MXPA98003554A - Frozen tropan derivatives, its preparation and - Google Patents

Abstract

The present invention describes a compound of the formula (See Formula) or any of its enantiomers or any mixture thereof, a pharmaceutically acceptable addition salt thereof, or the N-oxide thereof, characterized in that X and Y together form = 0 , = S, = NOR2, -CR3R4, = N-CN, = N-NR7R8, (CH2) m- or -W '- (CH2) pW ", or one of X and Y is hydrogen and the other is -OR5 , -SR5, or -NR5R6 Z is hydrogen, -COOR9, R3 and R4 are independently hydrogen, halogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, alkoxy, aryl, arylalkyl or - (CH2) 4-COOR2; R2, R5 and R6 are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl or arylalkyl, -co-alkyl or -SO2-alkyl, R7 and R8 are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl or arylalkyl R9 is alkyl, alkenyl or alkynyl, R1 is alkyl, alkenyl, alkynyl, aryl or arylalkyl, wherein said aryl groups can be subst one or more times with substituents selected from the group consisting of halogen: CF3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, alkylamino, dialkylamino and nitro; W'and W "are each independently O or S, n is 1,2,34, m is 2,3,4 or 5, p is 1,2,3,4 or 5, and d is 0,1,2,34, and the compounds have valuable properties as a monoamine neurotransmitter. say, inhibitors of the reuptake of dopamine and serotoni

Description

FUSED TROPAN DERIVATIVES. YOUR PREPARATION AND USE The present invention relates to novel fused tropane derivatives which are inhibitors of the reuptake of the monoamine neurotransmitter, i.e., dopamine, serotonin and noradrenaline. In particular, the present invention relates to novel fused tropane derivatives which are potent serotonin reuptake inhibitors and which are therefore useful in the treatment of disorders or diseases that respond to the inhibition of serotonin reuptake, such as depression and related disorders, obsessive-compulsive disorders, panic disorders, memory deficiencies, hyperactivity disorder due to lack of attention, obesity, anxiety and eating disorders.

BACKGROUND OF THE INVENTION The brain consists of a plurality of neurons that communicate with each other by means of chemical messengers. Each neuron generates neurochemicals, called neurotransmitters; and neurotransmitters act at sites on the cell membrane of neurons, these receptor sites being called. A group of neurotransmitters, called the monoamine neurotransmitters, includes serotonin, dopamine, and noradrenaline.

The monoamine neurotransmitters are released into the synaptic cleft to stimulate postsynaptic receptor activity. The removal (or inactivation) of the monoamine neurotransmitters occurs mainly by means of a reuptake mechanism at the presynaptic terminals. When reuptake inhibits, an increase in the physiological activity of the monoamine neurotransmitters occurs. Norepinephrine and serotonin reuptake inhibitors are currently used as pharmaceuticals in antidepressant therapy (Desipramine, Nortriptyline and Protriptyline are inhibitors of reuptake of nora renaline, and Imipramine and Amitriptyline are mixed inhibitors of serotonin reuptake and noradrenaline reuptake. The pathophysiology of most affective diseases is poorly understood, and several neurotransmitters have been implicated in the pathophysiology of major depressions, however, several lines of preclinical and clinical evidence indicate that an increase in serotonin-mediated neurotransmission may underlie the effect of the most recent drugs currently used in antidepressant therapy: Fluoxetine, Citalopram and Paroxetine: Paradoxical serotonin reuptake inhibitors inhibit the serotonin transporter in minutes while its full antidepressant effect is observed only after three to four weeks of treatment, indicating that the inhibition of reuptake per se is not responsible for the antidepressant response, but that additional adaptive changes underlie and / or contribute to its therapeutic effect. The delayed appearance of the antidepressant effect is considered a serious disadvantage for the currently used monoamine reuptake inhibitors. The compounds provided with the present invention are potent inhibitors of serotonin reuptake (5-hydroxy-tryptamine, 5-HT). The compounds of the invention also have reuptake inhibitory activity of noradrenaline and dopamine, the serotonin reuptake inhibitor and noradrenaline reuptake inhibitor activity of the compounds of the invention being stronger than the dopamine reuptake inhibitory activity of the compounds, see box later. A strong dopamine reuptake inhibitory activity is currently considered with the risk of undesirable central stimulation effects. On the other hand, it is currently believed that an activation effect in the mesolimbic dopamine system underlies the common mechanism of current antidepressant treatment through a mechanism that increases the endogenous remuneration system. Compounds with strong serotonin reuptake inhidora activity combined with moderate and well-balanced dopamine reuptake inhibitor activity can therefore provide agents with a rapid onset of the antidepressant effect. The serotonergic neural system of the brain has been shown to influence a variety of physiological functions, and it is predicted that the compounds of the present invention have the ability to treat in mammals, including humans, a variety of disorders associated with this neural system, such as eating disorders, depression, obsessive-compulsive disorders, panic disorders, alcoholism , pain, lack of memory and anxiety. Therefore, the present invention also provides methods for treating various disorders related to decreased neutransmission of serotonin in mammals. Included among these disorders are depression and related disorders such as pseudodementia or Ganser syndrome; migraine pain, bulimia, obesity, premenstrual syndrome or late luteal phase syndrome, alcoholism, tobacco abuse, panic disorders, anxiety, post-traumatic syndrome, memory loss, dementia due to aging, social phobia, hyperactivity disorder lack of attention, chronic fatigue syndrome, premature ejaculation, erectile difficulty, anorexia nervosa, sleep disorders, autism, mutism or trichotyl ania. In addition, compounds with dopamine reuptake inhibitory activity are also considered useful for the treatment of parkinsonism, depression, obesity, narcolepsy, addition or misuse of drugs, hyperactivity disorders due to lack of attention and senile dementia. Dopamine reuptake inhibitors indirectly increase the release of acetylcholine by means of dopamine neurons and are therefore useful for the treatment of memory deficiencies, eg. in Alzheimer's disease and presenile dementia, and chronic fatigue syndrome. Norepinephrine reuptake inhibitors are considered useful for increasing attention, alertness, wakefulness, vigilance and for treating depression.

OBJECTS OF THE INVENTION It is an object of the present invention to provide novel fused tropane derivatives which are inhibitors of the reuptake of the monoamine neurotransmitter. In particular, it is an object of the present invention to provide potent serotonin reuptake inhibitors which are useful for the treatment of depression and related disorders, obsessive-compulsive disorders, panic disorders, lack of memory, hyperactivity disorder due to lack of attention, Obesity, anxiety and eating disorders. Another object of the present invention is to provide novel pharmaceutical compositions containing the novel fused tropane derivatives that are useful for the treatment of disorders or diseases that respond to the reuptake inhibitory activity of the monoamine neurotransmitter of the compounds of the invention. Yet another object of the invention is to provide a method for treating diseases or disorders that respond to the inhibition of monoamine neurotransmitter reuptake and in particular the re-homing of serotonin, such as depression and related diseases, obsessive-compulsive disorders, panic disorders , memory deficiencies, hyperactivity disorder due to lack of attention, obesity, anxiety and eating disorders. Other objects will be apparent hereinafter to one skilled in the art.

