MX2008010039A - 3,9-diazabicyclo[3.3.1]nonane derivatives and their use as monoamine neurotransmitter re-uptake inhibitors - Google Patents

Abstract

This invention relates to novel 3,9-diazabicyclo[3.3.1]nonane derivatives useful as monoamine neurotransmitter re-uptake inhibitors. In other aspects the invention relates to the use of these compounds in a method for therapy and to pharmaceutical compositions comprising the compounds of the invention.

Description

DERIVATIVES OF 3, 9-DIAZABICICLO [3.3. IONONONE AND ITS USE AS INHIBITORS OF RE-CAPTATION OF THE MONOAMINE NEUROTRANSMITTER FIELD OF THE INVENTION This invention relates to derivatives of 3,9-diazabicyclo [3.3. l] nonane novel agents useful as inhibitors of re-uptake of the monoamine neurotransmitter. In other aspects the invention relates to the use of these compounds in a method for therapy and pharmaceutical compositions which comprise the compounds of the invention. BACKGROUND OF THE INVENTION Selective Serotonin Reuptake Inhibitors (SSRIs) currently provide efficacy in the treatment of several severe CNS disorders, including depression and panic disorder. SSRIs are generally perceived as effective, well tolerated and easily administered by psychiatrists and general practitioners. However, they are associated with a number of undesirable characteristics. Thus, there is still a strong need for compounds with an optimized pharmacological profile with respect to the activity in the reuptake of the monoamine neurotransmitters serotonin, dopamine and noradrenaline, such as proportion of serotonin reuptake activity against reuptake of REF. : 194019 noradrenaline and dopamine. United States Patent 3,196,154 (Sterling Drug Inc.) discloses 3-substituted-9-methyl-3,9-diazabicyclo [3.3. ljnonanos. The compounds 9-methyl-3-phenyl-3,9-diazabicyclo [3.3. ljnonanos and 3- (3-chloro-4-methylphenyl) -9-methyl-3,9-diazabicyclo [3.3. l] nonane. Fales H M and Barnes R A [J. Am. Chem. Seo .; 1954; 76 (7); 1947-48] describe the synthesis of 9-methyl-3,9-diazatricyclo [3.3.1.23 '9] undecane. The synthesis of picrate compound of N-picrile of 9-methyl-3,9-diazabicyclo [3.3. ljnonano. SUMMARY OF THE INVENTION In a first aspect, the invention provides a compound of Formula I: any of its isomers or any mixture of its isomers, or a pharmaceutically acceptable salt thereof; where Ra and R are as defined later. In its second aspect, the invention provides a pharmaceutical composition, which comprises a therapeutically effective amount of a compound of the invention, any of its isomers or any mixture thereof. isomers, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, excipient or diluent. In a further aspect, the invention provides the use of a compound of the invention, any of its isomers or any mixture of its isomers, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the treatment, prevention or alleviation of a disease or disorder or condition of a mammal, including a human, in which the disease, disorder or condition is receptive to the inhibition of reuptake of the monoamine neurotransmitter in the central nervous system. In a still further aspect, the invention relates to a method for the treatment, prevention or alleviation of a disease or disorder or condition of a living animal body, including a human, disorder, disease or condition that is responsive to the inhibition of reuptake of the monoamine neurotransmitter in the central nervous system, the method which comprises the step of administering to such a living animal body in need thereof a therapeutically effective amount of a compound of the invention, any of its isomers or any mixture of its isomers, or a pharmaceutically acceptable salt thereof.

Other objects of the invention will be apparent to the person skilled in the art from the following detailed description and examples. DETAILED DESCRIPTION OF THE INVENTION Derivatives of 3, 9-diazabicyclo [3.3. ljnonano In its first aspect, the invention provides compounds of Formula I: any of its isomers or any mixture of its isomers, or a pharmaceutically acceptable salt thereof, wherein Ra represents hydrogen or alkyl; alkyl which is optionally substituted with one or more substituents independently selected from the group consisting of: halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, nitro, alkoxy, cycloalkoxy, alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl and alkynyl; and Rb represents a monocyclic or bicyclic aryl group; the aryl group which is optionally substituted with one or more substituents independently selected from the group which consists of: halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, alkoxy, cycloalkoxy, alkoxyalkyl, cycloalkoxyalkyl, methylenedioxy, ethylenedioxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, sulfanyl, thioalkoxy, -NR'R ", - (C = 0) NR'R "and -NR '(C = 0) R"; wherein R' and R "independently of each other are hydrogen or alkyl; with the proviso that the compound is not 9-methyl-3-phenyl-3,9-diazabicyclo [3.3. l] nonane; 3- (3-Chloro-4-methylphenyl) -9-methyl-3,9-diazabicyclo [3.3. ljnonanos; or 9 -methyl -3- (2,4,6-trinitrophenol) -3,9-diazabicyclo [3.3. l] nonane. In one embodiment, R represents hydrogen or alkyl. In a special embodiment, Ra represents hydrogen. In a further embodiment, Ra represents alkyl, such as methyl. In a further embodiment, Rb represents a monocyclic aryl group; the aryl group which is optionally substituted with one or more substituents independently selected from the group consisting of: halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, alkoxy, cycloalkoxy, alkoxyalkyl, cycloalkoxyalkyl, methylenedioxy, ethylenedioxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, -NR'R ", - (C = 0) NR'R" or -NR '(C = 0) R ", wherein R' and R" independently of each other are hydrogen or alkyl. In a still further embodiment, Rb represents a phenyl group, the phenyl group which is optionally substituted with one or more substituents independently selected from the group which consists of: halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, and methylenedioxy. In yet a further embodiment, Rb represents a phenyl group, the phenyl group which is optionally substituted with one or more substituents independently selected from the group which consists of: halo, trifluoromethyl, trifluoromethoxy, cyano, nitro and alkoxy. In a further embodiment, Rb represents a phenyl group, the phenyl group which is substituted once or twice with substituents independently selected from the group consisting of: halo, trifluoromethyl, trifluoromethoxy, cyano, nitro and alkoxy. In a special embodiment, Rb represents dihalophenyl, such as dichlorophenyl or chlorofluorophenyl, such as 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl or 4-chloro-3-fluorophenyl. In a further embodiment, R represents halophenyl, such as 4-halophenyl, bromophenyl or chlorophenol, such as 4-bromophenyl or 4-chlorophenyl. In a further embodiment, Rb represents a group phenyl, the phenyl group which is substituted with methylenedioxy, such as benzo [l, 3] dioxolyl, such as benzo [l, 3] dioxol-5-yl. In a still further embodiment, Rb represents a bicyclic aryl group; the aryl group which is optionally substituted with one or more substituents independently selected from the group consisting of: halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, alkoxy, cycloalkoxy, alkoxyalkyl, cycloalkoxyalkyl, methylenedioxy, ethylenedioxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, sulfanyl, thioalkoxy, -NR'R ", - (C = 0) NR'R" or -NR '(C = 0) R "; wherein R' and R" independently of each other are hydrogen or alkyl. In a further embodiment, Rb represents a naphthyl group, the naphthyl group which is optionally substituted with one or more substituents independently selected from the group which consists of: halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxyl, alkoxy, alkoxyalkyl and methylenedioxy. In a further embodiment, Rb represents a naphthyl group, the naphthyl group which is optionally substituted with one or more substituents independently selected from the group which consists of: halo, trifluoromethyl, trifluoromethoxy, cyano, nitro and alkoxy. In a further embodiment, Rb represents a naphthyl group, the naphthyl group which is substituted once with a substituent selected from the group which consists of: halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, alkoxy and alkoxyalkyl. In a still further embodiment, Rb represents a naphthyl group, the naphthyl group which is substituted once with a substituent selected from the group which consists of halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy and alkoxy. In a special embodiment, Rb represents alkoxynaphthyl, such as methoxynaphthyl, ethoxynaphthyl or isopropoxy naphthyl, such as 6-methoxy-naphthalene-2-yl, 7-methoxy-naphthalene-2-yl, 6-ethoxy-naphthalene-2-yl or 6-isopropoxy-naphthalen-2-yl. In a further embodiment, Rb represents alkoxyalkylnaphthyl, such as alkoxymethylnaphthyl, such as methoxymethylnaphthyl, such as 6-methoxymethylnaphthalen-2-yl. In a still further embodiment, Rb represents hydroxynaphthyl, such as 6-hydroxynaphthalen-2-yl, or 7-hydroxynaphthalen-2-yl. In a further embodiment, Rb represents dihydroxynaphthyl, such as 6,7-dihydroxy-naphthalen-2-yl. In a further embodiment, Rb represents a naphthyl group which is substituted with methylenedioxy, such as naphtho [2, 3-d] [1,3] dioxolyl, such as naphtho [2, 3-d] [1,3] dioxol-6-yl. In a special embodiment, the compound of the invention is 3- (3,4-dichloro-phenyl) -9-methyl-3,9-diaza-bicyclo [3.3. ljnonano; 3-benzo [l, 3] dioxol-5-yl-9-methyl-3,9-diaza-bicyclo [3.3. ljnonano; 3 - (4-bromo-phenyl) -9-methyl-3, 9-diaza-bicyclo [3.3. ljnonano; 3 - (4-chloro-phenyl) -9-methyl-3,9-diaza-bicyclo [3.3. ljnonano; 3- (4-chloro-3-fluoro-phenyl) -9-methyl-3,9-diaza-bicyclo [3.3. ljnonano; 3- (3-chloro-4-fluoro-phenyl) -9-methyl-3,9-diaza-bicyclo [3.3. ljnonano; 3- (3,4-dichloro-phenyl) -3,9-diaza-bicyclo [3.3. ljnonano; 3-benzo [l, 3-dioxol-5-yl-3, 9-diaza-bicyclo [3.3. ljnonano; 3- (4-bromo-phenyl) -3,9-diaza-bicyclo [3.3. ljnonano; -chloro-phenyl) -3,9-diaza-bicyclo [3.3. ljnonano; 3- (4-chloro-3-fluoro-phenyl) -3,9-diaza-bicyclo [3.3. ljnonano; 3- (3-chloro-4-fluoro-phenyl) -3,9-diaza- bicycle [3.3. ljnonano; 3- (6-methoxy-naphthalen-2-yl) -9-methyl-3,9-diaza-bicyclo [3.3. ljnonano; 3- (6-methoxymethyl-naphthalen-2-yl) -9-methyl-3,9-diaza-bicyclo [3.3. ljnonano; 3- (9-methyl-3,9-diaza-bicyclo [3.3.1] non-3-yl) -naphthalen-2-ol; 3- (6-isopropoxy-naphthalen-2-yl) -9-methyl-3,9-diaza-bicyclo [3.3. ljnonano; 6- (9-methyl-3, 9-diaza-bicyclo [3.3.1] non-3-yl) -naphthalene-2,3-diol; 9-methyl-3-naphtho [2,3-d] [1, 3] dioxol-6-yl-3, 9-diaza-bicyclo [3.3. l] nonane; 3- (6-ethoxy-naphthalen-2-yl) -9-methyl-3,9-diaza-bicyclo [3.3. ljnonano; 3- (7-methoxy-naphthalen-2-yl) -9-methyl-3,9-diaza-bicyclo [3.3. ljnonano; 7- (9-methyl-3,9-diaza-bicyclo [3.3.1] non-3-yl) -naphthalen-2-ol; or a pharmaceutically acceptable salt thereof. Any combination of two or more of the embodiments as described above is considered to be within the scope of the present invention.

