Condensed troyanova derivatives as inhibitors of reuptake of neurotransmitters

 

(57) Abstract:

Condensed Troyanova derivatives of the formula I, where X and Y together form = O, = S, =NOR2, =CR3R4or one of X and Y is hydrogen and the other is-OR5, -SR5, -NR5R6; Z is hydrogen; R3and R4independently represent hydrogen, lower alkyl, lower alkenyl, phenyl(lower alkyl) or -(CH2)q-COOR2; R2, R5, R6independently represent hydrogen, lower alkyl, lower alkenyl, -CO-(lower alkyl), phenyl(lower alkyl), or-SO2-(lower alkyl); R1is lower alkyl or phenyl, possibly substituted with halogen, CF3, CN, lower alkyl or nitro; n = 1 or 2; q = 0, can be used as a drug that has the property to inhibit the reuptake of neurotransmitter monoamines in the Central nervous system. 4 C. and 3 h.p. f-crystals, 4 PL.

The present invention relates to novel condensed tropaeolum derivatives, which are inhibitors neurotransmitter reuptake of monoamines, i.e. dopamine, serotonin and norepinephrine. The present invention applies in particular to new condensed tropaeolum production the ri treatment of disorders or diseases sensitive to the inhibition of serotonin reuptake, such as depression and related disorders, obsessive-compulsive disorder, panic disorder, memory impairment, hyperactivity with attention deficit, obesity, anxiety and eating disorders.

Background of the invention

The brain consists of many nerve cells that communicate with each other through chemical mediators. Each nerve cell generates neurochemical substances, called neurotransmitters, and neurotransmitters act on the sites located on the cell membrane of nerve cells called receptors. One group of neurotransmitters called neurotransmitter monoamines, includes serotonin, dopamine and norepinephrine.

Neurotransmitter monoamines go into the synaptic gap to stimulate postsynaptic receptor activity. Delete (or destruction) of neurotransmitter monoamines occurs primarily by reuptake by presynaptic endings. Reuptake inhibition leads to increased physiological activity of neurotransmitter monoamines.

Inhibitors of clicks is when conducting antidepressant treatment (desipramine, nortriptyline and protriptyline are inhibitors of reuptake of norepinephrine and imipramine and amitriptyline - reuptake inhibitors of serotonin and noradrenaline).

The main pathophysiology of affective disorders remains poorly elucidated and it is assumed that in the pathophysiology of depression involved a variety of neurotransmitters. However, a number of preclinical and clinical data suggests that the enhancement is mediated by serotonin neurotransmission may underlie therapeutic effect of most currently used for antidepressant therapy drugs, such as fluoxetine, citalopram and paroxetine.

Paradoxical inhibitors serotonin reuptake inhibit the action vector of serotonin within minutes, while the full antidepressant effect is manifested only after three to four weeks of treatment, suggesting that inhibition of reuptake per se is not responsible for the antidepressant effect, and, most likely, based on its therapeutic actions lie and/or contribute to its therapeutic action further adaptive changes. Delay nacw reuptake of monoamines.

Compounds provided by the present invention are effective inhibitors of reuptake of serotonin (5-hydroxytryptamine, 5-HT). Compounds according to the invention also possess inhibitory activity against reuptake of norepinephrine and dopamine, but the inhibitory activity of these compounds against reuptake of serotonin and norepinephrine is stronger compared to the corresponding activity in relation to dopamine.

Strong inhibitory activity reuptake of dopamine currently associated with the risk of unwanted increasing the activity of the Central nervous system. On the other hand, assume that the activating effects on the mesolimbic dopamine system is the basis of a General mechanism currently used antidepressant treatment due to increased endogenous reinforcing system. Therefore, compounds with strong inhibitory activity of serotonin reuptake in combination with a well-balanced inhibitory activity against reuptake of dopamine may be the agents causing rapid antidepressant effect.

It was shown that serotonine the gat, the compounds of the present invention will have the ability to treat in mammals, including humans, a variety of diseases associated with the nervous system, such as eating disorders, depression, obsessive-compulsive disorder, panic disorder, alcoholism, pain, memory disorders and anxiety. Thus, according to the present invention also proposed methods of treatment of various diseases associated with decreased neurotransmission of serotonin in mammals. Such diseases can be attributed depression and related diseases, such as pseudodementia or syndrome Ganzera, pain caused by migraine, bulimia, obesity, premenstrual syndrome or syndrome, late luteal phase, alcoholism, Smoking, panic disorder and anxiety, post-traumatic syndrome, memory loss, senile dementia, social phobia, hyperactivity with attention deficit, chronic fatigue syndrome, premature ejaculation, erectile difficulty, anorexigenic neurosis, sleep disorders, autism, mutism or trichotillomania.

In addition, compounds with inhibitory activity against of obree, addiction to the excessive use of drugs or abuse, hyperactivity with attention deficit and senile dementia. Inhibitors of reuptake of dopamine indirectly through dopamine nerve cells enhance the release of acetylcholine and thus are useful for the treatment of memory disorders such as Alzheimer's disease and presenilny dementia, and chronic fatigue syndrome. Inhibitors of reuptake of norepinephrine are useful to improve attention, vigilance, activity, concentration and for the treatment of depression.

Objectives of the invention

The present invention solves the problem of creating new condensed troyanovich derivatives, which are inhibitors neurotransmitter reuptake of monoamines. The present invention, in particular, solves the problem of creating an effective inhibitors of serotonin reuptake, useful for the treatment of depression and related disorders, obsessive-compulsive disorders, panic disorders, memory disorders, hyperactivity with attention deficit, obesity, anxiety and eating disorders.

The invention also solves see, useful in the treatment of disorders or diseases that are sensitive to the inhibitory activity of the compounds according to the invention in relation to the neurotransmitter monoamine.

Another objective of this invention is to provide a method of treatment of diseases or disorders that are sensitive to inhibition of reuptake of the neurotransmitter monoamine, in particular serotonin reuptake, such as depression and related disorders, obsessive-compulsive disorder, panic disorder, memory impairment, hyperactivity with attention deficit, obesity, anxiety and eating disorders.

Other objectives will become clear to experts in the process of reading materials of the invention.

Summary of the invention

Thus, according to this invention, inter alia, offered the following, single or in combination:

The compound having the formula

< / BR>
or any of its enantiomers or any mixture of those pharmaceutically acceptable salt accession acid or its N-oxide,

where

X and Y together form =O, =S, =NOR2, =CR3R4, =N-CN, =N-NR7R8, (CH2)m- or-W'-(CH2)p-W"-, or one of X and Y is in dorog, -COOR9;

R3and R4independently represent hydrogen, halogen, alkyl, cycloalkyl, cycloalkenyl, alkenyl, quinil, alkoxy, aryl, arylalkyl or -(CH2)q-COOR2;

R2, R5and R6independently represent hydrogen, alkyl, cycloalkyl, cycloalkenyl, alkenyl, quinil, aryl or arylalkyl, -CO-alkyl or-SO2-alkyl;

R7and R8independently represent hydrogen, alkyl, cycloalkyl, cycloalkenyl, alkenyl, quinil, aryl or arylalkyl;

R9represents alkyl, alkenyl or quinil;

R1represents alkyl, alkenyl, quinil, aryl or arylalkyl;

where these aryl groups may be substituted by one or more than one Deputy, selected from the group consisting of halogen, CF3, CN, alkoxy, cycloalkane, alkyl, cycloalkyl, alkenyl, quinil, amino and nitro;

W' and W" each independently represents O 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;

the connection, as described above, which is a

(1S, 2S, 4S, 7R)-2-(3,4-dichlorophenyl)-8 - azatricyclo[5.4.0.04,8]undecane-11-he,