DESCRIPTION OF THE INVENTION The invention comprises, inter alia, the following, alone or in combination: A compound having the formula: or any of its enantiomers or any mixture thereof, a pharmaceutically acceptable addition salt thereof or the N-oxide thereof where X and Y together form = 0, = S, = N0R2, = CR3R *, = N-CN, = N-NR? R8, - (CH2) m- or -W '- (CH2 ) PW ", or one of X and Y is hydrogen and the other is -0R5, -SRS, or -NR5R6 Z is hydrogen, -COOR *; R3 and R * are independently hydrogen, halogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, alkoxy, aryl, arylalkyl or - (CH2) q -COOR2; R2, Rs and R6 are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl or arylalkyl, -CO-alkyl or -SO2-alkyl; R7 and R8 are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl or arylalkyl; R9 is alkyl, alkenyl or alkynyl; Ri is alkyl, alkenyl, alkynyl, aryl or arylalkyl; wherein said aryl groups can be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino and nitro; W and W "are each independently 0 or S; n is 1,2,3 or 4; m is 2,3,4 or 5; p is 1,2,3,4 or 5; and q is 0,1; 2,3 or 4: A compound like the previous one, which is (lS, 2S, 4S, 7R) -2- (3,4-Dichlorophenyl) -8-azatricyclo [5.4.0.04.8] _ undecan-11- ona, (1S, 2S, 4S, 7R) -2- (3,4-Dichlorophenyl) -8-azatricyclo [5.4.0.0 *. 8] -undecan-11-ol, (1S, 3S, 4S, 8R) - 3- (3,4-Dichlorophenyl) -7-azatricyclo [5.3.0.0 *. 8] _ decan-5-one, 0-methyl-oxime of (lS, 3S, 4S, 8R) -3- (3,4 -dichlorophenyl) -7- azatricyclo [5.3.0.0 * '8] decan-5-one, (lS, 2S, 4S, 7R) -2- (4-Chlorophenyl) -8-azatricyclo [5.4.0.0 *, 8] - undecan-11-one, (lS, 3S, 4S, 8R) -3- (3,4-Dichlorophenyl) -7-aza-tricyclo [5.3.0.0 * .8] decan-5-ol, Acetate (lS) , 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricyclo- [5.3.0.0 *. Β] dßc-5-yl, Sulfate (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricyclo- C5.3.0.0 * '8] dec-5-yl methane, (SS, 3S, 4S, 8R) -3- (3,4-Dichlorophenyl) -5- methoxy-7-azatricyclo- [5.3.0.0 * .8] decane, (lS, 3S, 4S, 8R) -3- (3,4-Dichlorophenyl) -5-ethoxy-7-azatricyclo- [5.3.0.0 *. 8] c (ecano, (lS, 3S, 4S, 8R) -3- (4-Chlorophenyl) ~ 7-azatricyclo [5.3.0.0 * .8] decan-5-one, (lS, 3S, 4S, 8R) -3- (4-Clo rofyl) -7-azat-ricyclo [5.3. 0.0 ^ .8] decan-5-ol, (SS, 3S, 4S, 8R) -3- (4-Clo rofyl) -5-ethoxy-7-azat ri cyclo- [5.3.0.0 *. 8] decane, O-benzyl oxime of (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricycloC5.3.0.0 * »8] decan-5-one, O-alyl -oxime of (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricyclo [5.3.0.0 * >; 8] decan-5-one, oxime of (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricyclo- [5.3.0.Q * '8] decan-5-one , O-tert-butyl oxime of (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-aza tri-cycle [5.3.0. O * »8] decan-5-one, 0-ethyl oxime of (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricyclo [5.3.0.0 * > 8] decan-5-one, (1S, 3S, 4S, 8R) -5-A1 and loxi -3- (3, 4-di-cyclo rofyl) -7-aza tri-cyclo [5.3.0.0 * .8 ] decane, (lS, 3S, 4S, 8R) -2- [3- (3,4-Dichlorophenyl) -7-azatricyclo [5.3.0.0 * -8] decan-5-ylidene] ethyl acetate, oxime ( 1S, 3S, 4S, 8R) -3- (4-dichlorophenyl) -7-azatricyclo- [5.3.0.0 * '8] decan-5-one, Nl- [lS, 3S, 4S, 8R) -3- ( 4-Chlorophenyl) -7-azatricyclo [5.3.0.0 * .8] dec-5-la lacetamide or (SS, 3S, 4S, 8R) -3- (4-Dichlorophenyl) -7-azatricycloC5.3.0.0 *. β] dec-5-yl amine or a pharmaceutically acceptable addition salt thereof; a pharmaceutical composition, comprising an effective amount of a compound as any of the foregoing together with at least one pharmaceutically acceptable carrier or diluent; the use of a compound as any of the foregoing for the manufacture of a medicament for the treatment of a disorder or disease of the body of a living animal, including a human, disorder or disease that responds to the inhibition of the reuptake of the monoamine neurotransmitter in the central nervous system; the use of a compound as any of the foregoing for the manufacture of a medicament for the treatment of a disorder or disease of the body of a living animal, including a human, disorder or disease that responds to the inhibition of serotonin reuptake in the Central Nervous System; the use of a compound like any of the foregoing for the manufacture of a medicament for the treatment of depression and related disorders such as pseudo-encia or Ganser syndrome, obsessive-compulsive disorders, panic disorders, lack of memory, hyperactivity disorder for lack of attention, obesity, anxiety and eating disorders; use as any of the above, in which the compound employed is (lS, 2S, 4S, 7R) -2- (3,4-Dichlorophenyl) -8-azatricyclo [5.4.0.0 * .8] -undecan-11 -one, (1S, 2S, 4S, 7R) -2- (3,4-Dichlorophenyl) -8-azatricyclo [5.4.0.0 *. 8] -undecan-11-ol, (1S, 3S, 4S, 8R) -3- (3,4-Dichlorophenyl) -7-azatricyclo [5.3.0.0 *. 8] -decan-5-one, O-methyl-oxime of (lS, 3S, 4S, 8R) -3- (3, 4-dichlorophenyl) -7-azat ri cycle [5.3.0.0 * • 8] decan-5-one, (lS, 2S, 4S, 7R) -2- (4-Chlorophenyl) -8-azatricyclo [5.4.0.0 * , 8] -undecan-11-one, (lS, 3S, 4S, 8R) -3- (3,4-Dichlorophenyl) -7-aza-tricyclo [5.3.0.0 * .8] -decan-5-ol, Acetate of (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricyclo- [5.3.0.0 * .8] dec-5-yl, Sulfate of (lS, 3S, 4S, 8R ) -3- (3,4-dichlorophenyl) -7-azatricyclo- [5.3.0.0 * .8] dec-5-yl methane, (SS, 3S, 4S, 8R) -3- (3,4-Dicyorophenyl) -5-methoxy-7-azatricyclo- CS.3.0.0 * «8] decane, (1S, 3S, 4S, 8R) -3- (3,4-Dicorophenyl) -5-ethoxy-7-azatricyclo-CS. 3.0. O * »8] decane, (SS, 3S, 4S, 8R) -3- (4-Chlorophenyl) -7-azatricyclo [5.3.0.0 *. sjdecan-5-one, (SS, 3S, 4S, 8R) -3- (4-Chlorophenyl) -7-azatricyclo [5.3.0.0 *. ßjdecan-5-ol, (1S, 3S, 4S, 8R) -3- (4-Chlorophenyl) -5-ethoxy-7-azatricyclo-CS.3.0. O * -8] decane, O-benzyl oxime of (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricycloC5.3.0.0 * > 8] decan-5-one, O-allyl oxime of (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricycloC5.3.0.0 * > 8] decan-5-one, oxime of (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricyclo-C5.3.0.0 * > 83decan-5-one, O-tert-butyl-oxime of (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricycloC5.3.0.0 * > 8] decan-5-one, 0-ethyl oxime of (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricycloC5.3.0.0 * .8] decan-5-one, (1S, 3S, 4S, 8R) -5-Allyloxy-3- (3,4-dichlorophenyl) -7-azatricyclo-C5.3.0.0 * '8] decane, (1S, 3S, 4S, 8R) -2 - [3- (3,4-Dichlorophenyl) -7-azatricycloC5.3.0.0 * .8] decan-5-ylidene] ethyl acetate, (lS, 3S, 4S, 8R) -3- (4- dichlorophenyl) -7-azatricyclo- C5.3.0.0 * .8] decan-5-one, N1-C1S, 3S, 4S, 8R) -3- (4-Chlorophenyl) -7-azatricycloC5.3.0.0 *. 83dec-5-yl] acetamide or (SS, 3S, 4S, 8R) -3- (4-Dichlorophenyl) -7-azatricycloC5.3.0.0 *. 8ldec-5-yl amine or a pharmaceutically acceptable addition salt thereof; a method of treating a disorder or disease of the body of a living animal, including a human, disorder or disease that responds to inhibition of the reuptake of the monoamine neurotransmitter, comprising the step of administering to said body a living animal, including a human, in need thereof, a thermically effective amount of a compound like any of the foregoing; a method for treating a disorder or disease in the body of a living animal, including a human, disorder or disease that responds to the inhibition of serotonin reuptake, comprising the step of administering to said body a living animal, including a human, in need thereof, a therapeutically effective amount of a compound as any of the foregoing; the method of conformance with any of the above, in which depression and related disorders are treated such as pseudodementia or Ganser syndrome, obsessive-compulsive disorders, panic disorders, memory deficits, hyperactivity disorder due to lack of attention, obesity, anxiety and eating disorders; and a method for the preparation of the compounds as above, which comprises forming a fused tropane ring having the formula wherein n and R1 is as defined in claim 1, by ring closure of a compound having the formula (CH2) n-QOOalkyl alkyl wherein n and R1 is as defined in claim 1 and then optionally converting the obtained compound to another compound of the invention using conventional methods, and / or optionally forming a pharmaceutically acceptable salt thereof. Examples of pharmaceutically acceptable addition salts include the inorganic and organic addition acid salts such as hydrochloride, hydrobromide, phosphate, nitrate, perchlorate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate, benzoate, ascorbate, cinnamate, benzenesulfonate, methanesulfonate, stearate, succinate, glutamate, glycollate, toluene-p-sulfonate, formate, malonate, naphthalene-2-sulfonate, salicylate and acetate. Said salts are formed by methods well known in the art. Other acids such as oxalic acid, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates for obtaining compounds of the invention and their pharmaceutically acceptable acid addition salts. Halogen is fluorine, chlorine, bromine or iodine. Alkyl means a straight chain or a branched chain of one to six carbon atoms, including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl; the groups that are preferred are methyl, ethyl, propyl and isopropyl. Cycloalkyl means cyclic alkyl of three to seven carbon atoms, including but not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; Alkenyl means a group of from two to six carbon atoms, including at least one double bond, for example, but not limited to, ethenyl, 1,2- or 2,3-propenyl or 1,2-, 2,3 -, or 3,4-butenyl. Alkynyl means a group of from two to six carbon atoms, including at least one triple bond, for example, but not limited to, ethynyl, 1,2-, 2,3-propynyl or 1,2-2,3- or 3,4-butinyl.