Definition of substituents In the context of this invention halo represents fluorine, chlorine, bromine or iodine. In the context of this invention, an alkyl group designates a saturated or univalent linear or branched hydrocarbon chain. The hydrocarbon chain preferably contains from one to six carbon atoms (Ci-6 alkyl), including pentyl, isopentyl, neopentyl, tertiary pentyl, exyl and isohexyl. In a preferred embodiment alkyl represents a C 1 -C 4 alkyl group, including butyl, isobutyl, secondary butyl, and tertiary butyl. In another preferred embodiment of this invention alkyl represents a C1-3 alkyl group, which may in particular be a methyl, ethyl, propyl or isopropyl. In the context of this invention an alkenyl group designates a carbon chain which contains one or more double bonds, including di-ions, tri-ions and poly-ions. In a preferred embodiment the alkenyl group of the invention comprises from two to six carbon atoms (C2-6 alkenyl) including at least one double bond. In a more preferred embodiment the alkenyl group of the invention is ethenyl; 1- or 2-propenyl; 1-, 2-, or 3-butenyl, or 1,3-butadienyl, 1-, 2-, 3-, 4- or 5-hexenyl, or 1,3-hexadienyl, or 1, 3, 5-hexatrienyl. In the context of this invention an alkynyl group designates a carbon chain which contains one or more triple bonds, including di-inas, tri-inas, and poly-inas. In a more preferred embodiment the alkynyl group of the invention comprises from two to six carbon atoms (C2-6 alkynyl) including at least one triple bond. In its most preferred embodiment, the alkynyl group of the invention is ethynyl; 1- or 2-propynyl; 1-, 2-, or 3-butynyl; or 1,3-butadinyl; 1-, 2-, 3-, 4-pentyl, or 1,3-pentadinyl; 1-, 2-, 3-, 4-, or 5-hexinyl, or 1,3-hexadinyl or 1,3, 5-hextrinyl. In the context of this invention a cycloalkyl group designates a cyclic alkyl group, which preferably contains from three to seven carbon atoms (cycloalkyl of C3.), Including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Alkoxy is O-alkyl, wherein alkyl is as defined above. Cycloalkoxy means O-cycloalkyl wherein cycloalkyl is as defined above. Cycloalkylalkyl means cycloalkyl as above, and alkyl as above, which means for example, cyclopropylmethyl. Thioalkoxy is -S-alkyl, wherein alkyl is as defined above. In the context of this invention a monocyclic aryl group designates an aromatic ring system monocyclic carbocyclic such as phenyl. In the context of this invention a bicyclic aryl group designates a bicyclic carbocyclic aromatic ring system such as naphthyl. Pharmaceutically acceptable salts The chemical compound of the invention can be provided in any suitable form for the proposed administration. Suitable forms include pharmaceutically (i.e., physiologically) acceptable salts and pre- or prodrug forms of the chemical compound of the invention. Examples of pharmaceutically acceptable addition salts include, without limitation, the non-toxic inorganic and organic acid addition salts such as the hydrochloride, the bromohydrate, the nitrate, the perchlorate, the phosphate, the sulfate, the formate, the acetate, the acetone, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, embonate, enanthate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene, 2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, toluene-p-sulfonate, and the like. Such salts can be formed by methods well known and described in the art. Other acids such as oxalic acid, which can not be considered pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates for obtaining a chemical compound of the invention and its pharmaceutically acceptable acid addition salt. Examples of pharmaceutically acceptable cationic salts of a chemical compound of the invention include, without limitation, the salt of sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, choline, Licinio, and ammonium and the like. Such cationic salts may be by methods well known and described in the art. In the context of this invention the "onium salts" of N-containing compounds are also contemplated as pharmaceutically acceptable salts. Preferred "onium salts" include the alkyl-onium salts, the cycloalkyl-onium salts, and the cycloalkylalkyl-onium salts. Examples of pre or profarmamic forms of the chemical compound of the invention include examples of suitable prodrugs of the substances according to the invention and include compounds modified in one or more reactive or derivable groups of the parent compound. Of particular interest are compounds modified in a carboxyl group, a hydroxyl group, or an amino group. Examples of suitable derivatives are esters or amides. The chemical compound of the invention can be provided in dissolvable or indissoluble forms together with a pharmaceutically acceptable solvent such as water, ethanol and the like. Dissolvable forms can also include hydrated forms such as the monohydrate, the dihydrate, the hemihydrate, the trihydrate, the tetrahydrate, and the like. In general, dissolvable forms are considered equivalent to indissoluble forms for the purpose of this invention. Isomers It will be appreciated by those skilled in the art that the compounds of the present invention can exist in different stereoisomeric forms, including enantiomers, diastereomers, and cis-trans isomers. The invention includes all such isomers and any mixtures thereof including racemic mixtures. The racemic forms can be resolved in the optical antipodes by known methods and techniques. One way to separate the isomeric salts is by the use of an optically active acid, and by releasing the optically active amine compound by treatment with a base. Another method for resolving racemic mixtures in optical antipodes is based on chromatography in an optical active matrix. The racemic compounds of the present invention can thus be resolved in their optical antipodes, for example by fractional crystallization of d- or (tartrate) salts. raandelatos or camphor sulfonate) for example. The chemical compounds of the present invention can also be resolved by the formation of diastereomeric amides by reaction of the chemical compounds of the present invention with an optically active activated carboxylic acid such as that derivative of (+) or (-) phenylalanine, (+ ) or (-) phenylglycine, (+) or (-) cananic acid or by the formation of diastereomeric carbamates by reaction of the chemical compound of the present invention with an optically active chloroformate or the like. Additional methods for resolving the optical isomers are known in the art. Such methods include those described by Jaques J. Collet A, & Wilen S in "Enantiomers, Racemates and Resolutions", John Wiley and Sons, New York, (1981). The optical active compounds can also be prepared from the optical active starting materials. Labeled compounds The compounds of the invention can be used in their labeled or unlabeled form. In the context of this invention the tagged compound has one or more atoms replaced by an atom which has an atomic mass or mass numbers different from the atomic mass or mass number usually found in nature. The labeling It will easily allow the quantitative detection of the compound. The labeled compounds of the invention may be useful as diagno tools, radiotracers, or monitoring agents, in various diagno methods, and for in vivo receptor imaging. The labeled isomer of the invention preferably contains at least one radionuclide as a label. Radionuclides that emit positrons are all candidates for use. In the context of this invention the radionuclide is preferably selected from 2H (deuterium), 3H (tritium). 13C, 14C, 131I, 125I, 12L and 18F. The physical method for detecting the labeled isomer of the present invention can be selected from positron emission tomography (PET). Computed tomography of simple photon imaging (SPECT), magnetic resonance spectroscopy (MRS), magnetic resonance imaging (MRI), and computed tomography. computerized axial X-rays (CAT), or combinations thereof. Methods of Preparation The chemical compounds of the invention can be prepared by conventional methods for chemical synthesis, for example those described in the working examples.