(1S, 2S, 4S, 7R)-2-(3,4-dichlorophen is h,

(1S, 3S, 4R,8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8] Decan-5-he O-methyloxime,

(1S,2S,4S,7R)-2-(4-chlorophenyl)-8-azatricyclo[5.4.0.04,8] undecane-11-he,

(1S,3S,4S,8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8] Decan-5-ol,

(1S, 3S, 4S,8R)-3-(3,4-dichlorophenyl)-7 - azatricyclo[5.3.0.04,8]Oct-5-ylacetic,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8] Oct-5-Ilmatar-sulfate,

(1S, 3S, 4S,8R)-3-(3,4-dichlorophenyl)-5-methoxy-7-azatricyclo [5.3.0.04,8] Dean,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-5-ethoxy-7-azatricyclo[5.3.0.04,8] Dean,

(1S,3S,4S,8R)-3-(4-chlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he,

(1S,3S,4S,8R)-3-(4-chlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-ol,

(1S,3S,4S,8R)-3-(4-chlorophenyl)-5-ethoxy-7-azatricyclo[5.3.0.4,8]Dean,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he O-benzyl-oxime,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he O-allyl-oxime,

(1S, 3S, 4S,8R)-3-(3,4-dichlorophenyl)-7 - azatricyclo[5.3.0.04,8]Decan-5-he oxime,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he O-tert-butyloctyl,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he O-ethyl-oxime,

(1S, 3S,4S,8R)-5-allyloxy-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8] Dean,

ethyl (1S, 3S, 4S, 8R)-2-[3-(3,4-dichlorophenyl)-7-asatru is N1-[(1S, 3S, 4S, 8R)-3-(4-chlorophenyl)-7-azatricyclo[5.3.0.04,8] Oct-5-yl] ndimethylacetamide or

(1S, 3S,4S,8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Oct-5-ylamine or its pharmaceutically acceptable salt of the merger;

pharmaceutical composition comprising an effective amount of a compound, such as any of the above, together with at least one pharmaceutically acceptable carrier or diluent;

the use of compounds, such as any of the above, for the manufacture of a medicinal product for the treatment of a disorder or disease of a living animal body, including a human, with a disorder or disease responsive to the inhibition of the reuptake of the neurotransmitter monoamine in the Central nervous system:

the use of compounds, such as any of the above, for the manufacture of a medicinal product for the treatment of a disorder or disease of a living animal body, including a human, with a disorder or disease responsive to the inhibition of serotonin reuptake in the Central nervous system;

applying the connection, such as any of the above, for the manufacture of drug substances is-compulsive disorder, panic disorder, memory impairment, hyperactivity with attention deficit, obesity, anxiety and eating disorders;

application, such as any of the above, in which the connection is:

(1S, 2S, 4S, 7R)-2-(3,4-dichlorophenyl)-8 - azatricyclo[5.4.0.04,8]undecane-11-he,

(1S, 2S, 4S, 7R)-2-(3,4-dichlorophenyl)-8-azatricyclo[5.4.0.04,8] undecane-11-ol,

(1S,3S,4S,8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8] Decan-5-he,

(1S, 3S, 4S,8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8] Decan-5-he O-methyl-oxime,

(1S,2S,4S,7R)-2-(4-chlorophenyl)-8-azatricyclo[5.4.0.04,8] undecane-11-he,

(1S,3S,4S,8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8] Decan-5-ol,

(1S, 3S, 4S,8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8] Oct-5-ylacetic,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8] Oct-5-Ilmatar-sulfate,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-5-methoxy-7-azatricyclo[5.3.0.04,8] Dean,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-5-ethoxy-7-azatricyclo[5.3.0.04,8] Dean,

(1S,3S,4S,8R)-3-(4-chlorophenyl)-7-azatricyclo[5.3.0.04,8] Decan-5-he,

(1S,3S,4S,8R)-3-(4-chlorophenyl)-7-azatricyclo[5.3.0.04,8] Decan-5-ol,

(1S,3S,4S,8R)-3-(4-chlorophenyl)-5-ethoxy-7-azatricyclo[5.3.0.4,8] Dean,

(1S, 3S, 4S,8R)-3-(who lo[5.3.0.04,8] Decan-5-he O-allyl-oxime,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he oxime,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he O-tert-butyloctyl,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he O-ethyl-oxime,

(1S, 3S,4S,8R)-5-allyloxy-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8] Dean, ethyl

(1S, 3S, 4S,8R)-2-[3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.4,8] Oct-5-ilidene]acetate

(1S,3S,4S,8R)-3-(4-chlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he oxime,

N1-[(1S, 3S, 4S, 8R)-3-(4-chlorophenyl)-7-azatricyclo[5.3.0.04,8] Oct-5-yl] ndimethylacetamide or

(1S,3S,4S,8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8] Oct-5-ylamine

or its pharmaceutically acceptable salt accession acid;

the method of treatment of a disorder or disease of a living animal body, including a human, with a disorder or disease responsive to the inhibition of the reuptake of the neurotransmitter monoamine in which such required treatment with a living body, including a human, is administered a therapeutically effective amount of a compound, such as any of the above;

the method of treatment of a disorder or disease of a living animal body, including cha, where such a need in the treatment of a living body, including a human, is administered a therapeutically effective amount of a compound, such as any of the above;

way, such as any of the above, when treating depression and related disorders, such as pseudodementia or syndrome Ganzera, obsessive-compulsive disorder, panic disorder, memory impairment, hyperactivity with attention deficit, obesity, anxiety or eating disorders; and

the method of obtaining the compounds as defined above, in which the formation of condensed tropenbos a ring having the formula

< / BR>
where n and R1such, as defined in paragraph 1 through the circuit in the cycle of compounds of formula

< / BR>
where n and R1such, as defined in paragraph 1, and after that can transform the compound obtained into another compound of the invention using conventional methods, and/or may carry out the formation of its pharmaceutically acceptable salts.

Examples of pharmaceutically acceptable salts of joining include salt accession of inorganic and organic acids, such as hydrochloride, gabat, cinnamate, bansilalpet, methanesulfonate, stearate, succinate, glutamate, glycolate, toluene-p-sulfonate, formate, malonate, naphthalene-2-sulfonate, salicylate and acetate. Such salts are formed by methods well known in this field.

Other acids, such as oxalic acid, while not in themselves pharmaceutically acceptable, may be useful for obtaining salts useful as intermediates in obtaining the compounds according to the invention and their pharmaceutically acceptable salts accession acids.

Halogen represents fluorine, chlorine, bromine or iodine.

Alkyl means a straight or branched chain of from one to six carbon atoms, including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl; preferred groups are methyl, ethyl, propyl and isopropyl.

Cycloalkyl means cyclic alkyl of from three to seven carbon atoms, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Alkenyl means a group of two to six carbon atoms, comprising at least one double bond, such as, but not limited to e is six carbon atoms, comprising at least one triple bond, such as, but not limited to this example, ethinyl, 1,2-, 2,3-PROPYNYL, 1,2-, 2,3 - or 3,4-butynyl.

Cycloalkenyl means cycloalkyl and alkyl, as defined above, such as cyclopropylmethyl.

Alkoxy represents O-alkyl, where alkyl such as defined above.

Cycloalkane is an O-cycloalkyl where cycloalkyl such as defined above.

Amino represents NH2or NH-alkyl or N-(alkyl)2where alkyl such as defined above.

Aryl represents an aromatic hydrocarbon, such as phenyl or naphthyl.

I. p. means known intraperitoneally route of administration of the drug.

P. o. means known oral route of administration of the drug.

Further, the compounds of this invention can exist as in resolutional and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc., In General, for the purposes of this invention, the solvated forms are considered equivalent nonsolvated.