Cycloalkylalkyl means cycloalkyl as above and alkyl as above, meaning for example, cyclopropylmethyl. Alkoxy is O-alkyl, wherein alkyl is as defined above. Cycloalkoxy is O-cycloalkyl, wherein cycloalkyl is as defined above. Amino is NH2 or NH-alkyl or N- (alkyl) 2, wherein alkyl is as defined above. Aryl is an aromatic hydrocarbon, such as phenyl or naphthyl. I.p. means intraperitoneally, which is a well-known route of administration. P.o. means peroral, which is a well-known administration route. In addition, the compounds of this invention can exist in unsolvated form as well as in solvated form with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the invention. It will be appreciated by those skilled in the art that some compounds of the present invention contain chiral centers and that said compounds exist in the form of isomers (ie, enantiomers). The invention includes all such isomers and any mixtures thereof, including racemic mixtures. Some of the compounds of the present invention exist in (+) and (-) forms, as well as in racemic forms. The racemic forms can be resolved at the optical antipodes by known methods, for example, by separation of the diastereomeric salts thereof with an optically active acid, and by releasing the optically active amine compound by treatment with a base. Another method for resolving the racemates in the optical antipodes is based on chromatography on an optically active matrix. The racemic compounds of the present invention can then be resolved in their optical antipodes, e.g., by fractional crystallization of d- or 1- (tartrate) salts, mandelic or camphor sulfonate) for example. The compounds of the present invention can also be resolved by the formation of reomeric diasterelsides by reacting the compounds of the present invention with an optically active carboxylic acid such as that derivative of (+) or (-) phenylalanine, (+) or (-) phenylglycine, O) or (-) camphoric acid or by the formation of diastereomeric carbamates by reaction of the compounds of the present invention with an optically active chloroformate or the like. Additional methods for resolution of optical isomers known to those skilled in the art may be used, and will be apparent to the average expert. Such methods include those described by J. Jaques, A. Collet and S. ilen in "Enantio ers, Race ates, and Resolutions", John Wiley and Sons, New York (1981). The compounds of the invention can be prepared in numerous ways. The compounds of the invention and their pharmaceutically acceptable derivatives can then be prepared by any method known in the art for the preparation of compounds of analogous structure, and as shown in the representative examples below. The following scheme illustrates a method by which the compounds of the invention can be prepared: The substituents R and R "signify alkyl, Hal is halogen and n and R1 is as defined above.

The procedures in the above reaction scheme are carried out in a conventional manner. The compounds of the invention wherein X and Y together form = 0 wherein one of X and Y is OH and the other is hydrogen can be converted to other compounds of the invention using conventional methods, as illustrated in the following schemes reaction: In the above reaction scheme W, W ", R1, R2, R7, R8, n and p are as defined above.

Ru In the above reaction schemes R ° is alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl and arylalkyl, and n and R1 is as defined above. The procedures in the above reaction schemes are carried out in conventional manner. The starting materials for the processes described in the present patent application are known or can be prepared by known procedures from commercially available materials, see for example, the patent application of E.U.A. No. 5,444,070. The products of the reactions described herein are isolated by conventional means such as extraction, crystallization, distillation, chromatography and the like.

BIOLOGY The compounds of the invention have been tested to verify their ability to inhibit the reuptake of dopamine (DA), noradrenaline (NA) and serotonin (5-HT) in synaptosomes.

BACKGROUND Specific neurotransmitter uptake / transporter sites at nerve terminals presumably function to terminate neuronal signaling by removing the neurotransmitters dopamine, noradrenaline, and serotonin, respectively, from the synaptic cleft. The activity of the integral proteins of the transporter can be measured in vitro by the synaptosomal uptake of 3H-dopamine, 3H-noradrenaline and 3H-serotonin, respectively.

In vitro inhibition of uptake of 3H-dopamine (3H-DA) in striatal synaptosomes Tissue preparation: The preparations are carried out at 0-4 ° C unless otherwise indicated. Striated bodies of male Wistar rats (150-200 g) are homogenized for 5-10 sec in 100 volumes of 0.32 M sucrose cooled with ice containing 1 mM pargyline using an Ultra-Turrax homogenizer. The activity of monoamine oxidase will be inhibited in the presence of pargyline. The homogenate is centrifuged at 1,000 x g for 10 min. The resulting supernatant is then centrifuged at 27,000 x g for 50 minutes and the supernatant discarded. The pellet (P2) is resuspended in pH regulator of oxygenated Krebs-Ringer incubation (equilibrated with an atmosphere of 96% O2: 4% CO2 for at least 30 min) (8,000 ml per g of original tissue) pH 7.2 containing 122 M NaCl, 0.16 mM EDTA, 4.8 mM KCl, 12.7 M de'Na2HP04, 3.0 mM NaH? PO *, 1.2 mM MgSO4, 1 M CaCl2, 10 M glucose and 1 mM of ascorbic acid. Test: Aliquots of 4.0 ml of tissue are added to 100 μl of test solution and 100 μl of 3H-DA (final concentration, InM) are mixed and incubated for 25 min at 37 ° C. Non-specific uptake is determined using benztropine (final concentration of 10 μM). After incubation the samples are emptied directly onto Whatman GF / C glass fiber filters under suction. The filters are then washed three times with 5 ml of 0.9% (v / v) NaCl solution cooled with ice. The amount of radioactivity in the filters is determined by conventional liquid syntactic counting. The specific uptake is calculated as the difference between total uptake and non-specific uptake. An inhibition of 25-75% of the specific binding must be obtained before calculating an ICso. The test value is given as IC50 (the concentration (μM) of the test substance that inhibits the specific binding of 3 H-DA by 50%).

In vitro inhibition of uptake of 3 H-noradrenaline (3 H-NA) hippocampal synaptasomes Tissue preparation: The preparations are carried out at 0-4 ° C unless otherwise indicated. Hypocampos of male Wistar rats (150-200 g) are homogenized for 5-10 sec in 100 volumes of 0.32 M sucrose cooled with ice containing 1 mM pargyline using an Ultra-Turrax homogenizer. The activity of monoamine oxidase will be inhibited in the presence of pargyline. The homogenate is centrifuged at 1,000 x g for 10 min. The resulting supernatant is then centrifuged at 27,000 x g for 50 minutes and the supernatant discarded. The pellet (P2) is resuspended in pH buffer of oxygenated Krebs-Ringer incubation (equilibrated with an atmosphere of 96% O2: 4% CO2 for at least 30 min) (2,000 ml per g of original tissue) pH 7.2 containing 122 M NaCl, 0.16 mM EDTA, 4.8 M KCl, 12.7 mM a2HP04, 3.0 mM NataPO *, 1.2 mM MgSO *, 0.97 M CaCl2, 10 M glucose and 1 mM ascorbic acid . Test: Aliquots of 4.0 ml of tissue are added to 100 μl of test solution and 100 μl of 3H-NA (final concentration, InM) are mixed and incubated for 90 min at 37 ° C. Non-specific uptake is determined using desipra ina (final concentration of 1 μM). After incubation the samples are emptied directly onto Whatman GF / C glass fiber filters under suction. The filters are then washed three times with 5 ml of 0.9% (v / v) NaCl solution cooled with ice. The amount of radioactivity in the filters is determined by conventional liquid syntactic counting. The specific uptake is calculated as the difference between total uptake and non-specific uptake. An inhibition of 25-75% of the specific binding must be obtained before calculating an ICso. The test value is given as ICso (the concentration (μM) of the test substance that inhibits the specific binding of 3H-NA by 50%).

In vitro inhibition of 3H-5-hydroxytryptamine uptake < 3H-5-HT. serotonin) in cortical synaptosomes Tissue preparation: The preparations are carried out at 0-4 ° C unless otherwise indicated. Cerebral cortexes of male Wistar rats (150-200 g) are homogenized for 5-10 sec in 100 volumes of 0.32 M sucrose cooled with ice containing 1 mM pargyline using an Ultra-Turrax homogenizer. The activity of monoamine oxidase will be inhibited in the presence of pargyline. The homogenate is centrifuged at 1,000 x g for 10 min. The resulting supernatant is then centrifuged at 27,000 x g for 50 minutes and the supernatant discarded. The pellet (P2) is resuspended in pH buffer of oxygenated Krebs-Ringer incubation (equilibrated with an atmosphere of 96% O2: 4% CO2 for at least 30 min) (1,000 ml per g of original tissue) pH 7.2 containing 122 M of NaCl, 0.16 mM of EDTA, 4.8 M of KCl, 12.7 M of Na HP0 ?, 3.0 M of aH2 0 *. 1.2 mM MgSO *, 1 mM CaCl2, 10 mM glucose and 1 mM ascorbic acid. Test: Aliquots of 4.0 ml of tissue are added to 100 μl of test solution and 100 μl of 3H-5-HT (final concentration, InM) are mixed and incubated for 30 min at 37 ° C. Non-specific uptake is determined using citalopram (final concentration of 1 μM). After incubation the samples are emptied directly onto Whatman GF / C glass fiber filters under suction. The filters are then washed three times with 5 ml of 0.9% (v / v) NaCl solution cooled with ice. The amount of radioactivity in the filters is determined by conventional liquid syntactic counting. The specific uptake is calculated as the difference between total uptake and non-specific uptake. An inhibition of 25-75% of the specific binding must be obtained before the calculation of an IC50. The test value is given as ICso (the concentration (μM) of the test substance that inhibits the specific binding of 3H-5-HT by 50%). The test results obtained by testing the selected compounds of the present invention appear from the table below: TABLE 1 The results presented above show that the tested compounds efficiently inhibit the reuptake of dopamine, noradrenaline and serotonin in synaptosomes.

