DERIVATIVES OF 3-ARI OXY-8-AZA-BXCICLOE3.2.1] OCT-6-ENO AND THEIR USE AS INHIBITORS OF THE REASSURANCE OF 8JEUROTRANSMI OR SSONOAMSNA FIELD OF THE INVENTION This invention relates to new derivatives of 8-aza-bicyclo [3.2. l] oct-6-ene useful as resorption inhibitors of the neurotransmitter monoamine. 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. BACKGROUND OF THE INVENTION Selective Serotonin Reuptake Inhibitors (SSRIs) currently provide efficacy in the treatment of various CNS disorders, including depression and panic disorder. SSRIs are generally perceived by psychiatrists and primary care physicians as effective, well tolerated and easily administered. However, they are associated with a number of undesirable characteristics. Thus, there is still a strong need for compounds with an optimized pharmacological profile in regard to the activity on the reabsorption of the neurotransmitters monoamines serotonin, dopamine and noradrenaline, such as the ratio of the reabsorption of serotonin to the activity of reabsorption of Ref. No.: 187093
noradrenaline and dopamine. SUMMARY OF THE INVENTION In its 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, wherein R3 and Rb are as defined above. In its second aspect, the invention provides a pharmaceutical composition, comprising 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, 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 relief of a disease or disorder or condition of a mammal, including a human, whose disease,
disorder or condition responds to the inhibition of the reabsorption of the neurotransmitter monoamine in the central nervous system. In yet a 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, whose disorder, disease or condition responds to the inhibition of the reabsorption of the neurotransmitter monoamine in the central nervous system, which method comprises the step of administering to the living animal body in need thereof a therapeutically effective amount of a cut-off 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 the following examples. DETAILED DESCRIPTION OF THE INVENTION Derivatives of 8 = aza = bicyclo [3"2" l] oct-S-ene substituted In its first aspect the present invention provides compounds of formula I:
any of its isomers or any mixture of its
isomers, or a pharmaceutically acceptable salt thereof; wherein R8 represents hydrogen or alkyl; the alkyl 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, cycloalkylalkyl, alkenyl and alkynyl; And Rb represents an aryl group; the aryl group 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 one another are hydrogen or alkyl, In one embodiment, Ra represents hydrogen or alkyl.
a special modality, Ra represents hydrogen. In a further embodiment, Ra represents alkyl, such as methyl.
Still in a further embodiment, Rb represents a phenyl group, the phenyl group is optionally substituted with one or more substituents independently selected from the group consisting of: halo, trifluoromethyl, trifluoromethoxy, cyano and alkoxy. In a further embodiment, Rb represents a phenyl group, the phenyl group is substituted twice with substituents independently selected from the group consisting of: halo, trifluoromethyl, trifluoromethoxy, cyano and alkoxy. Still in a further embodiment, Rb represents a naphthyl group, the