Professionals should take into attention to detail is uschestvuyut in the form of isomers (i.e., enantiomers). The invention includes all such isomers and any mixtures thereof, including racemic.

Some of the compounds of the present invention exist in (+)- and (-)-forms, as well as in racemic forms. The racemic forms can be separated into the optical antipodes by known methods, for example by separation of the diastereomeric salts with optically active acid and liberation of the optically active amino compounds by treatment with base. Another method of separation of racemates on the optical antipodes based on chromatography on optically active matrix. Alternatively, racemic compounds of the present invention can be separated into their optically active antipodes, for example by fractional crystallization of d - or l-salts (tartratami, mandelate or camphorsulfonate).

Compounds of the present invention can also be separated through the formation of diastereomeric amides by the interaction of these compounds of the present invention with an optically active activated carboxylic acid such as acid, derived from (+)- or (- ) phenylalanine, (+)or (- ) phenylglycine, (+)- or (-)- campanulas acid, Lee is in the shadow with optically active chloroformiate or similar connection.

Can be used well-known experts in this field additional methods of separation of optical isomers, which will be obvious to a worker with average skills in this area. Such methods include the methods discussed J. Jaques, A. Collet and S. Wilen in "Enantiomers, Racemates and Resolutions", John Wiley and Sons, New York (1981).

Compounds according to this invention can be obtained in a variety of ways. Because of this, the compounds according to the invention and their pharmaceutically acceptable derivatives may be obtained by any known in this field by the method of obtaining compounds of similar structure and as shown in the following examples.

Diagram 1 at the end of the description, illustrates one way by which can be obtained the compounds according to the invention.

In scheme 1, the substituents R and R 'denote alkyl, Hal is a halogen, and n and R' are such as defined above.

The processes in the reaction of scheme 1 is carried out in the traditional way.

Compounds according to the invention, in which X and Y together form =O or where one of X and Y is OH and the other is hydrogen, can be converted into other compounds according to the invention using the project)

In reaction scheme 2, W', W", R1, R2, R3, R4, R7, R8n and p are such as defined above.

In reaction scheme 3, R0represents alkyl, cycloalkyl, cycloalkenyl, alkenyl, quinil, aryl and arylalkyl, and n and R1such as defined above.

The processes in the above reaction schemes carry out the traditional way.

Starting materials for the processes described in this application for the invention are known or can be obtained by known methods from commercially available materials, see, for example, patent application U.S. N 5444070.

The products described herein reactions produce by conventional methods such as extraction, crystallization, distillation, chromatography, etc.

Biology

Compounds according to the invention were tested for their ability to inhibit the reuptake of dopamine (DA), noradrenaline (NA) and serotonin (5-HT) uptake.

Prerequisites

Specific centers of nerve endings responsible for transport/capture neurotransmitters, presumably acting terminera the passage of the neural signal by removing the neurotransmitters dopamine, nmout to be measured in vitro by synaptosomal capture2H-dopamine,3H-nordicana and3H-serotonin, respectively.

Inhibition capture3H-dopamine (3H-DA) in the veins uptake in vitro

Preparation of tissue preparations

The drugs are prepared at a temperature of 0-4oC, unless otherwise noted. Striatum of male Wistar rats (150-200 g) homogenized for 5-10 s in 100 volumes of the cooled in ice of 0.32 M sucrose solution containing 1 mm pargyline using a homogenizer Ultra-Turrax. The presence of pargyline will inhibit monoaminoxidase activity. The homogenate was centrifuged at 1000 x g for 10 minutes the resulting supernatant further centrifuged at 27000 x g for 50 min, then the supernatant discarded. The precipitate (P2) resuspending in the saturated oxygen (balanced in an atmosphere of 96% O2: 4% CO2for at least 30 min) buffered Krebs-ringer for incubation (8000 ml per g of original tissue) at a pH of 7.2, containing 122 mm NaCl, 0.16 mm EDTA, 4.8 mm KCl, 12.7 mm Na2HPO4, 3.0 mm NaH2PO4, 1.2 mm MgSO4, 1 mm CaCl2, 10 mm glucose and 1 mm ascorbic acid.

Analysis

Aliquots of tissue suspension with the volume of 4.0 ml added to 100 μl of test solution and 100 μl of a solution s takeover measure, using benztropine (final concentration 10 μm). After incubation the samples applied with suction directly on glass-fiber filters Whatman GF/C Then the filters are washed three times with cooled in ice 0,9% (V/o) NaCl, using each time 5 ml of this solution. The quantity of radioactive material on the filters was determined by conventional liquid scintillation spectroscopy. Specific capture is calculated as the difference between total and nonspecific capture.

Before you can calculate the value of the IC50you need to get 25-75% inhibition of specific binding.

The measured value is shown in the values of the IC50(the concentration (μm) test compound that causes inhibition of specific binding3H-DA at 50%).

Inhibition capture3H-norepinephrine (3H-NA) uptake in the hippocampus in vitro

Preparation of tissue preparations

The drugs are prepared at a temperature of 0-4oC, unless otherwise noted. The hippocampus of male Wistar rats (150-200 g) homogenized for 5-10 s in 100 volumes of the cooled in ice of 0.32 M sucrose solution containing 1 mm pargyline using a homogenizer Ultra-Turrax. Presets is their 10 minutes The obtained supernatant further centrifuged at 27000 x g for 50 min, then the supernatant discarded. The precipitate (P2) resuspending in the saturated oxygen (balanced in an atmosphere of 96% O2: 4% CO2for at least 30 min) buffered Krebs-ringer for incubation (2000 ml per g of original tissue) at a pH of 7.2, containing 122 mm NaCl, 0.16 mm EDTA, 4.8 mm KCl, 12.7 mm Na2HPO4, 3.0 mm NaH2PO4, 1.2 mm MgSO4, 0,97 mm CaCl2, 10 mm glucose and 1 mm ascorbic acid.

Analysis

Aliquots of tissue suspension with the volume of 4.0 ml added to 100 μl of test solution and 100 μl of solution3H-NA (final concentration 1 nm), mixed and incubated for 90 min at 37oC. Nonspecific capture measured using desipramine (final concentration 1 μm). After incubation the samples applied with suction directly on glass-fiber filters Whatman GF/C Then the filters are washed three times with cooled in ice 0,9% (V/o) NaCl, using each time 5 ml of this solution. The quantity of radioactive material on the filters was determined by conventional liquid scintillation spectroscopy. Specific capture is calculated as the difference between total and n is about inhibition of specific binding.

The measured value is shown in the values of the IC50(the concentration (μm) test compound that causes inhibition of specific binding3H-NA 50%).

Inhibition capture3H-5-hydroxytryptamine (3H-5-HT, serotonin) in the cortical uptake in vitro

Preparation of tissue preparations

The drugs are prepared at a temperature of 0-4oC, unless otherwise noted. The cerebral cortex of male Wistar rats (150-200 g) homogenized for 5-10 s in 100 volumes of the cooled in ice of 0.32 M sucrose solution containing 1 mm pargyline using a homogenizer Ultra-Turrax. The presence of pargyline will inhibit monoaminoxidase activity. The homogenate was centrifuged at 1000 x g for 10 minutes the resulting supernatant further centrifuged at 27000 x g for 50 min, then the supernatant discarded. The precipitate (P2) resuspending in the saturated oxygen (balanced in an atmosphere of 96% O2: 4% CO2at least for 30 min) buffered Krebs-ringer for incubation (1000 ml per gram of original tissue) at a pH of 7.2, containing 122 mm NaCl, 0.16 mm EDTA, 4.8 mm KCl, 12.7 mm Na2HPO4, 3.0 mm NaH2PO4, 1.2 mm MgSO4, 1 mm CaCl2, 10 mm glucose and 1 mm ascorbic acid.