PHARMACEUTICAL COMPOSITIONS Although it is possible that, for use in therapy, a compound of the invention can be administered as a pure chemical, it is preferable to present the active ingredient as a pharmaceutical formulation. The invention then provides pharmaceutical formulations comprising a compound of the invention or a pharmaceutically acceptable salt or derivative thereof together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and / or prophylactic ingredients. The vehicle or vehicles must be "acceptable" in the sense of being compatible as the other ingredients of the formulation and not harmful to the receiver of the same. Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including intramuscular, subcutaneous or intravenous) administration or in a form suitable for administration by inhalation or insufflation. The compounds of the invention, together with a conventional adjuvant, vehicle or diluent, can then be placed in the form of pharmaceutical compositions and unit doses thereof, and in said forms they can be employed as solids, such as filled tablets or capsules, or liquids such as solutions, suspensions, emulsions, elixirs or capsules filled therewith, all for oral use, in the form of suppositories for rectal administration or in the form of sterile injectable solutions for parenteral use (including subcutaneous). Said pharmaceutical compositions and the unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and said dosage unit forms may contain any effective and adequate amount of the active ingredient provided with the dosage regimen. desired daily dose to be used. Formulations containing ten (10) milligrams of active ingredient or, more broadly, 0.1 to one hundred (100) milligrams per tablet, are accordingly representative and suitable unit dose forms. The compounds of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of the invention or a pharmaceutically acceptable salt of a compound of the invention. To prepare pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, amylaceous capsules, suppositories and dispersible granules. A solid carrier can be one or more substances that 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 divided solid that is mixed with the finely divided active component. In tablets, the active component is mixed with the vehicle having the necessary agglutination capacity in suitable proportions and is compacted to give it 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, detrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like. The term "preparation" is designed to include the formulation of the active compound with an encapsulating material as a vehicle providing a capsule in which the active component, with or without vehicles, is surrounded by a vehicle, which is in this way in association with it. Similarly, amylaceous capsules and pills are included. Tablets, powders, capsules, pills, amylaceous capsules and pills can be used as solid forms suitable for oral administration. To prepare suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously therein by stirring. The melted homogenous mixture is then emptied into molds of suitable size, allowed to cool and then solidified. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient vehicles such as those known in the art as appropriate. Liquid form 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 an aqueous solution of polyethylene glycol. The compounds according to the present invention can then be formulated for parenteral administration (eg by injection, eg bolus injection or continuous infusion) and can be presented as a unit dose in ampules, pre-filled syringes, infusions of small volume or containers of multiple doses with an added preservative. The compositions may have forms such as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of a sterile solid or by lipophilization from the solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, Before its 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 obtained by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxylmethylcellulose, or other well-known suspending agents. Also included are solid form preparations which are intended to be converted, shortly before use, into liquid form preparations for oral administration. Said liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, pH regulators, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. For topical administration to the epidermis, the compounds according to the invention can be formulated as ointments, creams or lotions, or as a transdermal patch. Ointments and creams can be formulated, for example, with an aqueous or oily base with the addition of suitable thickeners and / or gelling agents. The lotions can be formulated with an aqueous or oily base and, in general, will also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include tablets comprising the active agent in a savorified base, usually sucrose and acacia or tragacanth.; pills comprising the active ingredient in an inert base such as gelatin and glycerin sucrose and acacia; and buccal washes comprising the active ingredient in a suitable liquid vehicle. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or sprinkler. The formulations can be provided individually or in multiple doses. In the latter case of a dropper or pipette, this can be done by the patient administering an appropriate and predetermined volume of a solution or suspension. In the case of a spray, this can be achieved for example by means of a spray atomizing metering pump. Administration to the respiratory tract can also be achieved by an aerosol formulation in which the active ingredient is supplied in a package under pressure with a suitable propellant such as chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other adequate gas. The aerosol may also conveniently contain a surfactant such as lecithin. The dose of the 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 vehicle 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 bubble packs from which the powder can be administered by an inhaler. In formulations that are administered to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size, for example, of the order of 5 microns or less. Said particle size can be obtained by methods known in the art, for example, by micronization. When desired, formulations adapted to give sustained release of the active ingredient can be used. The pharmaceutical preparations are preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing suitable quantities of the active component. The unit dosage form may be a packaged preparation, the package containing defined amounts of the preparation, such as tablets, capsules and powders packed in vials or ampoules. Similarly, the unit dosage form may be a capsule, tablet or lozenge, or they may be the appropriate number of any of these in packaged form. Tablets or capsules for oral administration and liquids for intravenous administration, are preferred compositions.

TREATMENT METHOD The compounds of the present invention are extremely useful in the treatment of depression and related disorders due to their inhibitory activity of serotonin, noradrenaline and dopamine uptake, together with their low degree of inconvenient side effects. These properties also make the compounds of this invention extremely useful in the treatment of obsessive compulsive disorders, panic disorders, memory deficits, attention deficit hyperactivity disorders, obesity, anxiety and eating disorders, as well as also other disorders sensitive to the inhibitory activity of serotonin, noradrenaline and dopamine uptake of the compounds of the present invention. Accordingly, the compounds of this invention can be administered to the body of a living animal, including a human, in need of treatment, alleviation, or elimination of an indication associated with, or responsive to, the inhibitory activity of dopamine uptake, noradrenaline and serotonin. The appropriate dose scale is 0.1 to 500 milligrams per day, and especially 10 to 70 milligrams per day, administered once or twice per day, usually depending on the exact mode of administration, the way in which it is administered, the indication to which administration is directed, the subject involved and the body weight of the same, and also the preference and experience of the doctor or veterinarian in charge. However, the following examples will better illustrate the invention, without being intended to be limiting thereof.

EXAMPLE 1 Ethyl acid ester (lR.2R.3S.5S) -3- (3,4-dichlorophenyl) -8- azabicyclo [3.2.1] octane-2-cart > oxyl (2b) Ethyl (lR, 2R, 3S, 5S) -3- (3,4-dicoprophenyl) -8-methy1-8-azabicyclo [3.2.1] -octane-2-carboxylic acid ester (lb) was dissolved (17.9 g ) in 100 ml of dry 1,2-dichloroethane, and l-chloroethyl chloroformate (7.5 ml) was added. The reaction mixture was refluxed for 3 hours, and then evaporated to an oil. The oil was dissolved in methanol, and the solution was refluxed for 40 hours and evaporated to an oil. The oil was dissolved in water, concentrated aqueous ammonia was added until the pH was = 10, and the aqueous phase was extracted with ether, and dried with magnesium sulfate, and evaporated to an oil. Yield 18.7 g (107%).

EXAMPLE 2 Ethyl ester of (lR.2R.3S, 5S) -3- (3,4-dichlorophenyl) -8- (2-ethoxycarbonyl ethyl) -8-azabicyclo [3.2.1] octane-2-cartyl) xylitol (3b) ) (LR, 2R, 3S, 5S) -3- (3,4-dichlorophenyl) -8-azabicyclo [3.2.1] octane-2-carboxylic acid ethyl ester (2b) (8.3 g) was dissolved in dimethyl sulfoxide. (40 ml), and potassium hydroxide (5.6 g) and ethyl 3-bromopropyanate (3.8 ml) were added. The reaction mixture was stirred at room temperature overnight, and poured into 200 ml of water, and this solution was washed with ether, and dried with magnesium sulfate and evaporated to an oil. Yield 8.5 g (80%), MS m / z 427 + 429.

EXAMPLE 3 (lS.2S.4S.7R) -2- (3,4-dichlorophenyl) -8-azatricyclo [5.4.0.0 .ß] A < jecan-ll-ona (4) Ethyl (lR, 2R, 3S, 5S) -3- (3,4-di-cyclohexyl) -8- (ethoxycarbonyl ethyl) -8-aza-bi-cycloC 3.2.1] -octane- ethyl ester was dissolved. 2-carboxylic acid (3b) (8.5 g) in dry toluene and sodium hydride (0.5 g) (60% suspension in oil) was added. The reaction mixture was refluxed for half an hour, and then evaporated to an oil, which was dissolved in 10 M aqueous HCl; this solution was refluxed for 16 hours, and then cooled to room temperature, and added Aqueous NaOH at 12 M until the pH was = 12. This solution was washed with ether, and dried with magnesium sulfate and evaporated to an oil. Yield 1.9 g (31%) GC / MS 96% pure M = 309 + 311.