naphthyl group is optionally substituted with one or more substituents independently selected from the group consisting of: halo, trifluoromethyl, trifluoromethoxy, cyano and alkoxy. In a special embodiment, Rb represents a dihalophenyl, such as dichlorophenyl, such as 3,4-dichlorophenyl. In a further embodiment, R b represents a bromo-chlorophenyl, such as 3-bromo-4-chloro-phenyl or 4-bromo-3-chloro-phenyl. Still in a further embodiment, R represents a chloro-fluorophenyl, such as 3-chloro-4-fluoro-phenyl or 4-chloro-3-fluoro-phenyl. In a special additional modality, Rb represents a
alkoxy-naphthyl, such as methoxy-naphthyl, such as β-methoxy-naphthalen-2-yl. In a special embodiment the compound of the invention is exo-3- (3,4-dichloro-phenoxy) -8-aza-bicyclo [3.2.1] oct-6-ene; exo-3- (3-Bromo-4-chloro-phenoxy) -8-aza-bicyclo [3.2.1] oct-6-ene; exo-3- (6-Methoxy-naphthalen-2-yloxy) -8-aza-bicyclo [3.2. l] oct-6-ene; exo-3- (3-Chloro-4-fluoro-phenoxy) -8-aza-bicyclo [3.2.1] oct-6-ene; exo-3- (4-Bromo-3-chloro-phenoxy) -8-aza-bicyclo [3.2.1] oct-6-ene;. exo-3- (4-Chloro-3-fluoro-phenoxy) -8-aza-bicyclo [3.2.1] oct-6-ene; exo-3- (3,4-Dichloro-phenoxy) -8-methyl-8-aza-bicyclo [3.2.1] oct-6-ene; exo-3- (3-Bromo-4-chloro-phenoxy) -8-methyl-8-aza-bicyclo [3.2.1] oct-6-ene; exo-3- (6-Methoxy-naphthalen-2-yloxy) -8-methyl-8-aza-bicyclo [3.2.1] oct-6-ene; exo-3- (3-Chloro-4-fluoro-phenoxy) -8-methyl-8-aza-bicyclo [3.2.1] oct-6-ene; exo-3- (4-Bromo-3-chloro-phenoxy) -8-methyl-8-aza-bicyclo [3.2.1] oct-6-ene; exo-3- (4-Chloro-3-fluoro-phenoxy) -8-methyl-8-aza-bicyclo [3.2.1] oct-6-ene; or a pharmaceutically acceptable salt thereof. Any combination of two or more of the modalities
as described above it is considered 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, straight or branched univalent hydrocarbon chain. The hydrocarbon chain preferably contains from one to six carbon atoms (C? -6 alkyl), including pentyl, isopentyl, neopentyl, pentyl, hexyl and tertiary isohexyl. In a preferred embodiment alkyl represents a C 1 - alkyl group, including butyl, isobutyl, secondary butyl, and tertiary butyl. In another preferred embodiment of this invention, alkyl represents a C? _3 alkyl group, which may be in particular methyl, ethyl, propyl or isopropyl. In the context of this invention an alkenyl group designates a carbon chain containing 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 (C 2-6 alkenyl) / including at least one double bond. In an even 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 containing one or more triple bonds, including di-ions, tri-ions and poly-ions. In a preferred embodiment the alkynyl group of the invention comprises from two to six carbon atoms (C 2-6 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-butadiinyl; 1-, 2-, 3-, 4-pentynyl, or 1,3-phenytoinyl; 1-, 2-, 3-, 4-, or 5-hexinyl, or 1,3-hexadiinyl or 1, 3, 5-hexatriinyl. In the context of this invention a cycloalkyl group designates a cyclic alkyl group, preferably containing from three to seven carbon atoms
(C3_ cycloalkyl), 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, meaning for example, cyclopropylmethyl. In the context of this invention an aryl group designates an aromatic carbocyclic ring system such as phenyl, naphthyl (1-naphthyl or 2-naphthyl) or fluorenyl.