The starting materials for the processes described in the present application are known or can be readily prepared by methods known from commercially available chemicals. Also a compound of the invention can be converted to another compound of the invention using conventional methods. The terminal products of the reactions described herein can be isolated by conventional techniques, for example by extraction, crystallization, distillation, chromatography, etc. Biological Activity The compounds of the invention can be tested for their ability to inhibit the reuptake of monoamines, dopamine, noradrenaline and serotonin in synaptosomes, for example, as described in the application WO 97/30997. Based on the balanced activity observed in these tests the compound of the invention is considered useful for the treatment, prevention or alleviation of a disease or disorder or condition of a mammal, including a human, disease, disorder, or condition that it is responsive to inhibition of reuptake of the monoamine neurotransmitter in the central nervous system. In a special embodiment, the compounds of the invention are considered useful for the treatment, prevention or relief of a mood disorder, depression, atypical depression, depression secondary to pain, major depressive disorder, dysthymic disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothal disorder, mood disorder due to a general medical condition, substance-induced mood disorder, pseudodementia, Ganser syndrome, obsessive-compulsive disorder, panic disorder, panic disorder without agoraphobia, panic disorder with agoraphobia, agoraphobia without a history of panic disorder, attack of panic, memory deficit, memory loss, attention deficit hyperactivity disorder, obesity, anxiety, generalized anxiety disorder, eating disorder, Parkinson's disease, parkinsonism, dementia, dementia due to aging, senile dementia, Alzheimer's disease, complex of dementia of acquired immunodeficiency syndrome, memory dysfunction aging, specific phobia, social phobia, social anxiety disorder, post-traumatic stress disorder, acute stress disorder, drug addiction, drug abuse, cocaine abuse, nicotine abuse, tobacco abuse, alcohol addiction , alcoholism, kleptomania, pain, chronic pain, inflammatory pain, neuropathic pain, migraine pain, tension type headache, chronic tension type headache, pain associated with depression, fibromyalgia, arthritis, osteoarthritis, rheumatoid arthritis, back pain, pain from cancer, irritable bowel pain, irritable bowel syndrome, post-operative pain, post-mastectomy pain syndrome (PMPS), post-infarct pain, drug-induced neuropathy, diabetic neuropathy, sympathetically maintained pain, trigeminal neuralgia, dental pain, myofacial pain, phantom limb pain, bulimia, pre-menstrual syndrome, premenstrual dysphoric syndrome, late luteal phase syndrome, post-traumatic syndrome, chronic fatigue, urinary incontinence, stress incontinence, urge incontinence, nocturnal incontinence, sexual dysfunction, premature ejaculation, erectile difficulty, erectile dysfunction, premature female orgasm, tired legs syndrome, periodic limb movement disorder, eating disorders, anorexia nervous, sleep disorders, developmental disorders penetrates Autism, autism, Asperger's disorder, Rett's disorder, disintegrated childhood disorder, learning difficulties, motor experience disorders, mutism, trichotillomania, narcolepsy, post-infarct depression, infarct-induced brain damage, infarct-induced neuronal damage, disease of Gilles de la Tourettes, tinnitus, tic disorders, bodily dysmorphic disorders, oppositional defiant disorder or post-infarct disabilities. In a modality preferred, the compounds are considered useful for the treatment, prevention or relief of depression. It is contemplated herein that a suitable dosage of the active pharmaceutical ingredient (API) is within the range of about 0.1 to about 1000 mg API per day, more preferably about 10 to about 500 mg API per day, more preferred from about 30 to about 100 mg of API per day, depending, however, on the exact mode of administration, the form in which it is administered, the indication considered, the subject and in particular the body weight of the subject involved, and also the preference and experience of the doctor or veterinarian in charge. The preferred compounds of the invention show a biological activity in the submicromolar and micromolar range, ie below 1 to about 100 μM. Pharmaceutical Compositions In another aspect the invention provides novel pharmaceutical compositions which comprise a therapeutically effective amount of the chemical compound of the invention. While a chemical compound of the invention for use in therapy can be administered in the form of the unpurified chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a salt pharmaceutically acceptable, in a pharmaceutical composition together with one or more customary adjuvants, excipients, carriers, buffers, diluents and / or other auxiliaries. In a preferred embodiment, the invention provides pharmaceutical compositions which comprise the chemical compound of the invention, or a pharmaceutically acceptable salt or derivative thereof, together with one or more pharmaceutically acceptable carriers, and optionally, other therapeutic and / or prophylactic ingredients, known and used in the art. