 (2H, m), 3.45-3.20 (2H, m), 3.20-3.00 (2H, m), 2.90- 2.65 (4H, m), 2.50-2.45 (2H, m) ), 1.80-1.05 (20H, m). IR (KBr): 3422, 1688 cm "1 Analysis, calculated for C32H46N4O-2HCI 0.5H2O: C, 65.74; H, 8.45; N, 9.58. Found: C, 65.34; H, 8.15; N, 9.44.

EXAMPLE 10 3- (6-Aminohexyl-8- (1-methylcycloheptyl) -1-phenyl-1,3,8-triazaspiror-4,11-decan-4-one This compound was prepared according to the procedure described in Example 2, using 8- (1-methylcycloheptyl) -1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one instead of 1-phenyl- 8- (1-phenylcycloheptyl) -1,8,8-triazaspiro [4.5] decan-4-one and 6-β-butoxycarbonylaminohexyl mesylate in place of 3-f-butoxycarbonylaminopropyl bromide. The yield was 35%. The Boc group was then removed by treatment with HCl solution in methanol for the title compound as an addition salt of HCl. 1 H NMR (270 MHz, DMSO-d 6) d 10.50 (1 H, br.s), 7.97 (3 H, br.s), 7.23-7.13 (4 H, m), 6.82-6.74 (1 H, m), 4.70 (2H, s), 3.78-3.60 (2H, m), 3.55-3.44 (2H, m), 3.20-3.04 (2H, m), 2.78-2.68 (2H, m), 2.20-2.05 (2H, m) , 1.90-1.25 (25H, m). IR (KBr): 3398, 1686 cm "1 Analysis, calc'd for C27H44N40-2HC .5H20: C, 59.99; H, 9.14; N, 10.36, Found: C, 59.78; H, 9.33; N, 10.22.

PREPARATION 4 3-f-Butoxycarbonylmethyl-1-phenyl-8- (1-phenylcycloheptyl) -1, 3,8-triazaspiroyl-4,11decan-4-one This compound was prepared according to the procedure described in example 2, using 8- (1-phenylcycloheptyl) -1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one and 2-bromoacetate of butyl instead of 3-butoxycarbonylaminopropyl bromide. The yield was 100%. 1 H NMR (270 MHz, CDCl 3) d 7.60-7.50 (2H, m), 7.35-7.10 (5H, m), 7.00-6.80 (3H, m), 4.71 (2H, s), 4.01 (2H, s), 3.00-2.45 (6H, m), 2.20-2.00 (4H, m), 1.85-1.40 (10H, m), 1.46 (9H, s). MS (El) m / z: 517 (M +), 489, 460, 404, 344, 289, 263, 91.

EXAMPLE 11 3-r2- (4-Aminopiperidin-1-yl) etiM-8- (1-phenylcycloheptyl) -1-phenyl-1,3,8-triazaspiro [4.51decan-4-one] To a stirred suspension of LiAIH4 (191 mg, 5.03 mmol) in THF (2 mL) was added a solution of 3-β-butoxycarbonylmethyl-1-phenyl-8- (1-phenylcycloheptyl) -1, 3,8-triazaspiro [ 4.5] decan-4-one (prepared in Preparation 4, 650 mg, 1.26 mmol) in THF (4 mL) at 0 ° C. After 1 h of stirring at room temperature, excess LiAIH4 was quenched with Na2SO4-10H20 (1.61 g) and KF (291 mg). After 1 h of stirring at room temperature, the mixture was diluted with CH 2 Cl 2 and the solid separated by filtration with Celite. The precipitate was concentrated and purified by preparative TLC (1 mm x 4 plate, n-hexane / acetone: 3/1) to give 177 mg (31%) of the alcohol derivative as a white amorphous solid. To a solution of this derivative alcohol (177 mg, 0.396 mmol) and NEt3 (82.8 μl, 0.594 mmol) in CH2Cl2 (2 mL) was added mesyl chloride (46 μL, 0.594 mmol) at 0 ° C. After 1 h of stirring at room temperature, NaHC03 solution was added to the reaction mixture and extracted with CH2-CI2. The combined extracts were washed with brine, dried (Na2SO), filtered, and concentrated to give 226 mg of pale yellow amorphous solid. A mixture of this derivative mesylate (226 mg, 0.396 mmol), At-butoxycarbonylaminopiperidine (166 mg, 0.99 mmol), K2CO3 (137 mg, 0.99 mmol), and DMF (5 mL) was stirred at 60 ° C for 15 h and 80 ° C for 4 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with a mixed solvent (ethyl acetate / toluene). The combined extracts were washed with water and brine, dried (Na 2 SO), filtered, and concentrated to give a light brown oil, which was purified by preparative TLC (1 mm x 3 plate, CH 2 Cl 2 / MeOH: / 1) to give 131 mg (53%) of Boc-protected derivative as a white amorphous solid. A solution of this Boc-protected derivative (131 mg, 0.208 mmol) in HCl solution in methanol (10 ml) was stirred at room temperature for 20 h. After evaporation of the solvent, the residue was diluted with 25% NH 4 OH and CH 2 Cl 2. The organic layer was separated and washed with brine, dried (Na2-S0), filtered, and concentrated. The residue was purified by preparative TLC (0.5 mm x 3 plate, CH 2 Cl 2 / MeOH: 10/1) to give 81.5 mg (74%) of colorless oil as the title compound. 1 H NMR (270 MHz, CDCl 3) d 7.60-7.50 (2H, m), 7.35-7.15 (5H, m), 6.96-6.80 (3H, m), 4.69 (2H, s), 3.50 (2H, t, J = 6.4 Hz), 3.00-2.45 (11 H, m), 2.20-2.00 (6H, m), 1.85-1.20 (16H, m). MS (El) m / z: 529 (M +), 356, 301, 251, 127, 91. This compound was converted to fumaric acid salt to give 78 mg of a pale yellow amorphous solid. IR (KBr): 3400, 1693 crt? 1 Analysis, calculated for C33H47N50-1.5C H404-1.5H20: C, 64.09; H, 7.72; N, 9.58. Found: C, 64.34; H, 7.92; N, 9.29.