Pharmaceutically Acceptable Salts The chemical compound of the invention can be provided in any suitable form for the intended administration. Suitable forms include pharmaceutically (i.e., physiologically) acceptable salts, and pre-drug or prodrug forms of the chemical compound of the invention. Examples of pharmaceutically acceptable addition salts include, without limitation, non-toxic organic and inorganic acid addition salts such as hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulfate, formate, acetate, Aconate, 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. The salts can be formed by methods well known and described in the art. Other acids such as oxalic acid, which may not be considered pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining a chemical compound of the invention and its pharmaceutically acceptable acid addition salt. Examples of pharmaceutically cationic salts
acceptable compounds of a chemical compound of the invention include, without limitation, the sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, choline, lysinium, and ammonium salts, and the like, of a chemical compound of the invention containing an anionic group. The cationic salts can be formed 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 predrug or prodrug forms of the chemical compound of the invention include examples of suitable prodrugs of the substances according to the invention which 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, in a hydroxyl group, or in 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 in conjunction with a pharmaceutically acceptable solvent such as water, ethanol, and the like. The dissolvable forms may also include hydrated forms such as the monohydrate, the dihydrate, the
hemihydrate, the trihydrate, the tetrahydrate, and the like. In general, the dissolvable forms are considered equivalent to the indissoluble forms for the purposes of this invention. Spherical Isomers Those skilled in the art will appreciate that the compounds of the present invention can exist in different stereoisomeric forms - including enantiomers, diastereomers and cis-trans isomers. The invention includes all isomers and any mixture thereof including racemic mixtures. Furthermore, the substituent -0-Rb at position 3 of the 8-aza-bicyclo [3.2.1] oct-6-ene skeleton of Formula I can be in particular in the exo or endo configuration. In one embodiment of the invention the substituent at position 3 is in the exo configuration. In another embodiment of the invention the substituent at position 3 is in the endo configuration. The invention includes all isomers and any mixture thereof including racemic mixtures. The racemic forms can be resolved at the optical antipodes by known methods and techniques. One way to separate enantiomeric compounds (including enantiomeric intermediates) is-in the case where the compound is a chiral acid-by the use of an amine
optically active, and the release of diastereomeric salt, resolved by treatment with an acid. Another method of resolution of racemates in the optical antipodes is based on chromatography on an optically 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 L- salts (tartrates, mandelates, or camphorsulfonates) for example. The chemical compounds of the present invention can also be resolved by the formation of diastereomeric amides by reacting the chemical compounds of the present invention with an optically active activated carboxylic acid such as that derived from (+) or (-) phenylalanine. , (+) or (-) phenylglycine, (+) or (-) campanic 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 the resolution of optical isomers are known in the art. The methods include those described by Jaques J, Collet A, & Wilen S in "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York (1981). The optically active compounds can also be
prepared from optically active starting materials or intermediates. Labeling Compounds The compounds of the invention can be used in their labeled or unlabeled form. In the context of this invention the labeled compound has one or more atoms replaced by an atom having an atomic mass number or a mass number different from the number of atomic mass or mass number usually found in nature. The labeling will allow an easy quantitative detection of the compound. The labeled compounds of the invention can be useful as diagnostic tools, radiotracers, or monitoring agents in various diagnostic methods, and for the reception of in vivo images. The labeled isomer of the invention preferably contains at least one radionuclide as a label. Positron emission radionuclides are all candidates for use. In the context of this invention the radionuclide is preferably selected from 2 H (deuterium), 3 H (tritium), 13 C 1 C 131 I, 125 I, 123 I, and 18F. The physical method for detecting the labeled isomer of the present invention may be selected from
Position Emission Tomography (PET), Computed Tomography by Single Photon Emission (SPECT), Spectroscopy
by Magnetic Resonance Imaging (MRS), Resonance Imaging
Magnetic (MRl), and X-ray Computed Axial Tomography
(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 operative examples. The starting materials for the processes described in the present application are known or can be readily prepared by conventional methods from commercially available chemicals. In addition, a compound of the invention can be converted to another compound of the invention using conventional methods. The final 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 the monoamines dopamine, noradrenaline and serotonin in synaptosomes for example as described in 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, whose disease, disorder or condition responds to the inhibition of the reabsorption of the neurotransmitter monoamine in the central nervous system. In a special embodiment, the compounds of the invention are considered useful for the treatment, prevention or relief of: mood disorder, depression, atypical depression, depression secondary to pain, major depressive disorder, dysthymic disorder, bipolar disorder, bipolar disorder type I, bipolar type II trait, 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 agarophobia, panic disorder with agarophobia, agoraphobia without a history of panic disorder, panic attack, memory deficits, memory loss, attention deficit hyperactivity disorder, obesity, anxiety, generalized anxiety disorder, eating disorder, Parkinsonism, parkinsonism, dementia, dementia in aging, dementia s enil, Alzheimer's disease, dementia complex of acquired immunodeficiency syndrome, memory dysfunction in aging, specific phobia, social phobia, dementia