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof. The pharmaceutical compositions of the invention may be those suitable for oral, rectal, bronchial, nasal, pulmonary, topical (including buccal and sublingual), transdermal, vaginal or parental (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, injection, intracerebral, intraocular or infusion), or those in a form suitable for administration by inhalation or insufflation, including powders and administration of liquid aerosol, or by sustained release systems. Suitable examples of sustained release systems include semi-permeable matrices of solid hydrophobic polymers which contain the compound of the invention, the matrices which may be in the form of shaped articles, for example films or microcapsules. The chemical compound of the invention, together with a conventional adjuvant, carrier, or diluent, can thus be placed in the form of pharmaceutical compositions and unit doses thereof. Such forms include solids, and in particular tablets, filled capsules, powder and granule forms, and liquids, in particular aqueous or non-aqueous solutions, suspensions, emulsions, elixirs and capsules filled therewith, all for oral use, suppositories for administration rectal, and sterile injectable solutions for parental use. Such pharmaceutical compositions and dosage unit forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such dosage unit forms may contain any suitable effective amount of the comminuted active ingredient with the range of daily dose proposed to be employed. The chemical compound of the present invention can be administered in a wide variety of oral and parental dosage forms. It will be obvious to those skilled in the art that the following dosage forms may understand, as the active component, either a chemical compound of the invention or a pharmaceutically acceptable salt of a chemical compound of the invention. To prepare the pharmaceutical compositions from a chemical compound of the present invention, the pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, wafers, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In the powders, the carrier is a finely divided solid, which is in admixture with the finely divided active component. In tablets, the active component is mixed with the carrier which has the necessary binding capacity in suitable proportions and compacted in the desired shape and size. The powders and tablets preferably contain from five to ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is proposed to include the formulation of the active compound with encapsulating material as a carrier which provides a capsule in which the active component, with or without carriers is surrounded by a carrier, which is thus in association with the same. Similarly, wafers and pills are included. Tablets, powders, capsules, pills, wafers, and lozenges can be used as solid forms suitable for oral administration. To prepare the suppositories, a low melting wax, such as a mixture of fatty acid glyceride or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by agitation. The molten homogeneous mixture is then emptied into molds of suitable size, allowed to cool and thereby solidify. Compositions suitable for vaginal administration can be presented as ovules, tampons, creams, gels, pastes, foams or dispersions which also contain the active ingredient such carriers as are known in the art to be appropriate. Liquid preparations include solutions, suspensions, and emulsions, for example, water or solutions of water-propylene glycol. For example, liquid parental injection preparations can be formulated as solutions in aqs polyethylene glycol solution. The chemical compound according to the present invention can thus be formulated for parental administration (for example by injection, for example bolus injection or continuous infusion) and can be presented in the form of unit doses in ampoules, pre-filled syringes, infusion of small volume or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqs vehicles, and may contain the formulating agents such as suspending, stabilizing and / or dispersing agents.

Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from the solution, for constitution with a suitable vehicle, for example sterile, pyrogen-free water, before use. Aqs solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing agents and thickeners, as desired. Aqs suspensions suitable for oral use can be made by dispersing the active component finely divided in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents. Also included are solid form preparations, proposals for rapid conversion prior to use for liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. In addition to the active component such preparations may comprise colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like. For topical administration to the epidermis the chemical compound of the invention can be formulated as ointments, creams or lotions, or as a transdermal patch. The ointments and creams can, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. The lotions can be formulated with an aqueous or oily base and will generally also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents or coloring agents. Compositions suitable for topical administration in the mouth include lozenges which comprise the active agent in a flavor base, usually sucrose and acacia or tragacanth; Pills which comprise the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia and mouthwashes which comprise the active ingredient in a suitable liquid carrier. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or dispersion. The compositions can be provided in simple form or muítidosis. Administration to the respiratory tract can also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurized package with a suitable propellant such as chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane , carbon dioxide, or other suitable gas. The aerosol may also conveniently contain a surfactant such as lectin. The dose of the drug can be controlled by provision of a metering valve. Alternatively the active ingredients may be provided in the form of a dry powder, for example a powder mixture of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidone.