EXAMPLE 4 O-methyl-oxime of (lS.2S.4S.7R) -2- (3,4-dichlorophenyl) -8-azatricyclo [5-4-0-Q4 »83undecan-ll-one (5) It was dissolved (lS, 2S, 4S, 7R) -2- (3,4-dichlorophenyl) -8-azatricyclo [5-4-0-04, 8] undecan-ll-one (4) in methanol and methoxylamine hydrochloride (0.6 g) and potassium carbonate (1.4 g) were added. This suspension was stirred at room temperature for 16 hours, and then evaporated to an oil, which was dissolved in 1 M HCl and washed with ether. NaOH was added to the aqueous phase until the pH was 12, and it was extracted with ether. The organic phase was dried with magnesium sulfate and evaporated to an oil. Yield 0.2 g MS: m / z 338 (M +, 80), 340 (M ++ 2.51), 342 (M + 4.8).

EXAMPLE 5 (lS.2S.4S.7R) -2- (3,4-dichlorophenyl) -8-azatricycloC5-4-0-Q * »ß] undßcan-ll-ol (6) It was dissolved (lS, 2S, 4S, 7R) -2- (3,4-dichlorophenyl) -8-azatricyclo [5-4-0-04,8] undecan-l-one (4) (0.5 g) in methanol (10 ml), and sodium borohydride (0.2 g) was added. The reaction mixture was stirred at room temperature for 2 hours, and then water (0.5 ml) was added and evaporated to an oil. To the oil was added ethyl acetate (10 ml) and aqueous sodium hydroxide to IM (10 ml), and the organic phase was dried with magnesium sulfate and evaporated to an oil. The oil was purified by flash chromatography on silica gel, and eluted with dichloroethane / methanol / aqueous ammonia at 25% (89/10/1 v / v). The product fractions were evaporated to a foam. Yield 200 mg (40%). MS (EI +): m / z 311 (M +, 100), 313 (M ++ 2.68), 315 (M ++ 4, 12). (lS.2S.4S.7R) -2- (3,4-dichlorophenyl) -8-azatricylC5-4-0- O * .83undecan-ll-ol (6a) The title compound was prepared in the same manner as (6S). ), but was purified by chromatography on silica gel (dichloroethane / acetone / methyl alcohol (4/1 /)).

Yield 0.2 g (18%) as white crystals P.F. 185.6-186.9 ° C.

EXAMPLE 6 Acid methyl ester (lR.2R.3R.5S) -3- (3,4-dichlorophenyl) -8- (ethoxycarbonylmethyl) -8-azabichloro [3.2.l3octane-2-cart > oxylic A (1R, 2R, 3R, 5S) -3- (3,4-dichlorophenyl) -8-methyl-8-azabicyclo [3.2.1] octane-2-carboxylic acid methyl ester (L) (19.4 g) in dry 1,2-dichloroethane (125 ml) was added l-chloroethyl chloroformate (10 ml). The reaction mixture was refluxed for 16 hours, then left at room temperature for 48 hours, and then evaporated to an oil. The oil was dissolved in methanol (125 ml), and refluxed for 45 minutes, and then evaporated to an oil. The oil was dissolved in water, and concentrated aqueous ammonia was added until the pH was 10, and the aqueous phase was extracted with ester, the organic phase was dried with magnesium sulfate, and evaporated to an oil. The oil was dissolved in absolute ethanol (180 ml) and ethyl bromoacetate (7.7 ml) and potassium carbonate (10.2 g) were added. The reaction mixture was refluxed for 2 hours, then stirred overnight at room temperature, and evaporated to an oil. To the oil was added water (0.5 1), and extracted with ether (2 x 300 ml), the combined ether phases were dried with magnesium sulfate, and evaporated to an oil. The oil was purified by flash chromatography on silica gel 60 (400 g), and eluted with ethyl acetate and petroleum ether (1: 1), and the product fractions were evaporated to an oil. Yield 10 g (42%) MS (EI +): m / z 399 (M +, 12), 401 (M ++ 2.7), 403 (M + 4.2).

EXAMPLE 7 (lS.3S.4S.8R) -3- (3,4-dichlorophenyl) -7-azatricyclo [5.3.0.0 * > 83decan -5-one (8) To the (1R, 2R, 3S, 5S) -3- (3,4-dichlorophenyl) -8- (ethoxycarbonylmethyl) -8-azabicyclo [3.2.1] octane-2-carboxylic acid methyl ester (7) (22.4) g) in xylene (200 ml) was added sodium ethoxide at 1 M in ethanol (63 ml). The solution was depilated until the temperature reached 138 ° C, and then refluxed for 30 minutes. To the reaction mixture was added water (50 ml) and concentrated hydrochloric acid (15 ml), and refluxed for 16 hours. Water (200 ml) was added to the reaction mixture and the xylene was removed by azeotropic distillation with water, and water was occasionally added to maintain the volume of the solution. To the residue was added water to a total volume of 0.5 1, concentrated aqueous ammonia was added until the pH was 10, and the product was precipitated, and after filtration, the precipitate was washed with ether (50 ml). Yield 13 g (78%) P.F. 176-182 ° C. EXAMPLE 8 O-methyl-oxime of (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7- azatricyclo [5-3-0-0 * »8] undecan-5-one (9) (SS, 3S, 4S, 8R) -3- (3, 4-di-cyclo-r-enyl) -7-azatri-cycloC 5-3-0-04,8] undecan-5-one (8) (0.29 g) and Methoxylamine hydrochloride (0.90 g) were dissolved in absolute ethanol (50 ml). The reaction mixture was refluxed for 4 hours, and then evaporated to an oil. The oil was suspended in water (50 ml), and concentrated aqueous ammonia was added until the pH was 10, and then it was extracted with ether. The ether phase was dried with magnesium sulfate, and evaporated to an oil. The residue was dissolved in absolute ethanol and then 0.4M fumaric acid in absolute ethanol (1.9 ml) was added, and the solution was evaporated to a foam. Yield 0.29 g (66%). P.F. 143-146 ° C.

EXAMPLE 9 Acid methyl ester (lR.2R.3S.5S) -3- (4-chlorophenyl) -8- (ethoxycarbonyl ethyl) -8-aza-bicyclo [3.2.1] octane-2-carboxylic acid (11) Methyl ester of (lS, 2S, 4S, 7S) -2- (4-chlorophenyl) -8- (me-8-azabicloC3.2.1] octane-2-carboxylic acid (IC) (23 g) was dissolved in 1 , Dried 2-dichloroethane (100 ml), and l-chloroethyl chloroformate (12 g) was added.The reaction mixture was refluxed for 4.5 hours, and then evaporated to an oil.The residue was dissolved in methanol ( 100 ml), and refluxed for 1 hour, the reaction mixture was evaporated to an oil, which was dissolved in water, and 25% aqueous ammonia was added until the pH was 10, this solution was extracted with ether, and washed with water and dried with magnesium sulfate and evaporated to an oil, which was crystallized after standing at room temperature.The solid was dissolved in absolute ethanol (200 ml), and potassium (15 g) and ethyl 3-bromopropionate (12 ml), the reaction mixture was refluxed for 3 hours, and then evaporated to an oil, to which was added ter and water. The ether phase was washed with water, and dried with magnesium sulfate, and evaporated to an oil. The oil was purified by flash chromatography on silica gel (300 g), and eluted with ethyl acetate. The product fractions were evaporated to an oil. Yield 24 g (80%) MS (EI +): m / z 379 (M ++ 2.17), 383 (M ++ 4, 2).

EXAMPLE 10 (lS.2S.4S.7R) -2- (4-chlorophenyl) -8- (azatriciclo [5.4.Q.0 * »83undecan-ll-one (12) (LR, 2R, 3S, 5S) -3- (4-chlorophenyl) -8- (ethoxycarbonylmethyl) -8-azabicyclo [3.2.1] octane-2-carboxylic acid methyl ether (10) (3.15 g) was dissolved. ) in dry xylene (20 ml), and sodium hydride (0.35 g 60% disp. in oil) was added; the reaction mixture was refluxed for 4 hours, and then cooled to room temperature and crushed ice and hydrochloric acid was added at 4N (15 ml). Then, the ice was melted, the phases were separated, the aqueous phase was washed with ether (1 x 50 ml), and concentrated aqueous ammonia was added until the pH was 10, and it was extracted with dichloromethane. The organic phase was washed with brine, and dried with magnesium sulfate and evaporated to an oil. To the oil was added concentrated hydrochloric acid (20 ml) and ethanol (96%), until everything was in solution; the reaction mixture was refluxed for 16 hours, cooled to room temperature and crushed ice was added and concentrated aqueous ammonia was added at which the pH was 10, and then extracted with dichloromethane; the organic phase was dried with magnesium sulfate, and evaporated to an oil, which was crystallized from ethanol (96%). Yield 0.24 g (11%) P.F. 156.157.7 ° C.

EXAMPLE 11 (lS.3S.4S.8R) -3- (3,4-chlorophenyl) -7- (azatricicloC5.3.0.0 * »8] decan-5-ol (13) It was dissolved (lS, 3S, 4S, 8R) - 3- (3,4-dichlorophenyl) -7- (azatricicloC5.4.0.04,8] decan-5-one (8) (1 g) in methanol, and sodium borohydride (0.26 g) was added. The reaction was stirred at room temperature for 30 minutes, then water (0.5 ml) was added and evaporated to dryness.To the residue was added ethyl acetate (200 ml) and aqueous sodium hydroxide at 1 N (50 ml), and the organic phase was dried with magnesium sulfate and evaporated to a foam Yield 0.67 g ({66%) PF 203-205 ° C. Fumarate: The title compound was dissolved in methyl alcohol and fumaric acid was added (7 g, 25.5 g. mmoles) (3 g, 16 mmol) in methyl alcohol, and heated to reflux until the solution was clear, the fumarate salt of the title compound was precipitated, and then the solution was cooled on an ice / water bath, and the crystals were recrystallized from ethyl alcohol ico absolute (150 ml) and water (46 ml). Yield 5.42 g P.F. 250.5-251 ° C.