social anxiety, 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 headache, chronic tension headache, pain associated with depression, fibromyalgia, arthritis, osteoarthritis, rheumatoid arthritis, back pain, pain from cancer, irritable bowel pain, bowel syndrome irritable, postoperative pain, postmastectomy pain syndrome (PMPS), post-infarct pain, drug-induced neuropathy, diabetic neuropathy, sympathetically maintained pain, trigeminal neuralgia, dental pain, myofacial pain, phantom limb pain, bulimia, premenstrual syndrome, disorder premenstrual dysphoric syndrome, late luteal phase syndrome, post-traumatic syndrome, chronic fatigue syndrome, inco urinary incontinence, stress incontinence, urge incontinence, nocturnal incontinence, sexual dysfunction, premature ejaculation, erectile difficulty, erectile dysfunction, early female orgasm, restless legs syndrome, periodic limb movements disorder, eating disorders, anorexia nervosa, sleep disorders, pervasive developmental disorders, autism, Asperger's disorder, Rett's disorder, childhood disintegrative disorder, learning disabilities,
disorders of motor skills, mutism, trichotillomania, narcolepsy, post-infarct depression, infarct-induced brain damage, infarct-induced neuronal damage, Gilles de la Tourettes disease, tinnitus, tic disorders, body dysmorphic disorders, oppositional defiant disorder or disabilities post-infarction In a preferred embodiment, the compounds are considered useful for the treatment, prevention or relief of depression. It is now contemplated that a suitable dosage of the active pharmaceutical ingredient (API) is within the range of from about 0.1 to about 1000 mg of API per day, more preferred from about 10 to about 500 mg of API per day, even more preferred from about 30 to approximately 100 mg of API per day, depending, however, on the exact mode of administration, the manner in which it is administered, the indication considered, the subject and in particular the body weight of the subject involved, and of the preference and experience of the doctor or veterinarian in charge. Preferred compounds of the invention show a biological activity in the submicromolar and micromolar range, i.e. from below 1 to approximately 100 M.
Pharmaceutical Compositions In another aspect the invention provides novel pharmaceutical compositions comprising 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 crude chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt, into a pharmaceutical composition in conjunction with one or more adjuvants, excipients, carriers, buffers, diluents, and / or other conventional pharmaceutical auxiliaries. In a preferred embodiment, the invention provides pharmaceutical compositions comprising 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 art. The carrier (s) must be "acceptable" in the sense that it is (are) compatible with the other ingredients of the formulation and that they are not harmful to the recipient thereof. The pharmaceutical compositions of the invention can be those suitable for oral, rectal administration,
bronchial, nasal, pulmonary, topical (including buccal and sublingual), transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, injection or intraocular infusion), or those in a form suitable for administration by inhalation or insufflation, including powders and administration of liquid by aerosol, or by sustained release systems. Suitable examples of sustained release systems include semipermeable matrices of solid hydrophobic polymers containing the compound of the invention, which matrices 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 put into the form of pharmaceutical compositions and unit dosages thereof. The forms include solids, and in particular tablets, filled capsules, pellet and powder forms, and liquids, in particular solutions, suspensions, emulsions, elixirs, aqueous or non-aqueous, and capsules filled therewith, all for oral use, suppositories for rectal administration, and sterile injectable solutions for parenteral use. The pharmaceutical compositions and unit dosage forms thereof may comprise
conventional ingredients in conventional proportions, with or without additional active compounds or ingredients, and the unit dosage forms may contain any suitable effective amount of the active ingredient in proportion to the daily dosage range intended to be employed. The chemical compound of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the following dosage forms may comprise, 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 pharmaceutical compositions from a chemical compound of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, 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 powders, the carrier is a finely solid
divided, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binder capacity in suitable proportions and which is compacted in the desired shape and size. The powders and tablets preferably contain from five or 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 point wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it. Similarly, seals and pills that dissolve in the mouth (lozenges) are included. Tablets, powders, capsules, pills, seals, and tablets that dissolve in the mouth can be used as solid forms suitable for oral administration. For the preparation of suppositories, a low-melting wax, such as a mixture of acid glyceride
Fatty or cocoa butter, is first melted and the active component is dispersed homogeneously therein, such as by means of agitation. The molten homogeneous mixture is then poured into molds of suitable sizes, allowed to cool, and consequently solidified. Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or aerosols containing in addition to the active ingredient the carriers which are known in the art to be appropriate. Liquid preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, liquid preparations for parenteral injection can be formulated as solutions in aqueous polyethylene glycol solution. The chemical compound according to the present invention can thus be formulated for parenteral administration (for example by injection, for example bolus injection or continuous infusion) and can be presented as a unit dose in ampoules, pre-filled syringes, infusions in small volume or in multi-dose containers with an added preservative. The compositions may take the forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as preservatives.