(PVP for its acronym in English). Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition can be presented in a unit dosage form for example in capsules or cartridges of, for example, gelatin, or ampoule packings from which the powder can be administered by means of an inhaler. In compositions proposed for administration to the respiratory tract, including intranasal compositions, the compound will generally have a small particle size for example of the order of 5 microns or less. Such particle size can be obtained by means known in the art, for example by micronization. When desired, compositions adapted to give sustained release of the active ingredient may be employed. The pharmaceutical preparations are preferably in dosage unit forms. In such form, the preparation is subdivided into unit doses which contain appropriate amounts of the active component. The dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packed tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, wafer or tablet by itself, or it can the appropriate number of any of these in the form packed . Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions. Additional details on the techniques for formulation and administration can be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publisching Co., Easton, PA). An effective dose therapeutically refers to that amount of the active ingredient, which improves the symptoms or condition. The therapeutic efficacy and toxicity, for example ED¾0 and LD¾0, can be determined by standard pharmacological procedures in cell cultures or experimental animals. The proportion of the dose between therapeutic and toxic effects is the therapeutic index and can be expressed by the LD50 / ED50 ratio. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dose administered must of course be carefully adjusted to the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and regimen, and the desired result, and the exact dose must of course be determined by the practitioner The current dose depends on the nature and severity of the disease being treated, and is within the discretion of the physician, and may be varied by titration of the dose to the particular circumstances of this invention to produce the desired therapeutic effect. However, it is presently contemplated that pharmaceutical compositions containing from about 0.1 to about 500 mg of active ingredient per single dose, preferably from about 1 to about 100 mg, more preferably from about 1 to about 10 mg, are suitable for therapeutic treatments. . The active ingredient can be administered in one or several doses per day. A satisfactory result can, in certain cases, be obtained in a dose as low as 0.1 g / kg i.v and 1 μg / kg p.o. The upper limit of the dose range is currently considered to be approximately 10 mg / kg i.v and 100 mg / kg p.o. Preferred ranges are from about 0.1 μg / kg to about 10 mg / kg / day i.v, and from about 1 μg / kg to about 100 mg / kg / day p.o. Methods of Therapy In another aspect the invention provides a method for the treatment, prevention or alleviation of a disease or disorder or condition of a living animal body, including a human, disease, disorder or condition. which is receptive to the inhibition of monoamine neurotransmitter reuptake in the central nervous system, and the method which comprises administering to such a living animal body, including a human, in need thereof an effective amount of a chemical compound of the invention. At the moment it is contemplated that the appropriate dose ranges are 0.1 to 1000 milligrams daily, 10-500 milligrams daily and especially 30-100 milligrams daily, depending as is usual on the exact mode of administration, the form in which it is administered, the indication to which addresses the administration, the subject involved and the body weight of the subject involved, and also the preference and experience of the doctor or veterinarian in charge. EXAMPLES The invention is further illustrated with reference to the following examples, which are not intended to be in any way limiting the scope of the invention as claimed. General: All reactions involving air-sensitive reagents or intermediates are carried out under nitrogen and in anhydrous solvents. Magnesium sulfate is used as a drying agent in development procedures and the solvents are evaporated under pressure : > _ > reduced. Method A [3- (3,4-Dichloro-phenyl) -9-methyl-3,9-diaza-bicyclo [3.3. l] nano fumaric A mixture of 9-methyl-3,9-diaza-bicyclo [3. 3. l] nonane (0.50 g, 3.56 mmol) and l-bromo-34-dichlorobenzene (1.61 g, 7.13 mmol), potassium tert-butoxide (0.80 g, 7.13 mmol), 2-dicyclohexylphosphino-2 ', 4', 6 '- triisopropyl-1, 1' -biphenyl (0.050) g, 0.105 mmole) and palladium (II) acetate (0.025 g, 0.111 mmole) at 110 ° C for 20 minutes. Water (30 ml) is added followed by extraction with ethyl lactate (3x10 ml). The organic phase is dried and evaporated. Purify the product without purification by silica gel column chromatography using a solvent mixture of dichloromethane, methanol and aqueous ammonia (18-1-1%). The pure product is isolated. Yield 211 mg (20%). The fumarate salt is precipitated from 1. 1 equivalent of fumaric acid and a mixture of ethanol and diethylether (2: 5). Melting point 187-189 ° C. LC-ESI-HRMS of [M + H] + shows 285,092 Da. Cale. 285.092529 Da, dev. -1.9 ppm. 3-benzo [l, 3] dioxol-5-yl-9-methyl-3,9-diaza-bicyclo [3.3. Inonium is prepared according to Method A. from 5-bromo-benzo [l, 3] dioxol. 3- (4-bromo-phenyl) -9-methyl-3,9-diaza-bicyclo [3.3. IJnonano It is prepared from method A from 1,4-dibromo-benzene. 3- (4-chloro-phenyl) -9-methyl-3,9-diaza-bicyclo [3.3. ljnonano It is prepared according to method A from 1-bromo-4-chloro-benzene. 3- (4-chloro-3-fluoro-phenyl) -9-methyl-3,9-diaza-bicyclo [3.3. ljnonano It is prepared according to method A from 4-bromo-l-chloro-2-fluoro-benzene. 3- (3-chloro-4-fluoro-phenyl) -9-methyl-3,9-diaza-bicyclo [3.3. ljnonano; It is prepared according to method A from 4-bromo-2-chloro-1-f luoro-benzene. Method B Salt of 3- (3,4-dichloro-phenyl) -3,9-diaza-bicyclo [3.3. l] nanohydrochloric acid is stirred under refluxing a mixture of 3- (3,4-dichloro-phenyl) -9-methyl-3,9-diazabicyclo [3.3. ljnonan (0.50 g, 1.7 mmol), 2, 2, 2-trichloroethylchloroformate (1.11 g, 5.26 mmol) and toluene (30 ml) for 15 hours. Water (30 ml) is added and the phases are separated. The organic phase is evaporated. Acetic acid (10 ml) and water (10 ml) and zinc powder (0.57 g, 8.8 mmol) are added. The mixture is stirred for 15 hours. Aqueous sodium hydroxide (20 ml, 1M) is added followed by Extraction with dichloromethane (3x10 ml). Purify the product without purification by silica gel column chromatography using a solvent mixture of dichloromethane, methanol and aqueous ammonia (9: 1: 1%). Yield 150 mg (32%). The corresponding salt is obtained by the addition of a mixture of hydrogen chloride dissolved in diethyl ether (1 ml, 2M). melting point 295.4 ° C. LC-ESI-HR S of [M + H] + shows 271.0769 Da. Cale. 271.076879 Da, dev. 0.1 ppm. 3-benzo [l, 3] dioxol-5-yl-3, 9-diaza-bicyclo [3.3. l] nonane Prepared according to method B from 3-benzo [l, 3] dioxol-5-yl-9-methyl-3,9-diazabicyclo [3.3. l] nonane. 