EXAMPLE 12 Fumarate acetate (lS.3S, 4S.8R) -3- (3,4-dichlorophenyl) -7-azatricyclo [5.3.0.0 * .83dec-5-yl (14) It was dissolved (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricyclo [5.3.0.04 «8] decan-5-ol (13) (lg, 3.3 mmole) in glacial acetic acid (5 ml), and concentrated hydrochloric acid (5 ml) was added, the reaction mixture was heated to reflux for 90 minutes, and then cooled to room temperature and aqueous ammonia was added at room temperature. % until the pH was 9.5, and the aqueous phase was extracted with diethyl ether. The ether phase was concentrated to an oil, and the residue was chromatographed on silica gel (dichloroethane / acetone / methyl alcohol 4/1/1.) The fractions of the product were concentrated to an oil, the oil was dissolved in diethyl ether. methyl alcohol and a solution of fumaric acid (0.14 g, 1.2 mmol) in methyl alcohol was added, after which white crystals were precipitated, and the product was isolated by filtration Yield 0.36 g (24%) PF 214-216 ° C.

EXAMPLE 13 Sulfate of (lS.3S, 4S.8R) -3- (3,4-dichlorophenyl) -7- azatricyclo [5.3.0.Q »3dec-5-yl methane (15) It was dissolved (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricycloC5.3.0.04 «8] decan-5-ol (13) (lg, 3.3 mmol) in dichloromethane (150 ml) and metalsulfonyl chloride (0.3 ml, 3.7 mmol) and triethylamine (1.6 ml, 12 mmol) were added. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour, and then concentrated to an oil. To the oil was added 4M NaOH and dichloromethane, and the organic phase was dried (magnesium sulfate) and concentrated to a foam. Yield 0.61 g (46%) P.F. 139-141 ° C. EXAMPLE 14 Sulfate of (lS.3S.4S.8R) -3- (3,4-Dichlorophenyl) -5-me oxy-7- aza ricicloC5.3.0.0 * »8] dean (16) It was dissolved (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricycloC5.3.0.0 * «8] decan-5-ol (13) (1.3g, 4.4 mmoles) in tetrahydrofuran anhydrous rofuran (30 ml), and potassium tert-butoxy (1.54 g, 13.8 mmol) was added, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 45 minutes, and then cooled to -70 ° C.; dimethyl sulfate (4.3 ml, IM in anhydrous tetrahydrofuran, 4.3 mmole) was added at a rate such that the temperature did not exceed -65 ° C, the reaction mixture was stirred at this temperature for 1 hour, and then allowed to react. warm to room temperature, and water (50 ml) was added and then extracted with diethyl ether (3X50 ml). The organic phase was dried (sodium sulfate) and concentrated to an oil, which crystallized after standing at room temperature. Yield 0.32 g (24%) P.F. 119. 2-120.3 ° C. EXAMPLE 15 Fumarate of (lS.3S.4S.8R) -3- (3,4-dichlorophenyl-5-ethoxy-7-azatricyclo [5.3.0.04.8] decane (17) It was dissolved (lS, 3S, 4S, 8R) -3- (3,4-Dichlorophenyl) -7-azatricycloC5.3.0.04.8] decan-5-ol was dissolved (13) (2 g, 6.7) mmoles) in tetrahydrofuran anhydrous (40 ml), and potassium terbutoxide was added, and stirred for one hour at room temperature under a nitrogen atmosphere, and then cooled to minus 70 ° C, and diethyl sulfate was added at a rate such that the temperature did not exceed minus 65 ° C; the reaction mixture was stirred at that temperature for 2 hours, and then allowed to warm to room temperature, and water (50 ml) was added and extracted with diethyl ether (3X100 ml); The organic phase was dried (magnesium sulfate) and concentrated to an oil. The oil was dissolved in methyl alcohol and fumaric acid (0.6 g, 5.2 mmol) in methyl alcohol was added, and the product was precipitated. Yield 2g (67%) as white crystals P.F. 164.1-165.9 ° C.

EXAMPLE 16 COOEt 2-C (IR.3S.5R) -3- (4-chlorophenyl) -2-meoxycarbonyl-8-azabicyclo [3.2.1] oct-8-yl] ethyl acetate (18) (1R, 3S, 5R) -3- (4-chlorophenyl) -8-azabicycloC3.2.1] octane-2-carboxylic acid methyl ester (10) (0.88 g, 0.31 mol) was dissolved in absolute ethyl alcohol (approximately 600 ml) and potassium carbonate (55.2 g, 0.4 mol) and ethyl bromoacetate (66.3 g, 0.4 mol) were added; the reaction mixture was heated to reflux for 2 hours and then concentrated to an oil; the residue was chromatographed on silica gel (ethyl acetate), and the product fractions were concentrated to an oil. Yield 98 g (87%).

EXAMPLE 17 Fumarate of (lS.3S.4S.8R) -3- (4-chlorophenyl) -7- azatricicloC5.3.0.Q -83decan-5-one (19) 2-C (lR, 3S, 5R) -3- (4-chlorophenyl) -2-methoxycarbonyl-8-azabicycloC3.2.1] oct-8-yl] ethyl acetate (18) (42.8 g, 0.12 mol) was dissolved in toluene (400 ml), and the solution was heated to reflux; with a Dean-stark trap, the solvent was collected until no water remained, and the solution was cooled to room temperature and sodium methoxide (65 ml, at 2.1, a 2.1 M solution in methyl alcohol, 0.14 mol) was added.; the reaction mixture was distilled until the temperature reached 100 ° C, and then it was left at room temperature overnight and then concentrated; To the residue was added ethyl alcohol (100 ml) and concentrated to an oil; 4 M hydrochloric acid (35 ml, 0.14 mol) was added to the residue and the mixture was refluxed for 2 hours; the reaction mixture was cooled to room temperature and 25% aqueous ammonia was added until the pH was 10; a white compound was precipitated and isolated by filtration, and the solid was recrystallized from toluene (200 ml). Yield 16 g (52%) as white crystals. Some of the crystals (0.78 g, 3 mmol) were dissolved in absolute ethyl alcohol (25 ml), and fumaric acid (0.45 g, 3.8 mmol) and absolute ethyl alcohol (5 ml) were added; the mixture was heated until everything was dissolved, and then cooled to 5 ° C, and the product was precipitated and isolated by filtration. Yield 0.99 g (88% from the free base) as beige crystals P.F. 205-206 ° C.

EXAMPLE 18 Fumarate of (lS.3S.4S.8R) -3- (4-chlorophenyl) -7- azatricyclo [5.3.0.0 * »8] decan-5-ol (20) The free base of the title compound was prepared analogously to lS, 3S, 4S, 8R) -3- (4,3-dichlorophenyl) -7-azatricylC5.3.0.0 * «8] decan-5-ol. The fumarate salt was obtained from the free base (0.7 g, 2.7 mmol) dissolved in ethyl alcohol (10 ml, 96%), and fumaric acid (0.35 g, 2.7 mmol) in ethyl alcohol (15 ml, 96%); the title compound was precipitated and isolated by filtration. Yield 0.9 g (80%) as white crystals P.F. 230-231 ° C.

EXAMPLE 19 (lS.3S.4S.8R) -3- (4-chlorophenyl) -5-ethoxy-7-azatricyclo [5.3.0.0 * '8] decane (21) The title compound was prepared analogously to lS, 3S, 4S, 8R-3- (3,4-dichlorophenyl) -5-ethoxy-7-azatricylC5.3.0.0 * »8] decane. Yield 0.31 g (36%) P.F. 72-74 ° V.

EXAMPLE 20 Q-benzyl oxime of (lS.3S.4S, 8R) -3- (3,4-dichlorophenyl) -7- azatricycloC5.3.0.0 * »8] decan-5-one (22) The free base of the title compound was prepared analogously to the 0-methyl-oxime (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricylC5.3.0.0 '?' 8] - decan-5-one (9) Yield 0.51 g (25%) P.F. 125.3-126.4 ° C.

EXAMPLE 21 O-allyl oxime fumarate (lS.3S, 4S.8R) -3- (3,4-Dichlorophenyl) -7-azatricyclo [5.3.0.0 * '8] decan-5-one (23) The title compound prepared analogously to the 0-methyl oxime of (1S, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricycloC5.3.0.0 * > 8-decan-5-one (9); the free base of the title compound 1 g, 2.8 mmol) was dissolved in ethyl alcohol and fumaric acid (0.35 g, 3 mmol) was added, the mixture was concentrated to a foam. Yield 0.98 g (42%) P.F. 45-52 ° C.