suspension, stabilizers and / or dispersants. Alternatively, the active ingredient may be in powder form, be 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. Aqueous 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. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as gums, natural or synthetic resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents. Also included are solid form preparations, directed for conversion shortly before use to liquid form preparations for oral administration. Liquid forms include solutions, suspensions, and emulsions. In addition to the active component the preparations may comprise colorants, flavors, stabilizers, buffers, natural and artificial sweeteners, dispersants, thickeners, solubilizing agents, and the like. For topical administration to the epidermis the
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 also generally 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 tablets that dissolve in the mouth comprising the active agent in a flavored base, usually sucrose and acacia or tragacanth; pills comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouth rinses comprising the active ingredient in a suitable liquid carrier. The solutions or suspensions are applied directly to the nasal cavity through conventional means, for example with a dripper, pipette or aerosol. The compositions can be provided in single dose or multiple dose form. Administration to the respiratory tract can also be achieved by means of an aerosol formulation in which the active ingredient is provided in a container
pressurized with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. The aerosol may also conveniently contain a surfactant such as lecithin. The dose of drug can be controlled by the 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 hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition can be presented in unit dosage form for example in capsules or cartridges of, for example, gelatin, or blister packs from which the powder can be administered by means of an inhaler. In compositions directed to 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. The particle size can be obtained by means known in the art, for example by micronization. When desired, compositions may be employed
adapted to provide sustained release of the active ingredient. The pharmaceutical preparations are preferably in unit dosage forms. In the form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as tablets, capsules, and powders packed in vials or ampoules. Also, the unit dosage form can itself be a capsule, tablet, seal, tablet that dissolves in the mouth, or this can be the appropriate number of any of these in packaged form. Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions. Further details on techniques for formulation and administration can be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, PA). A therapeutically effective dose refers to that amount of active ingredient, which improves the symptoms or condition. The therapeutic efficacy and toxicity, for example ED50 and LD50, can be determined by standard pharmacological procedures in cell cultures
or in experimental animals. The ratio of the dose between therapeutic and toxic effects is the therapeutic index and can be expressed by the LD50 / ED50 ratio. Preferred are pharmaceutical compositions that exhibit high therapeutic indices. The dose administered must of course be carefully adapted to the age, weight and condition of the individual being treated, as well as to the route of administration, the dosage form and dosage, and the desired result, and the exact dosage It should of course be determined by the professional. The actual dosage depends on the nature and severity of the disease being treated, and is within the discretion of the practitioner, and can be varied by titration of the dosage to the particular circumstances of this invention to produce the therapeutic effect wanted. However, it is presently contemplated that pharmaceutical compositions containing from about 0.1 to about 500 mg of active ingredient per individual dose, preferably from about 1 to about 100 mg, even more preferred from about 1 to about 10 mg, are suitable for treatments therapeutic The active ingredient can be administered in one or several doses per day. In certain circumstances, it may be