3- (4-bromo-phenyl) -3,9-diaza-bicyclo [3.3. l] nonane. It is prepared according to method B from 3- (4-chloro-phenyl) -9-methyl-3,9-diaza-bicyclo [3.3. l] nonane. 3- (4-chloro-phenyl) -3,9-diaza-bicyclo [3.3. ljnonano It is prepared according to method B from 3- (4-chloro-phenyl) -9-methyl-3,9-diaza-bicyclo [3.3. ljnonano 3- (4-chloro-3-fl-oro-phenyl) -3,9-diaza-bicyclo [3.3. l] nonane is prepared according to method B from 3- (4-chloro-3-fluoro-phenyl) -9-methyl-3, 9-diaza-bicyclo [3.3. l] nonane. 3- (3-chloro-4-fluoro-phenyl) -3,9-diaza-bicyclo [3.3. ljnonano It is prepared according to Method B from 3- (3-chloro-4-f luoro-f-enyl) -9-methyl-3,9-diaza-bicyclo [3.3. ljnonano Method C Salt of 3- (6-methoxy-naph talen-2-yl) -9-methyl-3,9-diaza-bicyclo [3.3. Fummary ljnonano A mixture of 9-methyl-3,9-diazabicyclo [3.3. l] nonane (2.0 g, 14.3 mmol), 2-bromo-6-methoxynaph (5.07 g, 21.4 mmol), paladacycle (100 mg, 0.11 mmol), potassium tert-butoxide (3.2 g, 28.5 mmol) and dioxane. (30 mi) refluxing for 40 hours. The mixture is cooled to room temperature. Water (50 ml) is added and the mixture is extracted with ethyl acetate (3 x 30 ml). Purify the product without purification by silica gel column chromatography using a solvent mixture of di chloromethane, methanol and aqueous ammonia (18: 1: 1%). The fumarate salt is precipitated from 1.1 equivalents of fu aric acid and a mixture of ethanol and diethylether (2: 5). Yield 1.4 g (33%). Melting point 190.0-198.3 ° C. LC-ESI-HRMS of [M + H] + shows 297.1955 Da. Cale. 297.196688 Da, dev. -4 ppm. 3- (6-Methoxymethyl-naphthalen-2-yl) -9-methyl-3,9-diaza-bicyclo [3.3. Ljnonano fumaric It is prepared according to Method C starting from 2-bromo-6-methoxymethylnane taleno. LC-ESI-HRMS of [M + HJ + sample 311.2116 Da. Cale. 311.212338 Da, dev. -2.4 ppm. Free base of 6- (9-methyl-3,9-diaza-bicyclo [3.3.1] non-3-yl) -naphthalen-2-ol It is prepared according to Method C from 6-bromo-naphthalen-2-ol. LC-ESI-HRMS of [M + H] + shows 283.1801 Da. Cale. 283.181038 Da, dev. -3.3 ppm. Free base of 3- (6-isopropoxy-naphthalen-2-yl) -9-methyl-3, 9-diaza-bicyclo [3.3. l] nonane Prepared according to method C from 2-bromo-6-isopropoxy-naphthalene. LC-ESI-HRMS of [M + H] + shows 325.2288 Da. Cale. 325.227988 Da, dev. 2.5 ppm. 6- (9-methyl-3, 9-diaza-bicyclo [3.3.1] non-3-yl) -naphthalene-2,3-diol Prepared according to method C of 6-bromo-naphthalene-2, 3 -diol. 9-methyl-3-naphtho [2,3-d] [1, 3] dioxol-6-yl-3, 9-diaza-bicyclo [3.3. l] nonane Prepared according to method C from 6-bromo-naphtho [2,3-d) dioxol. 3- (6-ethoxy-naphthalen-2-yl) -9-methyl-3,9-diaza-bicyclo [3.3. l] nonane Prepared according to method C from 2-bromo-6-ethoxy-naphthalene. 3- (7-methoxy-naphthalen-2-yl) -9-methyl-3,9-diaza-bicyclo [3.3. l] nonano; It is prepared according to method C from 2-bromo-7-methoxy-naphthalene. 7 -. 7 - (9-methyl-3, 9-diaza-bicyclo [3.3.1] non-3-yl) -naf talen- 2 -ol Prepared according to Method C from 7-bromo-naph talen-2 -ol. (6-bromo-naphthalen-2-yl) -methane (intermediate) Methyl-6-bromo-2-naphthoate (25 g, 94.3 mmol) is reduced with lithium aluminum anhydride (5.35 g, 141.4 mmol) in tetrahydrofurane (200 ml). The crystalline product is recrystallized from ethanol (96%). Yield 15.84 (70.8%). 2-bromo-6-methyloxymethylene (intermediate) The iodomethane (18.96 g, 133.6 mmol) is added dropwise to an ice-cooled mixture of (6-bromo-naphthalen-2-yl) -methanol. (15.84 g, 66.8 mmol), 60% sodium hydride in oil (3.84 g, 100.2 mmol) and DMF (100 mL). The water is added and the product is filtered. Performance 16.7 (99%). Test Example Inhibition Activity vi A variety of compounds are tested for their ability to inhibit the reuptake of the monoamine neurotransmitters dopamine (DA for its acronym in English, noradrenaline (NA) and serotonin (5). -HT) in synaptosomes as described in the application WO 97/16451. The values of the test are given as IC50 (the concentration (μ) of the test substance which inhibits the specific binding of 3H-DA, 3H-NA, or 3H-5-HT by 50%). The results of the test obtained by testing selected co-positions of the present invention appear in the following table: It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (7)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A compound characterized in that it has the
2. Formula 1. any of its isomers or any mixture of its isomers, or a pharmaceutically acceptable salt thereof, wherein Ra represents hydrogen or alkyl; alkyl which is optionally substituted with one or more substituents independently selected from the group consisting of: halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, nitro, alkoxy, cycloalkoxy, alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl and alkynyl; and Rb represents a monocyclic or bicyclic aryl group; the aryl group which is optionally substituted with one or more substituents independently selected from the group which consists of: halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, alkoxy, cycloalkoxy, alkoxyalkyl, cycloalkoxyalkyl, methylenedioxy, ethylenedioxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, sulfañyl, thioalkoxy, -NR'R ", - (C = 0 ) NR'R "and -NR '(C = 0) R"; wherein R' and R "independently of each other are hydrogen or alkyl; with the proviso that the compound is not 9-methyl-3-phenyl-3,9-diazabicyclo ['3.3. l] nonane; 3- (3-Chloro-4-methylphenyl) -9-methyl-3,9-diazabicyclo [3.3. l] nonane; or 9-methyl-3- (2,4,6-trinitrophenol) -3,9-diazabicyclo [3.3. ljnonano. 2. The compound according to claim 1, characterized in that Ra represents hydrogen or alkyl. 