3H-5-HT (final concentration 1 nm), mixed and incubated for 30 min at 37oC. Nonspecific capture measured using citalopram (final concentration 1 μm). After incubation the samples applied with suction directly on glass-fiber filters Whatman GF/C Then the filters are washed three times with cooled in ice 0,9% (V/o) NaCl, using each time 5 ml of this solution. The quantity of radioactive material on the filters was determined by conventional liquid scintillation spectroscopy. Specific capture is calculated as the difference between total and nonspecific capture.

Before you can calculate the value of the IC50you need to get 25-75% inhibition of specific binding.

The measured value is shown in the values of the IC50(the concentration (μm) test compound that causes inhibition of specific binding3H-5-HT by 50%).

The test results for selected compounds of the present invention seen from the above at the end of table 1.

The above results indicate that the tested compounds effectively inhibit reverse smotra, what for therapeutic purposes in connection with this invention can be used as a source of a chemical, it is preferable to present the active ingredient as a pharmaceutical preparation.

Thus, according to this invention proposed pharmaceutical preparations containing the compound according to the invention, or its pharmaceutically acceptable salt, or its derivative together with one or more pharmaceutically acceptable carriers and, possibly, other therapeutic and/or prophylactic ingredients. The carrier(s) must be "acceptable" in the sense that it is compatible with other ingredients of the drug and safety for the recipient.

Pharmaceutical drugs include drugs that are suitable for oral, rectal, nasal, local (including transbukkalno and sublingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration or drugs in a form suitable for inhalation or insufflation.

Thus, the compounds according to this invention, together with a conventional adjuvant, carrier, or diluent, may be moulded into the form of pharmaceutical compositions and the x capsules either in the form of liquids of the type of solutions, suspensions, emulsions, elixirs, or filled these liquids ampoules (all oral dosage forms), in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and their form in the form of standard doses may contain conventional ingredients in conventional proportions, with an additional active compounds or components, or without them, and such forms of standard doses may contain any effective amount of the active ingredient commensurate with the assigned daily dose. Compositions containing ten (10) milligrams of active ingredient or, in a wider range, from 0.1 to 100 milligrams per tablet, are therefore the most appropriate standard dose.

Compounds of the present invention can be administered orally and parenterally in a wide range of dose forms. For professionals it is obvious that these dose forms may contain as an active ingredient or compound according to this invention, or pharmaceutically acceptable salt of the compounds according to the invention.

ielemia media can be used in solid, and in liquid form. Solid dosage forms are powders, tablets, pills, capsules, starch wafers, suppositories and dispersed granules. A solid carrier can be one or more substances, which may additionally serve as diluents, corrigentov, solubilization, lubricants, suspendida agents, binders, preservatives, agents, providing the necessary raspadaemost tablet, or encapsulating material.

In powders, the carrier is a finely powdered solid substance, which is present in a mixture with finely ground active ingredient.

In tablets, the active ingredient in the desired proportions are mixed with carrier having the necessary binding capacity, and pressed to the desired shape and size.

The powders and tablets preferably contain from five or ten to about seventy percent of the active compounds. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragakant, methylcellulose, sodium form of carboxymethyl cellulose, low melting wax, cocoa, together with the encapsulating material, used as a carrier providing a capsule in which the active component, with or without carriers, is surrounded by carrier, which thus becomes associated with him. Similarly this applies to the starch wafers and cakes. Tablets, powders, capsules, pills, starch wafers and cakes can be applied in the form of solid forms suitable for oral administration.

To obtain suppositories initially melted low-melting wax such as a mixture of glycerides of fatty acids or cocoa butter, and homogeneous dispersed active component, for example by stirring. The molten homogeneous mixture is then poured into forms convenient sizes, leave to cool and, respectively, from hardening.

Pharmaceutical preparations for vaginal introduction can be presented in the form of vaginal suppositories, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient necessary, well-known specialists in the media.

Liquid dosage forms include solutions, suspensions and emulsions, such as water or water-propylene glycol solutions. Naparima.

Thus, the compounds of the present invention can be prepared as part of preparations for parenteral administration (e.g. by injection, for example bolus-injection or continuous infusion) and may be presented in the form of standard doses in ampoules, pre-filled syringes, containers for infusion of small volumes or containers for repeated dosing with added preservative. Song data can be presented in such forms as suspensions, solutions or emulsions in oily or aqueous solvents, and can contain suspendida, stabilizing and/or dispersing agents. On the other hand, the active ingredient may be in powder form, obtained by selection in aseptic conditions with sterile solid content or by lyophilization from solution intended for dilution prior to use in a suitable solvent, such as sterile pyrogen-free water.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding, if desired, suitable tint agents, corrigentov, stabilizers and thickeners.

In addition, this invention provides preparations in solid form intended to become immediately before by oral administration in liquid form. Such liquid forms are solutions, suspensions and emulsions. These drugs, in addition to the active ingredient may contain tinted agents, corrigentov, stabilizers, buffers, artificial and natural sweeteners, dispersing agents, thickeners, solubilizing agents, etc.

For topical application to the epidermis of the compounds of the present invention can be prepared in the form of ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be made on an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions can be prepared in water or oil based and, as a rule, must contain one or more emulsifiers, stabilizers, dispersing agents, suspendida agents, C is the actu, represent the pellet containing the active agent enclosed in corrigent, usually sucrose and Arabian gum or tragakant; tablets containing the active ingredient enclosed in an inert basis of the type of gelatin, glycerin, or sucrose and Arabian gum: fluid for rinsing the mouth, containing the active ingredient in a suitable liquid carrier.

The solutions or suspensions are injected directly into the nasal cavity by conventional means, for example using a dropper, pipette or spray. Drugs can be applied in the form of single and multiple doses. In the latter case, when using a dropper or pipette, this is achieved by introducing the patient is appropriate, predetermined volume of solution or suspension. When using spray this can be achieved, for example, by using a metering spray filing of the aerosol.

Introduction to the respiratory tract may also be achieved through the use of the drug in aerosol form, the active ingredient of which is presented in a sealed package with the appropriate propellant, such as chlorofluorocarbon (CFC), for example DICHLORODIFLUOROMETHANE, trichlor the neigh surfactant, such as lecithin. The dose of a drug can be controlled by setting the metering valve.

On the other hand, the active ingredients can be represented in the form of a dry powder, such as powder of a mixture of compounds according to the invention with a suitable powder base type lactose, starch, derivatives of starch, hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP). Convenient is the formation in the nasal cavity of a gel based powder media. Composition in powder form can be represented in the form of a standard dose of, for example, capsules or cartridges, in particular, gelatin, or in the exhaust transparent packaging, powder of which can be entered using the inhaler.

Particles of compounds in preparations intended for administration to the respiratory tract, including intranasal preparations typically will be small, for example of the order of 5 microns or less. Such particle size can be obtained by means known in the art methods, for example by grinding in the micron mill.

If desired, can be applied drugs, adapted for long-term release of the active ingredient.

Pharmaceuticalindustry dose containing appropriate quantities of the active component. The standard dose can be a packaged preparation, the package contains the separated quantity of the drug, such as packaged tablets, capsules, and powders in vials or ampoules. In addition, the standard dose itself may be represented in the form of capsules, tablets, starch wafer or pellet, or it can represent the appropriate number of any of these forms in Packed form.

The preferred compositions are tablets or capsules for oral administration and liquid forms for intravenous administration.