EXAMPLE 12 3-Methoxycarbonylmethyl-1-phenyl-8- (1-phenylcyclohexyl), 3,8-triazaspiro [4.51decan-4-one] A mixture of 3-f-butoxycarbonylmethyl-1-phenyl-8- (1-phenyl-cycloheptyl) -1,3,8-triazaspiro [4.5] decan-4-one (prepared in preparation 4, 100 mg, 0.193 mmol) ) and HCl solution in methanol (10 ml) was stirred at 60 ° C for 16 h. After evaporation of the solvent, the residue was basified with 25% NH 4 OH and extracted with CH 2 Cl 2. The combined extracts were dried (Na2SO4), filtered, and concentrated. The residue was purified by preparative TLC (1 mm x 2 plate, hexane / acetone: 5/2) to give 68.8 mg (75.1%) of the title compound as an amorphous white solid. 1 H NMR (270 MHz, CDCl 3) d 7.56-7.50 (2H, m), 7.34-7.14 (5H, m), 6.98-6.83 (3H, m), 4.72 (2H, s), 4.16 (2H, s), 3.75 (3H, s), 2.95-2.72 (4H, m), 2.58-2.42 (2H, m), 2.20-1.99 (4H, m), 1.85-1.40 (1 OH, m). This compound was converted to the addition salt of HCl by treatment with HCl solution in methanol. IR (KBr): 3391, 1747, 1699 crn "1 Analysis, calculated for C29H37N303 HCl: C, 68.02; H, 7.48; N, 8.21, Found: C, 67.69; H, 7.51; N, 8.17. The compounds of formula (I) prepared in Examples 1 to 12 are summarized in the following table.

PICTURE Example R1 No. R¿ R X 1 cycloheptyl hydrogen phenyl phenyl 2 cycloheptyl aminopropyl phenyl phenyl 3 cycloheptyl piperidinylethyl phenyl phenyl 4 cycloheptyl hydrogen methyl phenyl cycloheptyl piperidinylethyl methyl phenyl 6-cycloheptenyl hydrogen methyl phenyl 7 cyclohexyl hydrogen benzyl phenyl 8 cycloheptyl aminopropyl methyl phenyl 9 cycloheptyl aminohex-6-yl phenyl phenyl cycloheptyl aminohex-6-yl methyl phenyl 11 cycloheptyl 2- (4-amino-piperidinyl-1 • -yl) ethyl phenyl phenyl 12 cycloheptyl methoxycarbonylmethyl phenyl phenyl

Claims (9)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the following formula: or its pharmaceutically acceptable salt, wherein R 1 and R 2 are independently C 1 -C 4 alkyl; or R1 and R2, taken together with the carbon atom to which they are attached, form a mono-, bi-, tri- or spiro-cyclic group having 3 to 13 carbon atoms, in which the cyclic group is optionally substituted with one to five substituents independently selected from halo, C4 alkyl, C2-C alkenyl, C4 alkoxy, hydroxy, oxo, = CH2 and = CH-CrC4 alkyl, with the proviso that the bi- or tri-cyclic group does not it is a benzocondensed ring; A is C7 alkyl, C2-C5 alkenyl, C2-Cs alkynyl, C1-C5 phenylalkyl, phenyl or heteroaryl selected from furyl, thienyl, pyrrolyl and pyridyl, in which phenyl and heteroaryl are optionally substituted with one to three substituents selected from halo, C 1 alkyl and C 1 -C 3 alkoxy; R is hydrogen, C? -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, CrC6 alkanoyl, (C4 alkyl) -Z-CrC6 alkyl, (C3-C cycloalkyl) -Z-CrC6 alkyl , heterocycloalkyl CrC6, phenyl-alkyl