3. The compound according to any of claims 1-2, characterized in that Rb represents a phenyl group, the phenyl group which is optionally substituted with one or more substituents independently selected from the group which consists of: halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, and methylenedioxy. 4. The compound in accordance with claims 1 or 2, characterized in that Rb represents a phenyl group, the phenyl group which is optionally substituted once or twice with substituents independently selected from the group consisting of: halo, tri fluoromethyl, trifluoromethoxy, cyano, nitro and alkoxy. The compound according to claim 1 or 2, characterized in that Rb represents a naphthyl group, the naphthyl group which is optionally substituted with one or more substituents independently selected from the group consisting of: halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, alkoxy, alkoxyalkyl and methylenedioxy. 6. The compound according to claim 1 or 2, characterized in that Rb represents a naphthyl group, the naphthyl group which is optionally substituted with one or more substituents independently selected from the group which consists of: halo, tri fluoromethylo, trifluoromethoxy, cyano, nitro, hydroxy, alkoxy and alkoxyalkyl. 7. The compound according to claim 1, characterized in that it is
3. 3- (3,
4. 4-Dichloro-phenyl) -9-methyl-3,9-diaza-bicyclo [3.3. ljnonano; 3-benzofl, 3] dioxol-
5. 5-yl-9-methyl-3,9-diaza-bicyclo [3.3. ljnonano; 3 - (4-bromo-phenyl) -9-methyl-3,9-diaza-bicyclo [3.3. l] nonane; 3- (4-chloro-phenyl) -9-methyl-3,9-diaza-bicyclo [3.3. ljnonano; 3- (4-chloro-3-fluoro-phenyl) -9-methyl-3,9-diaza-bicyclo [3.3. ljnonano; 3- (3-chloro-4-fluoro-phenyl) -9-methyl-3,9-diaza-bicyclo [3.3. ljnonano; 3- (3,4-dichloro-phenyl) -3,9-diaza-bicyclo [3.3. ljnonano; 3-benzofl, 3] dioxol-5-yl-3, -diaza-bicyclo [3.3. ljnonano; 3- (4-bromo-phenyl) -3,9-diaza-bicyclo [3.3. ljnonano; 3- (-chloro-phenyl) -3,9-diaza-bicyclo [3.3. ljnonano; 3 - (4-chloro-3-fluoro-phenyl) -3,9-diaza-bicyclo [3.3. ljnonano; 3- (3-chloro-4-fluoro-f-enyl) -3,9-diaza-bicyclo [3.3. ljnonano; 3 - (
6. 6-methoxy-naphthalen-2-yl) -9-methyl 1-3, 9-diaza-bicyclo [3.3. ljnonano; 3- (6-methoxymethyl-naphthalen-2-yl) -9-methyl-3, 9-diaza bicycle [3.3. l] nonane; 3- (9-methyl-3,9-diaza-bicyclol3.3.1] non-3-yl) -naphthalen-2-ol; 3- (6-isopropoxy-naphthalen-2-yl) -9-methyl-3,9-diaza-bicyclo [3.3. l] nonane; 6- (9-methyl-3,9-diaza-bicyclo [3.3.1] non-3-yl) -naphthalene-2,3-diol; 9-methyl-3-naphtho [2,3-dl [l, 3] dioxol-6-yl-3, 9-diaza-bicyclo [3.3. ljnonano; 3- (6-ethoxy-naphthalen-2-yl) -9-methyl-3,9-diaza-bicyclo [3.3. l] nonane; 3- (
7. 7-methoxy-naphthalen-2-yl) -9-methyl-3,9-diaza-bicyclo [3.3. l] nonane; 7- (9-methyl-3, 9-diaza-bicyclo | 3.3.1] non-3-yl) -naphthalen-2-ol; A pharmaceutical composition characterized in that it comprises a therapeutically effective amount of a compound according to any of claims 1-7, any of its isomers or any mixture of its isomers, or pharmaceutically acceptable salt thereof, together with at least a pharmaceutically acceptable carrier, excipient or diluent. 9. The use of a compound according to any of claims 1-7, any of its isomers or any mixture of its isomers, or a salt pharmaceutically acceptable thereof, for the manufacture of a medicament. The use according to claim 9, for the manufacture of a pharmaceutical composition for the treatment, prevention or alleviation of a disease or disorder or condition of a mammal, including a human, disease, disorder or condition that is receptive to the inhibition of reuptake of monoamine neurotransmitter in the central nervous system. The use according to claim 10, wherein the disease, disorder or condition is a mood disorder, depression, atypical depression, depression secondary to pain, major depressive disorder, dysthymic disorder, bipolar disorder, bipolar disorder I , bipolar disorder II, cyclothymic disorder, mood disorder due to a general medical condition, substance-induced mood disorder, pseudodementia, Ganser syndrome, obsessive-compulsive disorder, panic disorder, panic disorder without agoraphobia, disorder of panic with agoraphobia, agoraphobia without a history of panic disorder, panic attack, memory deficit, memory loss, attention deficit hyperactivity disorder, obesity, anxiety, generalized anxiety disorder, eating disorder, Parkinson's disease, parkinsonism dementia, dementia aging, senile dementia, Alzheimer's disease, dementia complex of acquired immunodeficiency syndrome, memory dysfunction at aging, specific phobia, social phobia, social anxiety disorder, post-traumatic stress disorder, acute stress disorder, addiction to drugs, drug abuse, cocaine abuse, nicotine abuse, tobacco abuse, alcohol addiction, alcoholism, kleptomania, pain, chronic pain, inflammatory pain, neuropathic pain, migraine pain, tension type headache, chronic tension type headache, pain associated with depression, fibromyalgia, arthritis, osteoarthritis, rheumatoid arthritis, back pain, cancer pain, irritable bowel pain, irritable bowel syndrome, post-operative pain, post-pain syndrome mastectomy (PMPS), post-infarction pain, drug-induced neuropathy, diabetic neuropathy, pain maintained sympathetic amente, trigeminal neuralgia, dental pain, myofacial pain, phantom limb pain, bulimia, pre-menstrual syndrome, premenstrual dysphoric syndrome, late luteal phase syndrome, post-traumatic syndrome, chronic fatigue syndrome, urinary incontinence, stress incontinence, incontinence due to desire, nocturnal incontinence, sexual dysfunction, premature ejaculation, erectile difficulty, erectile dysfunction, premature female orgasm, tired legs, periodic limb movement disorder, eating disorders, anorexia nervosa, sleep disorders, penetrating development disorders, autism, Asperger's disorder, Rett's disorder, disintegrated childhood disorder, learning difficulties, motor experience disorders, mutism, trichotillomania, narcolepsy, post-infarct depression, infarction-induced brain damage , infarct-induced neuronal damage, Gilles de la Tourettes disease, tinnitus, tic disorders, bodily dysmorphic disorders, oppositional defiant disorder or post-infarct disabilities.