Treatment

The compounds of this invention are particularly useful in the treatment of depression and related diseases due to their activity, inhibiting the capture of serotonin and dopamine, and minor unwanted side effects. These properties make the compounds of the present invention is extremely useful for the treatment of obsessive-compulsive disorders, panic disorders, memory disorders, disorders hyperactivity with attention deficit, obesity, anxiety and eating disorders, as well as other Rasso the present invention. In accordance with these compounds in this invention can be introduced to the living animal body, including human, in need of the treatment, alleviation or elimination of symptoms associated with or responsible for the activity, inhibitory capture of dopamine and serotonin.

Acceptable doses are in the range of 0.1 to 500 milligrams daily, and especially 10-70 mg per day, administered in one or two steps, that is usually defined by way of introduction, the form of the medication, indications for use, condition and body weight is affected by the disease of the patient, as well as the opinion and experience of the attending physician or veterinarian.

The following examples illustrate the invention, however, they should not be construed as limiting the scope of invention.

Example 1

< / BR>
Ethyl ester of (1R, 2R, 3S,5S)-3-(3,4-dichlorophenyl)-8 - azabicyclo[3.2.1] octane-2-carboxylic acid (2b)

Ethyl ester of (1R, 2R, 3S, 5S)-3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1] octane-2-carboxylic acid (1b) (17.9 g) was dissolved in 100 ml of anhydrous 1,2-dichloroethane and the solution was added 1-chloroethylphosphonic (7.5 ml). The reaction mixture is refluxed for 3 hours and then evaporated to state marivoet to the state of the oil. The oil is dissolved in water, add conc. ammonia (aqueous) to pH 10 and the aqueous phase is extracted with ether, the organic phase is dried over magnesium sulfate and evaporated to a oil. The output of 18.7 g (107%).

Example 2

< / BR>
Ethyl ester of (1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-8-(2 - ethoxycarbonylethyl)-8-azabicyclo[3.2.1]octane-2-carboxylic acid (3b)

Ethyl ester of (1R, 2R, 3S,5S)-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]- octane-2-carboxylic acid (2b) (8,3 g) dissolved in dimethyl sulfoxide (40 ml) and to the solution was added potassium hydroxide (5.6 g) and ethyl-3-bromopropionate(3.8 ml). The reaction mixture was stirred over night at room temperature and poured into 200 ml of water, the resulting solution was washed with ether, dried over magnesium sulfate and evaporated to a oil. Yield 8.5 g (80%), MS m/z 427 + 429.

Example 3

< / BR>
(1S, 2S, 4S,7R)-2-(3,4-Dichlorophenyl)-8 - azatricyclo[5.4.0.0.4,8]undecane-11-he (4)

Ethyl ester of (1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-8-(ethoxycarbonylethyl)-8 - azabicyclo[3.2.1] octane-2-carboxylic acid (3b) (8.5 g) was dissolved in anhydrous toluene and to the solution was added sodium hydride (0.5 g) (60% DISP. in the oil). The reaction mixture is refluxed for a half hour and then evaporated to oil condition that restore matney temperature and add 12 M NaOH (aq.) to pH 12. The solution is washed with ether, dried over magnesium sulfate and evaporated to a oil. The output of 1.9 g (31%), GC/MS 96% purity, M = 309 + 311.

Example 4

< / BR>
(1S, 2S, 4S, 7R)-2-(3,4-Dichlorophenyl)-8 - azatricyclo[5.4.0.04,8]undecane-11-he O-methyloxime (5)

(1S, 2S, 4S, 7R)-2-(3,4-Dichlorophenyl)-8-azatricyclo[5.4.0.04,8] undecane-11-he (4) (1.4 g) is dissolved in methanol and to the solution add methoxylamine hydrochloride (0.6 g) and potassium carbonate (1.4 g). The suspension is stirred for 16 hours at room temperature and then evaporated to a oil which was dissolved in 1 M HCl and washed with ether. To the aqueous phase add 12M NaOH to pH 12 and extracted with ether. The organic phase is dried over magnesium sulfate and evaporated to a oil. Yield 0.2 g, MS: m/z 338 (M+80), 340 (M++2, 51), 342 (M++ 4, 8).

Example 5

< / BR>
(1S, 2S, 4S, 7R)-2-(3,4-Dichlorophenyl)-8 - azatricyclo[5.4.0.04,8]undecane-11-ol (6)

(1S, 2S, 4S, 7R)-2-(3,4 - Dichlorophenyl)-8-azatricyclo[5.4.0.04,8]undecane-11-he (4) (0.5 g) dissolved in methanol (10 ml) and to the solution was added sodium borohydride (0.2 g). The reaction mixture is stirred for 2 hours at room temperature, then add water (0.5 ml) and evaporated to a oil. To the oil is added ethyl acetate (10 ml) and 1 M the SLA. The oil is purified using flash chromatography on silica gel, elwira a mixture of dichloromethane/methanol/25% ammonia (aq. ) (89/10/1 about/about). The fractions containing the product evaporated to a foam. Yield 200 mg (40%). MS(EI+): m/z 311 (M+, 100), 313 (M++ 2, 68), 315 (M++ 4, 12).

(1S, 2S, 4S, 7R,11R)-2-(3,4-Dichlorophenyl)-8-azatricyclo[5.4.0.04,8] undecane-11-ol (6a)

Specified in the header of the get connection as well as connection (6), but the cleaning is performed by chromatography on silica gel (dichloromethane/acetone/methyl alcohol (4/1/1)). Yield 0.2 g (18%) as white crystals, so pl. 185,6-186,9oC.

Example 6

< / BR>
Methyl ester (1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-8- (ethoxycarbonylmethyl)-8-azabicyclo[3.2.1]octane-2-carboxylic acid (7)

To methyl ether (1R,2R,3S,5S)-3-(3,4-dichlorophenyl)- 8-methyl-8-azabicyclo[3.2.1] octane-2-carboxylic acid (1A), (19,4 g) in anhydrous 1,2-dichloroethane (125 ml) was added 1-chloroethylphosphonic (10 ml). The reaction mixture is refluxed for 16 hours, leave at room temperature for 48 hours and then evaporated to a oil. The oil was dissolved in methanol (125 ml) and the solution refluxed for 45 minutes, then evaporated to a oil. The oil is dissolved over magnesium sulfate and evaporated to a oil. The oil is dissolved in absolute ethanol (180 ml) and to the solution add ethylbromoacetate (7.7 ml) and potassium carbonate (10.2 g). The reaction mixture is refluxed for 2 hours, then stirred at room temperature overnight and evaporated to a oil. To the oil add water (0.5 l) and extracted with ether (2 x 300 ml); the combined ether phases are dried over magnesium sulfate and evaporated to a oil. The oil is purified flash chromatography on silica gel 60 (400 g), elwira with ethyl acetate and petroleum ether (1:1); the fractions containing the product evaporated to oil condition. Yield 10 g (42%). MS(EI+): m/z 399 (M+, 12), 401 (M++ 2, 7), 403 (M++ 4, 2).

Example 7

< / BR>
(1S, 3S, 4S,8R)-3-(3,4-Dichlorophenyl)-7 - azatricyclo[5.3.0.04,8]Decan-5-he (8)

To methyl ether (1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-8-(ethoxycarbonylmethyl)-8 - azabicyclo[3.2.1] -octane-2-carboxylic acid (7) (22,4 g) in xylene (200 ml) was added 1 M ethoxide sodium in ethanol (63 ml). The solution is distilled until the temperature reaches 138oC, then refluxed for 90 minutes. To the reaction mixture are added water (50 ml) and conc. hydrochloric acid (15 ml) and refluxed for 16 hours. To the reaction mixture EXT is to maintain a constant volume of solution. To the residue add water to a final volume of 0.5 l, add conc. ammonia (aqueous) to pH 10, and the product which precipitates after separation by filtration washed with ether (50 ml). Yield 13 g (78%), so pl. 176-182oC.