EXAMPLE 22 Oxime of (SS 3S.4S84) -3- (3,4-dichlorophenyl) -7-azatricyclo [5.3.0.0 * 8decan-5-one (24) The title compound was prepared analogously to the O-methyl-oxime of (lS, 3S, 4S, 84) -3- (3,4-dichlorophenyl) -7-azatricyclo [5.3.0.0 * 8] decan-5-one -0-methyl-oxime (9).

Yield 0.5 g (32%) as light brown crystals P.F. 143.9-144.7 ° C.

EXAMPLE 23 OOH O-tert-butyl-oxime fumarate (lS.3S.4S.8R) -3- (3,4-dichlorophenyl) -7-azatricyclo [5.3.0.Q48] decan-5-one (25) The free base of the title compound was prepared analogously to the O-methyl-oxime of (1S, 3S, 4S, 84) -3- (3,4-dichlorophenyl) -7-azatricyclo 5.3.0.0.48decan-5-one (9) Smoke salt yield 0.51 g (21%) as light gray crystals P.F. 234-236 ° C.

EXAMPLE 24 O-ethyl oxime fumarate (lS.3S.4S.8R) -3- (3,4-dichlorophenyl) -7-azatricyclo [5.3.0.Q 83decan-5-one (26) The free base was prepared analogously to the O-methyl-oxime of (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricycloC5,3,0,0 * 8] decan-5- ona (9). The free base (0.77 g, 2.3 mmol) was dissolved in methyl alcohol, and fumaric acid (0.29 g, 2.5 mmol) was added; The mixture was concentrated to dryness. Yield 0.52 g (23%) as a light beige solid P.F. 62-69 ° C.

EXAMPLE 25 Fumarate of (lS, 3S.4S.8R) -3- (3,4-dichlorophenyl) -7- azatricicloC5.3.Q.0 * 83decan-5-ol (27) The anhydrous tetrahydrofuran lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricycloC5,3,0,0 * 8] decan-5-ol (13) (2 g, 6.7 mmol) is added potassium tert-butoxide (40 ml), and stirred under a nitrogen atmosphere at room temperature for 90 minutes, and then cooled to -70 ° C; allyl bromide (0.8 g, 6.6 mmol) was added dropwise to this mixture, while the temperature was maintained below -65 ° C; the reaction mixture was stirred at this temperature for 2 hours and allowed to warm to room temperature, and water (50 ml) was added; the mixture was extracted with diethyl ether 2X100 ml), the organic phase was dried (magnesium sulfate) and concentrated to an oil; the oil was dissolved in diethyl ether (10 ml) and fumaric acid (0.49 g, 4.2 mmol) in methyl alcohol was added; The mixture was concentrated to an oil, the oil was triturated in diethyl ether, and the title compound was precipitated and isolated by filtration. Yield 1.77 g (58%) as white crystals P.F. 150.5-152.2 ° C. EXAMPLE 26 Fumarate of (lS.3S.4S.8R) -2-C3- (3,4-dichlorophenyl) -7- azatricyclo [5.3.0.0 * 83dec-5-iiiden3 ethyl acetate (28) Triethyl phosphonoacetate (2.51 g, 11.2 mmol) was added dropwise to a mixture of sodium hydride (0.5 g of a suspension at 60% in mineral oil, 12 mmol) in anhydrous toluene under a nitrogen atmosphere; the mixture was stirred at room temperature for 30 minutes and then added (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricylC5,4,0,0 * 8] decan-5- ona (8) (3.3 g, 11.1 mmol); the reaction mixture was filtered and the filtrate was concentrated; the residue was chromatographed on silica gel (dichloromethane / methyl alcohol / acetone, 4/1/1), and the product fractions were concentrated to an oil, whose yield was 1.22 g (30%). Part of the oil (0.36 g, 1 mmol) was dissolved in diethyl ether and fumaric acid (0.13 g, 1.1 mmol) in methyl alcohol was added; The mixture was concentrated to an oil, the oil was taken up with diethyl ether, and the title compound was precipitated. Yield 0.37 g (77% from the free base) as white crystals P.F. 158-159 ° C.

EXAMPLE 27 Oxime Hydrochloride of (lS.3S.4S.8R) -3- (4-chlorophenyl) -7- azatricyclo [5.3.Q.Q483decan-5-one (29) It was dissolved (lS, 3S, 4S, 8R) -3- (4-chlorophenyl) -7-azatricycloC5,3,0,0A8] decan-5-one (19) (4 g, 15.3 mmol) was dissolved (40 ml ), in absolute ethyl alcohol (13. g, 18.4 mmol), and hydroxylamine hydrochloride (1.3 g, 18.4 mmol) was added; the reaction mixture was heated to reflux for 39 minutes, then more hydroxylamine hydrochloride (0.2 g, 2.9 mmol) was added and it was heated at reflux for 2 hours; the reaction mixture was stirred on an ice / water bath, and the title compound was precipitated and isolated by filtration, whose yield was 3.93 g (82%), part of the solid (1 g, 3.2 mmol) was crystallized from ethyl alcohol (approximately 25 ml) and water (approximately 5 ml).

Yield 0.6 g (60%) for crystallization) P.F. 284-285 ° C.

EXAMPLE 28 Nl-ClS.3S.4S.8R) -3- (4-chlorophenyl) -7-azatricicloC5.3.0.0 * 83dec- 5-il3acetamida (30) Oxime hydrochloride of (lS, 3S, 4S, 8R) -3- (4-chlorophenyl) -7-azatricicloC5.3.0.0'i8 Idecan 5-one (29) (3.13 g, 10 mmol) in methyl alcohol was dissolved. (300 ml and a certain amount of Raney Nikkel (50% suspension in water) was added, the reaction mixture was stirred under a nitrogen atmosphere for 40 hours (use of hydrogen, 0.62 1, 26 mmol); The reaction was filtered through Hyflo Super Cel from USA, the filtrate was concentrated to dryness, and water (150 ml) and 25% aqueous ammonia were added to the residue until the pH was equal to 10, the aqueous phase was extracted with diethyl ether (3X100 ml) and with dichloromethane (100 ml), the organic extracts were combined and dried (magnesium sulfate), and concentrated to dryness, the residue was dissolved in water (20 ml) and hydrochloric acid (5 ml, 4 m, 20 mmol) and stirred on an ice / water bath and acetic anhydride (8.6 g, 85 mmol) and sodium acetate (8 g, 98 mmol) were added, the mixture of The reaction was stirred on an ice / water bath for 2 hours, the reaction mixture was filtered, and 25% aqueous ammonia was added to the filtrate until the pH equaled 10, and a solid was precipitated and isolated by filtration.; the precipitate was chromatographed on silica gel (dichloromethane / methyl alcohol / acetone 4/1/1), and the product fractions were crystallized after standing at room temperature. Yield 0.54 g (18%) P.F. 122-123.5 ° C.

EXAMPLE 29 Fumarate of (lS.3S.4S.8R) -3- (3,4-dichlorophenyl) -7- azatricyclo [5.3.0.0 * 8 dec-5-yl amine (31) Sodium borohydride (0.81 g, 21.5 mmol) was suspended in anhydrous tetrahydrofuran (40 ml), and stirred under a nitrogen atmosphere, and trifluoroacetic acid (2.45 g, 21.5) in anhydrous tetrahydrofuran (5 ml) was added dropwise. during a period of 10 minutes; then it was stirred at room temperature for 20 minutes, and to the reaction mixture was added O-methyl oxime of (1S, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricyclo [5.3.0.0 ^ 8] decan-5-one (9) (1.4 g, 4.3 mmol) in anhydrous tetrahydrofuran (5 ml) over a period of 20 minutes; it was then stirred at room temperature for 30 minutes, and then heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and water (10 ml) was added and stirred for 1 hour; it was then concentrated until the only solvent was water, and then it was extracted with dichloromethane (50 ml); the organic phase was dried (magnesium sulfate) and concentrated to a foam; the yield was 1.22 g (95%); Part of the foam (0.5 g, 1.7 mmol) was dissolved in methyl alcohol (10 ml) and fumaric acid (0.205 g, 1.77 mmol) was added, the mixture was concentrated to a foam, the foam was stirred with diethyl ether and filtered, and the product was dried on a filter. Yield 0.35 g (20%) P.F. 208-211 ° C.

Claims (8)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound that has the formula. or any of its enantiomers or any mixture thereof, a pharmaceutically acceptable addition salt thereof, or the N-oxide thereof, characterized in that X and Y together form = 0, = S, = N0R2, = CR3R, rN- CN, = N-NR? R8, - (CH2) m- O -W - (CH2) P- W ", O one of X and Y is hydrogen and the other is -OR5, -SR5, or -NR5R6 Z is hydrogen, -COOR9, R3 and R * are independently hydrogen, halogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, alkoxy, aryl, arylalkyl or - (CH2) q -COOR2; R2, R5 and R6 are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl or arylalkyl, -CO-alkyl or -SO2-alkyl; R7 and R8 are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl or arylalkyl; R * is alkyl, alkenyl or alkynyl, R 1 is alkyl, alkenyl, alkynyl, aryl or arylalkyl, wherein said aryl groups can be substituted one or more times with selected substituents. of the group consisting of halogen, CF3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, alkylamino, dialkylamino and nitro; W and W "are each independently 0 or S; n is 1,2,3 or 4; m is 2,3,4 or 5; p is 1,2,3,4 or 5; and q is 0,1; 2,3 or 4.