obtained a satisfactory result at a dosage as low as 0.1 μg / kg i.v. and 1 μg / kg p.o. The highest limit of the dosage range is currently considered to be between about 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. 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, whose disease, disorder or condition responds to the inhibition of the reabsorption of the neurotransmitter monoamine in the central nervous system, and which method comprises administration to the living animal body, including a human, in need thereof of an effective amount of a chemical compound of the invention. At present it is contemplated that suitable dosage ranges are 0.1 to 1000 milligrams daily, 10-500 milligrams daily, and especially 30-100 milligrams daily, which depend as usual on the exact mode of administration, the way in which they are administered, of the indication to which the administration is directed, of the subject involved and of the
body weight of the subject involved, and in addition to the preference and experience of the physician or veterinarian in charge. EXAMPLES The invention is illustrated further with reference to the following examples, which are not intended in any way to limit the scope of the invention as claimed. General: All reactions involving reagents or intermediates sensitive to air were carried out under nitrogen and in anhydrous solvents. Magnesium sulphate was used as a drying agent in the evaporation processes and the solvents were evaporated under reduced pressure. Method A Salt of acid exo = 3 = (3,4-Dichloro-f-noad.) ~ 8-aza-bicyclo [3 »2.1] oct-6-en-hydrochloride Chloroformate 2, 2, 2-Trichloroethyl (2.99 g, 14.1 mmol) was added to a mixture of 3- (3,4-dichloro-phenoxy) -8-methyl-8-aza-bicyclo [3.2.1] oct-6-ene (1.34 g, 4.7 mmol) and toluene ( 25 ml). The mixture was stirred for 30 min followed by 15 h at 100 ° C. Water (50 ml) was added and the organic phase was separated and washed with water (2 x 25 ml). The crude mixture obtained by evaporation was dissolved in acetic acid (40 ml) and water (10 ml). Zinc powder (2.0 g)
was added to the mixture in portions followed by stirring for 5 h. Ice-water (50 ml) was added followed by concentrated aqueous ammonia (50 ml). The mixture was extracted with dichloromethane (2 x 50 ml). The hydrochloric acid salt was precipitated by the addition of hydrochloric acid dissolved in ethanol to the free base dissolved in diethyl ether. Yield 0.84 g (58%). Mp 200 ° C (decomp.). Salt of exo-3- (3-Bromo- -chloro-f-noxy) acid = 8-aza-bicyclo [3.2.1] oct-6-hydrochloric acid was prepared according to method A. Pf 240- 243 ° C.
LC-ESI-HRMS of [M + H] + shows 313.9952 Da. Cale. 313.99473
Da, desv. 1.5 ppm. Exo-3- (6-methoxy-naphthalene-2-yloxy) -8-aza-phenyl cyclo [3.2"13oct-6-hydrochloric acid salt was prepared according to method A. LC-ESI-HRMS
[M + H] + shows 282.1501 Da. Cale. 282.149404 Da, desv. 2.5 ppm. Exo-3- (3-chloro-6-fluoro-phenoxy) -8-aza-bicyclo [3"2.13oct-d-hydrochloric acid salt] It was prepared according to method A. Pf 216-219 ° C.
LC-ESI-HRMS of [M + H] + shows 254.0737 Da. Cale. 254.074795
Da, desv. -4.3 ppm. Exo-3- (4-Bromo-3-chloro-phenoxy) -8-aza-bicyclo [3.2 or 13 oct-d-hydrochloric acid salt] It was prepared according to method A. LC-ESI-HRMS
[M + H] + shows 313,995 Da. Cale. 313.99473 Da, det. 0.9 ppm. Salt of exo-3- (4-chloro-3-fluoro-phenoxy) -8-aza-bicyclo [3 or 2 or 13-oct-6-hydrochloric acid] It was prepared according to method A. LC-ESI-HRMS [M + H] + shows 254.0749 Da. Cale. 254.074795 Da, detour 0.4 ppm. Method B Exo-3- (3¡, 4-Dichloro-phenoxy) -8-methyl = 8-aza-bicyclo (3.2 o! 3oct-6-hydrochloric acid) A mixture of diethylazodicarboxylate (4.0 g, 23 mmol) in dioxane (10 ml) was added to triphenylphosphine (6.03 g, 23 mmol), dissolved in dioxane (40 ml) at room temperature.The mixture was stirred for 15 min. endo-8-Methyl-8-aza-bicyclo [3.2 1] oct-6-en-3-ol (3.3 g, 19 mmol) dissolved in dioxane (10 ml) was added to the mixture followed by 3,4-dichlorophenol (3.3 g, 20 mmol). until
° C due to an exothermic reaction. The mixture was stirred at room temperature overnight. Water (100 ml) and aqueous hydrochloric acid (15 ml, 4 M) were added and they were washed with diethyl ether (3 x 50 ml). The aqueous phase was obtained alkaline by the addition of sodium hydroxide
(20 ml, 4 M) followed by extraction with diethyl ether (3 x 80 ml). The crude mixture was purified by column chromatography on silica gel using dichloromethane followed by a mixture of methane) and dichloromethane and aqueous ammonia.