Example 8

< / BR>
(1S, 3S, 4S,8R)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.04,8] Decan-5-he O-methyloxime (9)

(1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-7 - azatricyclo[5.3.0.04,8]Decan-5-he

(8) (0.29 grams) and methoxylamine hydrochloride (0.09 g) was dissolved in absolute ethanol (50 ml). The reaction mixture is refluxed for 4 hours and then evaporated to a oil. The oil is suspended in water (50 ml) and to it add conc. ammonia (aqueous) to pH 10, then extracted with ether. The ether phase is dried over magnesium sulfate and evaporated to a oil. The residue is dissolved in absolute ethanol and to it add 0.4 M fumaric acid in absolute ethanol (1.9 ml); the solution is evaporated to a foam. The output of 0.29 g (66%), so pl. 143-146oC.

Example 9

< / BR>
Methyl ester (1R,2R,3S,5S)-3-(4-chlorophenyl)-8- (ethoxycarbonylethyl)-8-azabicyclo[3.2.1]octane-2-carboxylic acid (11)

Methyl ester of (1S, 2S, 4S, 7R)-2-(4-chlorophenyl)-8-methyl-8 - azabicyclo[3.2.1] octane-2-carboxylic kilotonne the mixture is refluxed for 4.5 hours and then evaporated to a oil. The residue is dissolved in methanol (100 ml) and the solution refluxed for 1 hour. The reaction mixture was evaporated to a oil which is dissolved in water, add 25% ammonia (aqueous) to pH 10 and the solution is extracted with ether; the organic phase is washed with water, dried over magnesium sulfate and evaporated to a oil which crystallizes as standing at room temperature. The solid is dissolved in absolute ethanol (200 ml) and to the solution was added potassium carbonate (15 g) and ethyl-3-bromopropionate (12 ml); the reaction mixture is refluxed for 3 hours, then evaporated to a oil, to which is added ether and water. The ether phase is washed with water, dried over magnesium sulfate and evaporated to a oil. The oil is purified flash chromatography on silica gel (300 g), elwira with ethyl acetate. The fractions containing the product evaporated to oil condition. Yield 24 g (80%). MS(EI+); m/z 379 (M+, 52), 381 (M++ 2, 17), 383 (M++ 4, 2).

Example 10

< / BR>
(1S, 2S, 4S, 7R)-2-(4-Chlorophenyl)-8-azatricyclo[5.4.0.04,8] undecane-11-he (12)

Methyl ester (1R,2R,3S,5S)-3-(4-chlorophenyl)-8- (ethoxycarbonylmethyl)-8-azabicyclo[3.2.1]octane-2-carboxylic acid (10) (3,15 g) dissolve the ü is refluxed for 4 hours, cooled to room temperature and add the crushed ice and 4 n hydrochloric acid (15 ml). Then the ice melted, carry out the separation of the phases, the aqueous phase washed with ether (2 x 50 ml), add conc. ammonia (aqueous) to pH 10 and extracted with dichloromethane. The organic phase is washed with saline, dried over magnesium sulfate and evaporated to a oil. To the oil is added conc. hydrochloric acid (20 ml) and ethanol (96%) as long as there remains a state of solution; the reaction mixture is refluxed for 16 hours, cooled to room temperature and add the crushed ice and conc. ammonia (aqueous) to pH 10, then extracted with dichloromethane; the organic phase is dried over magnesium sulfate and evaporated to a oil which crystallized from ethanol (96%). Yield 0.24 g (11%), so pl. 156,5-157,7oC.

Example 11

< / BR>
(1S, 3S, 4S,8R)-3-(3,4-Dichlorophenyl)-7 - azatricyclo[5.3.0.04,8]Decan-5-ol (13)

(1S, 3S, 4S,8R)-3-(3,4 - Dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he (8) (1 g) is dissolved in methanol and to the solution was added sodium borohydride (0.26 g). The reaction mixture is stirred for 30 minutes at room temperature, then add water (0.5 ml) and evaporated over magnesium sulfate and evaporated to a foam. The yield of 0.67 g (66%), so pl. 203-205oC.

Fumarate

Specified in the title compound (7 g, 25.5 mmole) is dissolved in methyl alcohol, the solution was added fumaric acid (3 g, 16 mmol) in methyl alcohol and refluxed until then, until the solution remained transparent; salt fumaric acid specified in the title compound precipitates, then the solution is cooled in a bath containing ice water, the crystals are subjected to recrystallization from absolute ethanol (150 ml) and water (46 ml). Output 5,42 g, so pl. 250,5-251oC.

Example 12

< / BR>
(1S, 3S, 4S,8R)-3-(3,4-Dichlorophenyl)-7 - azatricyclo(5.3.0.04,8]Oct-5-ylacetic fumarate (14)

(1S, 3S, 4S,8R)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.04,8] Decan-5-ol (13) (1 g, 3.3 mmole) was dissolved in glacial acetic acid (5 ml) and to the solution was added concentrated hydrochloric acid (5 ml); the reaction mixture is refluxed for 90 minutes, then cooled to room temperature and added 25% aqueous ammonia to a pH value of 9.5; the aqueous phase is extracted with diethyl ether. The ether phase is concentrated to the state of the oil, the residue chromatographic on silica gel (dichloromethane/acetone/methyl alcohol 4/1/1). Fractions of alcohol, and to the solution was added a solution of fumaric acid (0.14 g; 1.2 mmole) in methyl alcohol, whereupon the product precipitates in the form of white crystals, which are separated by filtration. Yield 0.36 g (24 %), so pl. 214-216oC.

Example 13

< / BR>
(1S, 3S, 4S, 8R)-3-(3,4-Dichlorophenyl)-7 - azatricyclo[5.3.0.04,8]Oct-5-Ilmatar-sulfate (15)

(1S, 3S, 4S, 8R)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-ol (13) (1 g, 3.3 mmole) dissolved in dichloromethane (150 ml) and to the solution add methanesulfonate (0.3 ml; 3.7 mmole) and triethylamine (1.6 ml, 12 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for one hour, then concentrated to a oil. To the oil is added 4M NaOH and dichloromethane, the organic phase is dried (magnesium sulfate) and concentrated to a foam. The output of 0.61 g (48%), so pl. 139-141oC.

Example 14

< / BR>
(1S, 3S, 4S,8R)-3-(3,4-Dichlorophenyl)-5-methoxy-7 - azatricyclo[5.3.0.04,8] Dean (16)

(1S, 3S, 4S,8R)-3-(3,4 - Dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-ol (13) (1.3 g; 4.4 mmole) dissolved in anhydrous tetrahydrofuran (30 ml) and to the solution was added tert-piperonyl potassium (1.54 g; of 13.8 mmole); the reaction mixture is stirred at room temperature in a nitrogen atmosphere at t is e; 4.3 mmole) with such speed that the temperature of the mixture did not exceed -65oC; the reaction mixture is stirred at this temperature for one hour, after which she is allowed to warm to room temperature and to it was added water (50 ml), then extracted with diethyl ether (3 x 50 ml). The organic phase is dried (sodium sulfate) and concentrate to the condition of the oil, which crystallized in the process of standing at room temperature. Yield 0.32 g (24%), so pl. 119,2 to 120.3oC.