CrC6, heterocycle- (CrC6 alkyl) -Z-CrCß alkyl, phenyl- (CrC6 alkyl) -Z-alkyl

CI-CT, heterocycle-Z-alkyl CrC6, (C3-C7 cycloalkyl) -heterocycle-alkyio CrC6 > heterocycle-heterocycle-C-Cd alkyl, in which the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclic groups are optionally substituted with one to three substituents selected from halo, hydroxy, amino, guanizine, carboxy, amidino, ureido, CrC3 alkyl , C1-C3 alkoxy, and mono- or di-alkylamino CrC4, and in which Z is O, S, SO, SO2, CO,

C (= 0) 0, OC (= 0), N (R), C (= 0) N (R) or N (R) CO; and X is phenyl, heterocycle, CrC6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C2-C7 alkynyl, in which the phenyl, heterocyclic, alkyl, alkenyl, cycloalkyl and alkynyl groups are optionally substituted with one to three selected substituents of halo, C1-C3 alkyl and C1-C3 alkoxy. 2. A compound according to claim 1, wherein R1 and R2 are independently CrC4 alkyl; or R1 and R2, taken together with the carbon atom to which they are attached, form a monocyclic group selected from C3-C13 cycloalkyl and C3-C13 cycloalkenyl, in which the monocyclic group is optionally substituted with one or two substituents independently selected from halo and CrC4 alkyl; A is phenyl-C1-C5 alkyl or phenyl optionally substituted with one to three substituents independently selected from halo, C1-C3 alkyl and C1-C3 alkoxy; R is hydrogen, CrCß alkyl, C2-C6 alkenyl, heterocyclo-d-Cß alkyl or (C 4 alkyl) -Z-CrCβ alkyl, in which the alkyl, alkenyl and heterocyclic groups are optionally substituted with one to three substituents selected from halo, hydroxy, amino, guanizino, carboxy, amidino, ureido, C1-C3 alkyl, C1-C3 alkoxy, mono- and di-alkylamino CrC4; and X is phenyl, heterocycle, C 1 -C 6 alkyl or C 2 -C 6 alkenyl, in which the phenyl, heterocycle, alkyl and alkenyl groups are optionally substituted with one to three substituents selected from halo, C 3 alkyl and C 1 -C 3 alkoxy. 3. A compound according to claim 2, wherein

R1 and R2, taken together with the carbon atom to which they are attached, form a monocyclic group selected from C5-C10 cycloalkyl and C5-C10 cycloalkenyl, in which the monocyclic group is optionally substituted with one or two independently selected substituents of C1-C3 alkyl; A is phenyl or benzyl; R is hydrogen, C1-C3 alkyl, amino-CrCß alkyl, heterocyclo C1-C3 alkyl in which the heterocyclic group is optionally substituted with amino or (CrC4 alkyl) -Z-C-Cß alkyl in which Z is OC (= 0); and X is C1-C3 alkyl or phenyl. 4. A compound according to claim 3, in which R1 and R2, taken together with the carbon atom to which they are attached, form cyclohexyl, cycloheptyl or cycloheptenyl; A is phenyl or benzyl; R is hydrogen, aminopropyl, aminohexyl, piperidinylethyl, 4-aminopiperidinylethyl or methoxycarbonylmethyl; and X is phenyl. 5. A compound according to claim 1, selected from 3- (3-aminopropyl) -1-phenyl-8- (1-phenylcycloheptyl) -1,3,8-triazaspiro [4.5] decan-4-one; 8- (1-methylcycloheptyl) -1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one; and their pharmaceutically acceptable salts.

6. A pharmaceutical composition for the treatment of a disorder or condition mediated by the ORL1 receptor and its endogenous ligands in a mammal including a human, or to anesthetize a mammal including a human being, comprising an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

7. A pharmaceutical composition for the treatment of a disorder or condition selected from the group consisting of inflammatory diseases, hyperalgesia related to inflammation, disorders of food intake, arterial blood pressure disorders, tolerance to narcotic analgesics, dependence on narcotic analgesics, anxiety, stress disorders, psychic trauma, schizophrenia, Parkinson's disease, chorea, depression, Alzheimer's disease, dementias, epilepsy and seizures, useful as analgesic, anesthetic, neuroprotective agent or analgesic enhancer, or useful for controlling water balance, regulating the ear, controlling the excretion of sodium ion or improving brain function, comprising an amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, which is effective in treating said disorder or condition in a mammal including a human being hand, and a pharmaceutically acceptable vehicle.

8. - The use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a disorder or condition, or anesthetizing a mammal including a human, whose treatment and anesthesia can be effected or facilitated by ORL1 receptor activation.

9. The use of a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier for the manufacture of a medicament for treating a disorder or condition that is selected from the group consisting of inflammatory diseases, hyperalgesia related to inflammation , disorders of food intake, arterial blood pressure disorders, tolerance to narcotic analgesics, dependence on narcotic analgesics, anxiety, stress disorders, psychic trauma, schizophrenia, Parkinson's disease, chorea, depression, Alzheimer's disease, dementias, epilepsy and seizures, or to anesthetize a mammal including a human being, or to relieve pain, produce a neuroprotective effect, intensify analgesics, control water balance, regulate the ear, control the excretion of sodium ion or improve brain function in a mammal including a human being.