(40: 9: 1) The hydrochloric acid salt was prepared by the addition of a mixture of hydrochloric acid dissolved in ethanol. Yield 2.52 g (41%). Mp 248.8 ° C. Salt of exo-3- (3-Bromo-4-chloro-phenosd.) - 8-mephenyl-8-aza-bicyclo [3 = 2 < , 13oct-6 in hydrochloric It was prepared according to method B. Pf 234-236 ° C. LC-ESI-HRMS of [M + H] + shows 328.0098 Da. Cale. 328.01038 Da, det. -1.8 ppm. Free base of exo-3- (S-Methoxy-naphthalen-2-yloxy) -8-methyl-8-aza-bicyclo [3o2.1] oct-d-ene was prepared according to method B. Pf 240 ° C (dec.) LC-ESIHRMS of [M + H] + shows 296.1639 Da. Cale. 296.165054 Da, desv. -3.9 ppm. Salt of exo-3- (3-Chloro-4-fluoro-phenosi) -8-methyl-8-aza-bicyclo acid [3 < »2ol3oct-6 in hydrochloric It was prepared according to the method B. Pf 200-203 ° C. LC-ESI-HRMS of [M + H] + shows 268.0891 Da. Cale. 268.090445 Da, det. -5 ppm. Free base of exo-3- (4-Bromo-3-chloro-phenos.) -8-methyl-8-aza-bicyclo [3.2 ol3oct-6-ene It was prepared according to method B. LC-ESI-HRMS of [M + H] + shows 328.0092 Da. Cale. 328.01038 Da, det. -3.6 ppm. Salt of exo-3- (4-chloro-3-fluoro-phenoxy) -8-methyl-8-aza-bicyclo [3 «2 ol3oct-6 in hydrochloric acid was prepared according to method B. LC-ESI- HRMS of
[M + H] + shows 268.0915 Da. Cale. 268.090445 Da, det. 3.9 ppm. Method C endo-8-Methyl-8-aza-bicyclo [3"2ol3oct-6-en-3-ol (intermediate) A mixture of zinc powder (10 g) and hydrochloric acid (10 ml, 1 M) was stirred for 1 minute and was washed with hydrochloric acid (3 x 10 ml, 1 M) and water (5 x 10 ml) followed by aqueous copper sulfate (25 ml, 2%), water (5 x 10 ml), ethanol ( 10 ml, 96%) and diethyl ether (10 ml) followed by drying. The title compound was prepared from scopolamine hydrobromide trihydrate and zinc powder followed by hydrolysis by treatment with aqueous sodium hydroxide according to Tetrahedron Letters 42 (2001), p 1975. Test Example Inhibition activity ± n vitZO Were A number of compounds were tested for their ability to inhibit the reuptake of the neurotransmitters monoamine dopamine (DA) noradrenaline (NA) and serotonin (5-HT) in synaptosomes as described in WO 97/16451. The assay values are given as IC50 (the concentration (μM) of the test substance that inhibits the specific binding of 3H-DA, 3H-NA, or 3H-5-HT in 50%). The test results obtained by compounds
selected for the assay of the present invention appear in the table below: Table 1
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.