Example 15

< / BR>
(1S, 3S, 4S, 8R)-3-(3,4-Dichlorophenyl)-5-ethoxy-7 - azatricyclo[5.3.0.04,8] Dean fumarate (17)

(1S, 3S, 4S,8R)-3-(3,4-Dichlorophenyl)-7 - azatricyclo[5.3.0.04,8]Decan-5-ol (13) (2 g, 6.7 mmole) was dissolved in anhydrous tetrahydrofuran (40 ml), to the solution was added tert-piperonyl potassium and stirred at room temperature under nitrogen atmosphere for one hour, then cooled to -70oC and add diethylsulfate with such speed that the temperature of the mixture did not exceed -65oC; the reaction mixture is stirred at this temperature for 2 hours, after which she is allowed to warm to room temperature, add water (50 ml) and extracted with diethyl ether (3 x 100 ml); the organic phase is dried (shamarova acid (0.6 g; 5.2 mmole) in methyl alcohol, and the product precipitates. Output 2 g (67%), so pl. 164,1-165,9oC.

Example 16

< / BR>
Ethyl 2-[(1R, 3S, 5R)-3-(4-chlorophenyl)-2-methoxycarbonyl-8 - azabicyclo[3.2.1]-Oct-8-yl]acetate (18)

Methyl (1R,3S,5R)-3-(4 - Chlorophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate (10) (0.88 g: 0,31 mol) dissolved in absolute ethanol (approximately 600 ml), add potassium carbonate (55,2 g; 0,4 mol) and ethylbromoacetate (66,3 g; 0,4 mol), the reaction mixture is refluxed for 2 hours, then concentrated to a oil which chromatographic on silica gel (ethyl acetate); the fractions containing the product, concentrate to the condition of the oil. Exit 98 g (87%).

Example 17

< / BR>
(1S, 3S, 4S,8R)-3-(4-Chlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan - 5-he fumarate (19)

Ethyl 2-[(1R, 3S, 5R)-3-(4-Chlorophenyl)-2 - methoxycarbonyl-8-azabicyclo[3.2.1] Oct-8-yl]acetate (18) (42.8 g; 0.12 moles) dissolved in toluene (400 ml); the solution is heated to the temperature of reflux distilled, using traps Dean-stark collect the solvent until until no more water; the solution is cooled to room temperature and is added sodium methoxide (65 ml; 2.1 M solution in methyl alcohol; of 0.14 mol); the reaction mixture is distilled until then, until the temperature in ethyl alcohol (100 ml) and concentrated to oil condition to which is added 4M hydrochloric acid (35 ml of 0.14 mol) and refluxed for 2 hours; the reaction mixture is cooled to room temperature and to it was added 25% aqueous ammonia to pH 10 with precipitation of the compounds in white, which is separated by filtration and recrystallized from toluene (200 ml). Yield 16 g (52%) as white crystals. Part of the crystals (0,78 g, 3 mmole) was dissolved in absolute ethanol (25 ml) and to the solution was added fumaric acid (0.45 g; 3.8 mmole) and absolute ethanol (5 ml); the mixture is heated to dissolve the contents, then cooled to 5oC and precipitated precipitated product is separated by filtration. The output of 0.99 g (88% (based on free base) in the form of beige crystals color, so pl. 205-206oC.

Example 18

< / BR>
(1S, 3S, 4S,8R)-3-(4-Chlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan - 5-ol fumarate (20)

Specified in the title compound in the form of free base get similarly to (1S, 3S, 4S,8R)-3-(3,4 - dichlorophenyl)-7-azatricyclo[5.3.0.04,8]-decane-5-Ola. Salt of fumaric acid is obtained from the free base (0.7 g; 2.7 mmole) dissolved in ethanol (10 ml; 96%) and the addition of fumaric acid is jut by filtration. Yield 0.9 g (80%) as white crystals, so pl. 230-231oC.

Example 19

< / BR>
(1S, 3S, 4S,8R)-3-(4-Chlorophenyl)-5-ethoxy-7 - azatricyclo[5.3.0.04,8]Dean (21)

Specified in the header of the connection get similarly to (1S,3S,4S,8R)-3-(3,4-dichlorophenyl)-5-ethoxy-7 - azatricyclo[5.3.0.04,8] decane. Yield 0.31 g (36%), so pl. 72-74oC.

Example 20

< / BR>
(1S, 3S, 4S,8R)-3-(3,4-Dichlorophenyl)-7 - azatricyclo[5.3.0.04,8]Decan-5-he O-benzyloxy (22)

Specified in the header of the connection get similarly to (1S,3S,4S,8R)-3-(3,4 - dichlorophenyl)-7-azatricyclo[5.3.0.04,8] Decan-5-he O-methyloxime (9). The yield of 0.51 g (25%), so pl. 125,3-126,4oC.

Example 21

< / BR>
(1S, 3S, 4S,8R)-3-(3,4-Dichlorophenyl)-7 - azatricyclo[5.3.0.04,8]Decan-5-he O-allyloxy fumarate (23)

Specified in the title compound in the form of free base get similarly to (1S, 3S,4S,8R)-3-(3,4-dichlorophenyl)-7 - azatricyclo[5.3.0.04,8]Decan-5-he O-methyloxime (9). The free base is specified in the header of the compound (1 g, 2.8 mmole) is dissolved in ethanol, added fumaric acid (0.35 g, 3 mmole) and the mixture is concentrated to a foam. The output of 0.98 g (42%), so pl. 45-52oC.

Example 22

< / BR>
(1S, 3S, 4S, 8R)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he OKS the P>4,8] Decan-5-he O-methyloxime (9). Yield 0.5 g (32%) in the form of crystals light brown color, so pl. 143,9-144,7oC.

Example 23

< / BR>
(1S, 3S, 4S,8R)-3-(3,4-Dichlorophenyl)-7 - azatricyclo[5.3.0.04,8]Decan-5-he O-tert-butyloctyl fumarate (25)

Specified in the title compound in the form of free base get similarly to (1S, 3S,4S,8R)-3-(3,4-dichlorophenyl)-7 - azatricyclo[5.3.0.04,8]Decan-5-he O-methyloxime (9). Output salts of fumaric acid, 0.51 g (21%) in the form of crystals of light-gray color, so pl. 234-236oC.

Example 24

< / BR>
(1S, 3S, 4S,8R)-3-(3,4-Dichlorophenyl)-7 - azatricyclo[5.3.0.04,8]Decan-5-he O-acyloxy fumarate (26)

Free base get similarly to (1S,3S,4S,8R)-3-(3,4 - dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he O-methyloxime (9).

The free base (0,77 g, 2.3 mmole) is dissolved in methyl alcohol, added fumaric acid (0.29 grams; 2.5 mmole) and the mixture concentrated to dryness. Yield 0.52 g (23%) as a solid light beige color, so pl. 62-69oC.

Example 25

< / BR>
(1S,3S,4S,8R)-5-Allyloxy-3-(3,4-dichlorophenyl)-7 - azatricyclo[5.3.0.04,8] Dean fumarate (27)

To (1S,3S,4S,8R)-3-(3,4 - dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-Olu (13) (2 g, 6.7 mmole) in anhydrous tetrahydrofuran is within 90 minutes then cooled to - 70oC. To this mixture is added dropwise allylbromide (0.8 g; 6.6 mmole) so that the temperature did not exceed -65oC; the reaction mixture is stirred at this temperature for 2 hours, then left to warm to room temperature and add water (50 ml). The mixture is extracted with diethyl ether (CH ml), the organic phase is dried (magnesium sulfate) and concentrate to the condition of the oil. The oil was dissolved in diethyl ether (10 ml) and added fumaric acid (0,49 g, 4.2 mmole) in methyl ether. The mixture is concentrated to a oil, which was triturated in diethyl ether. Specified in the title compound precipitates and is filtered. Yield 1.77 g (58%) as white crystals, so pl. 150,5-152,2oC.