2. A compound of claim 1, characterized in that it is (lS, 2S, 4S, 7R) -2- (3,4-dichlorophenyl) -8-azatriciclo 5.4.0.04 »8] -undecan -ll-ona, (lS, 2S, 4S, 7R) -2- (3,4-dichlorophenyl) -8-azatricycloC5.4.0.0 * -83-undecan-ll-ol, (lS, 3S, 4S, 8R ) -3- (3,4-dichlorophenyl) -7-azatricycloC5.3.0.0 * '81-decan-5-one, O-methyl-oxime of (1S, 3S, 4S, 8R) -3- (3, 4-dichlorophenyl) -7-azatricyclo 5.3.0.0 * '8] decan-5-one, (lS, 2S, 4S, 7R) -2- (4-chlorophenyl) -8-azatricicloC5.4.0.0 *, 8] undecan-11-one, (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-aza-tricyclo [5.3.0.0 * «8] -decan-5-ol, acetate ( 1S, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricyclo-C5.3.0.0 * »8] dec-5-yl, sulfate of (SS, 3S, 4S, 8R) - 3- (3,4-dichlorophenyl) -7-azat-ricyclo [5.3.0.04.8] dec-5-yl methane, (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -5 -methoxy-7-azatricyclo- 5.3.0.0 * »8] decane, (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -5-ethoxy-7-azatricyclo-C5.3.0.0 * .83 decan, (lS, 3S, 4S, 8R) -3- (4-chlorophenyl) -7-azatricycloC5.3.0.O * »83decan-5-one, (lS, 3S, 4S, 8R) -3- (4-chlorophenyl) -7-azatricycloC5. 3.0.0 * .8] decan-5-ol, (1S, 3S, 4S, 8R) -3- (4-chlorophenyl) -5-ethoxy-7-azatricyclo- [5.3.0.0 * «8] decane, 0 -benzyl oxime of (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricycloC5.3,0.04'8] decan-5-one, O-allyl oxime of (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7- azatricycloC5.3.0.0 * '8] decan-5-one, oxime of (lS, 3S, 4S, 8R) -3- (3 , 4-dichlorophenyl) -7-azatricyclo- [5.3.0.04 > 8] decan-5-one, 0-tert-butyl-oxime of (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricycloC5.3.0.0 * '8] decan-5 -one, 0-ethyl oxime of (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-aza tri-cycloC 5.3.0.0 * > 8] decan-5-one, (lS, 3S, 4S, 8R) -5-allyloxy-3- (3,4-dichlorophenyl) -7-azatricyclo-C5.3.0.0 / i > 8] decane, (lS, 3S, 4S, 8R) -2- [3- (3,4-dichlorophenyl) -7-azatricyclo [5.3.0.0 > 8] decan-5-ylidene] ethyl acetate, (lS, 3S, 4S, 8R) -3- (4-dichlorophenyl) -7-azatricyclo- C5.3.0.0 * -8] decan-5-one oxime. , Nl-ClS, 3S, 4S, 8R) -3- (4-chlorophenyl) -7-azatricycloC5.3.0.0 * «8] dec-5-yl] acetamide or (lS, 3S, 4S, 8R) -3 - (4-dichlorophenyl) -7-azatricyclo [5.3.0.0 * »8] dec-5-yl amine, or a pharmaceutically acceptable addition salt thereof.

3. A pharmaceutical composition comprising an effective amount of a compound of claims 1 to 2, together with at least one pharmaceutically acceptable carrier or diluent.

4. The use of a compound according to claim 1, for the manufacture of a medicament for the treatment of a disorder or disease of the body of a living animal, including a human, whose disorder or disease is sensitive to the inhibition of the reuptake of the monoamine neurotransmitter in the central nervous system.

5. The use of a compound according to claim 1, for the manufacture of a medicament for the treatment of a disorder or disease of the body of a live animal, including a human, whose disorder or disease is sensitive to the inhibition of serotonin reuptake in the central nervous system.

6. The use of a compound according to claim 1, for the manufacture of a medicament for the treatment of depression and related disorders, such as pseudodementia or Ganser syndrome, obsessive-compulsive disorders, panic disorders, memory deficits, hyperactivity disorder due to attention deficit, obesity, anxiety and eating disorders.

7. The use as in claims 4 to 6, characterized in that the compound used is (lS, 2S, 4S, 7R) -2- (3,4-dichlorophenyl) -8-azatricicloC5.4.0.0 * '8] -undecan-ll-ona, (ÍS, 2S.4S.7R) -2- (3,4-dichlorophenyl) -8-azatricicloC5.4.0.0 * -8] -undecan-11-ol, (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricycloC5.3.0.0 * «8] -decan-5-one, O-methyl-oxime of (lS, 3S, 4S, 8R) -3 - (3,4-dichlorophenyl) -7-azatricycloC5.3.0.0 * «83decan-5-one, (lS, 2S, 4S, 7R) -2- (4-chlorophenyl) -8-azatriciclo [5.4.0.0 * , 8] -undecan-ll-one, (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-aza-tricycloC5.3.0.0 * '8] -decan-5-ol, acetate (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricyclo-C5.3.0.0 * .8] dec-5-yl, sulfate (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricyclo-C5.3.0.0l »8] dec-5-yl methane, (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) ) -5-methoxy-7-azatricyclo- C5.3.0.0 * -83decano, (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -5-ethoxy-7-azatricyclo- [5.3. 0.0 * >; 8] decane, (lS, 3S, 4S, 8R) -3- (4-chlorophenyl) -7-azatricycloC5.3.0.0 * -8] decan-5-one, (1S, 3S, 4S, 8R) - 3- (4-cyclo-phenyl) -7-azatricycloC5.3.0.0 * • 8] decan-5-ol, (lS, 3S, 4S, 8R) -3- (4-chlorophenyl) -5-ethoxy-7-azatricyclo - C5.3.0.0 * '8] decane, 0-benzyl oxime of (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricicloC5.3.0.0 *' 8] decan -5-one, 0-allyl-oxy of (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricycloC5.3.0.0 * '8] decan-5-one, oxime of (lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-aza riciclo-C5.3.0.0 * '8] decan-5-one, 0-tert-butyl-oxime of ( lS, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricycloC5.3.0.0 * «8 decan-5-one, 0-ethyl oxime of (lS, 3S, 4S, 8R) - 3- (3,4-dichlorophenyl) -7-azatricycloC5.3.0.0 * '8] decan-5-one, (lS, 3S, 4S, 8R) -5-Allyloxy-3- (3,4-dichlorophenyl) -7-azatriciclo-C5.3.0.0 * '8] dean, (lS, 3S, 4S, 8R) -2-C3- (3,4-dichlorophenyl) -7-azatriciclo [5.3.0.0 * «8] decan -5-ylidene] ethyl acetate, (1S, 3S, 4S, 8R) -3- (-di-cyclohexyl) -7-azatrici-clo-C5.3.0.0 * .8 decan-5-one oxime, Nl-ClS, 3S, 4S, 8R) -3- (4-chlorophenyl) -7-azatricyclo [5 .3.0.0 * .83dec-5-yl3acetamide or (lS, 3S, 4S, 8R) -3- (4-dichlorophenyl) -7-azatricycloC5.3.0.0 * > 83dec-5-yl amine, or a pharmaceutically acceptable addition salt thereof.

8. A method for the preparation of the compounds of claim 1, comprising forming a fused tropane ring having the formula characterized in that n and R1 are as defined in claim 1, by ring closure of a compound having the formula , (CH2) n-COOalkyl alkyl characterized in that n and R * are as defined in claim 1, and then optionally converting the compound obtained, to another compound of the invention using conventional methods, and / or optionally forming a pharmaceutically acceptable salt thereof. SUMMARY OF THE INVENTION The present invention describes a compound of the formula, or any of its enantiomers or any mixture thereof, a pharmaceutically acceptable addition salt thereof, or the N-oxide thereof, characterized in that X and Y together form = 0, = S, = N0R2, = CR3R *. = N-CN, = N-NR7R8, - (CH2) m- O -W - (CH2) PW ", O one of X and Y is hydrogen and the other is -OR5, -SR5, or -NR5R6 Z is hydrogen , -COOR9; R3 and R * are independently hydrogen, halogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, alkoxy, aryl, arylalkyl or - (CH2) -COOR2; R2, Rs and R6 are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl or arylalkyl, -CO-alkyl or -SO2-alkyl; R7 and R8 are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl or arylalkyl; R9 is alkyl, alkenyl or alkynyl; is alkyl, alkenyl, alkynyl, aryl or arylalkyl, wherein said aryl groups may be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino , alkylamino, dialkylamino and nitro; W and W "are each independently 0 or S; n is 1,2,3 or 4; is 2,3,4 or 5; p is 1,2,3,4 or 5; and q is 0,1,2,3 or 4; the compounds possess valuable properties as a monoamine neurotransmitter, ie, inhibitors of the reuptake of dopamine and serotonin. JN / MG / ram * elt * fac * blm * lss * P98 / 382F