Example 26

< / BR>
Ethyl (1S, 3S, 4S, 8R)-2-[3-(3,4-dichlorophenyl)-7 - azatricyclo[5.3.0.04,8] Oct-5-ilidene]acetate fumarate (28)

Triethylphosphate (of 2.51 g, 11.2 mmole) dropwise under nitrogen atmosphere is added to a mixture of sodium hydride (0.5 g of 60% dispersion in mineral oil, 12 mmol) in anhydrous toluene; the mixture is stirred at room temperature for 30 minutes, after which it was added (1S,3S,4S,8R)-3-(3,4-dichlorophenyl)-7 - azatricyclo[5.4.0.04,8] de is silicagel (dichloromethane/methyl alcohol/acetone, 4/1/1). The fractions containing the product are concentrated to a oil. Yield 1.22 g (30%). Part of the oil (0.36 g; 1 mmol) is dissolved in diethyl ether and added fumaric acid (0,13 g; 1.1 mmole) in methyl alcohol, the mixture is concentrated to oil condition, oil is stirred with diethyl ether and indicated in the title compound precipitates. The yield of 0.37 g (77% (based on free base) in the form of white crystals, so pl. 158 -159oC.

Example 27

< / BR>
(1S,3S,4S,8R)-3-(4-Chlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan - 5-he oxime hydrochloride (29)

(1S, 3S,4S,8R)-3-(4-Chlorophenyl)-7 - azatricyclo[5.3.0.04,8]Decan-5-he (19) (4 g, 15.3 mmole) is dissolved in absolute ethanol (40 ml) and to the solution was added hydroxylamine hydrochloride (1.3 g; an 18.4 mmole). The reaction mixture is refluxed for 90 minutes, then add hydroxylamine hydrochloride (0.2 g, 2.9 mmole) and refluxed for 2 hours. The reaction mixture was stirred in a bath with a mixture of ice/water and indicated in the title compound precipitates. It is separated by filtration. Output 3,93 g (82 %). Part of the product (1 g, 3.2 mmole) crystallized from ethanol (approximately 25 ml) and water (approximately 5 ml). In enyl)-7 - azatricyclo[5.3.0.04,8]Oct-5-yl] ndimethylacetamide (30)

(1S,3S,4S,8R)-3-(4-Chlorophenyl)-7 - azatricyclo[5.3.0.04,8]Decan-5-he oxime hydrochloride (29) (3.13 g; 10 mmol) is dissolved in methyl alcohol (300 ml) and to the solution add a certain amount of Raney Nickel (50% slurry in water). The reaction mixture is stirred in hydrogen atmosphere for 40 hours (flow rate of hydrogen 0,62 l; 26 mmol), filtered through several filters Hyflo Super Cel USA, the filtrate is concentrated to dryness, the residue is added water (150 ml) and 25% aqueous ammonia to pH 10. The aqueous phase is extracted with diethyl ether (3 x 100 ml) and dichloromethane (100 ml), the organic extracts are combined dried (magnesium sulfate) and concentrate to dryness. The residue is dissolved in water (20 ml) and hydrochloric acid (5 ml; 4 M; 20 mmol), stirred, termostatico in the bath with a mixture of ice and water, and add acetic anhydride (8.6 g; 85 mmol) and sodium acetate (8 g, 98 mmol). The reaction mixture is stirred, termostatico in the bath with a mixture of ice and water for 2 hours, filtered, the filtrate add 25% aqueous ammonia to pH 10 with solid which precipitates is separated by filtration, and then chromatographic on silica gel (dichloromethane/methyl alcohol/acetone, 4/1/1). In factions, sod. 22-123,5oC.

Example 29

< / BR>
(1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.04,8] Oct-5-ylamine fumarate (31)

Sodium borohydride (0,81 g, 21.5 mmole) is suspended in anhydrous tetrahydrofuran (40 ml), stirred under nitrogen atmosphere and within 10 minutes added dropwise triperoxonane acid (2,45 g, 21.5 mmole) in anhydrous tetrahydrofuran (5 ml). Next, the reaction mixture was stirred at room temperature for 20 minutes and within 20 minutes add (1S,3S, 4S,8R)-3-(3,4-dichlorophenyl)-7 - azatricyclo[5.3.0.04,8]Decan-5-he O-methyloxime (9) (1.4 g; 4.3 mmole) in anhydrous tetrahydrofuran (5 ml). The reaction mixture was stirred POI room temperature for 30 minutes, then refluxed for 2 hours, cooled to room temperature, add water (10 ml) and stirred for 1 hour. Next, the reaction mixture was concentrated up until only the solvent does not remain water, extracted with dichloromethane (50 ml), the organic phase is dried (magnesium sulfate) and concentrated to a foam with a yield 1.22 g (95%). Part of the product (0.5 g, 1.7 mmole) is dissolved in methyl alcohol (10 ml) solution was added fumaric acid (0,205 g; or 1.77 mmole), the mixture is concentrated up to 35 g (20%), so pl. 208-211oC.

Example 30

Pharmaceutical compositions

Chemical compound according to the invention can be provided in any desired shape and composition can be metered in the desired quantity. This example illustrates the preparation in the form of standard capsules of the drug in the form of standard pills and drugs in the form of a standard solution for injection, respectively. As the active ingredient was used connection 13 [(1S,3S,4S,8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan - 5-ol] from Example 11.

The drug is in the form of standard capsules

Capsules containing 1 mg of active pharmaceutical ingredient (API) to capsule, can be obtained using the composition shown in table. 2.

The calculated amount of drug substance and filler corresponding to 1 mg of active drug and 117 mg of filler on the capsule, were weighed and mixed in a dry form.

This mixture was then filled in capsules (size 4).

The drug is in the form of a standard tablet

Tablets containing 1,585 mg of active ingredient per tablet were obtained using the composition, Providenciales and water, and then used for the granulation of microcrystalline cellulose. The granulate was left to dry on the pallet.

As mentioned above, the granulate containing the active pharmaceutical ingredient (API), microcrystalline cellulose, lactose and crosscarmelose sodium was weighed, sieved into a mixer and mixed.

Magnesium stearate was weighed and sieved in a mixer with a sample of the above mixture and mixed.

The resulting mixture was then extruded into pellets.

The drug is in the form of a standard solution for injection

Solution for injection containing 1 mg active ingredient/ml was obtained with the composition given in table. 4.

The calculated amount of active ingredient was weighed, was dissolved in sterile purified water, was added a given amount of sodium chloride and sodium citrate, and then brought the pH to the desired value, typically in the range of from about pH 6.5 to about pH 8.

1. Condensed Troyanova derivative having the formula

< / BR>
or any of its enantiomers or any mixture of its pharmaceutically acceptable salt of the connection or its N-oxide,

where X and Y together form =O, =S, =NOR2 IS-NR5R6,

Z represents hydrogen;

R3and R4independently represent hydrogen, lower alkyl, lower alkenyl, phenyl(lower alkyl) or -(CH2)q-COOR2;

R2, R5and R6independently represent hydrogen, lower alkyl, lower alkenyl, -CO-(lower alkyl), phenyl(lower alkyl), or-SO2-(lower alkyl);

R1represents lower alkyl or phenyl, and the phenyl group may be substituted by one or more than one Deputy, selected from the group consisting of halogen, CF3, CN, lower alkyl and nitro;

n is 1 or 2;

q is 0.

2. Connection on p. 1, which is a

(1S, 2S,4S,7R)-2-(3,4-dichlorophenyl)-8-azatricyclo[5.4.0.04,8]undecane-11-he,

(1S, 2S,4S,7R)-2-(3,4-dichlorophenyl)-8-azatricyclo[5.4.0.04,8]undecane-11-ol,

(1S,3S,4S,8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he-methyloxime,

(1S,2S,4S,7R)-2-(4-chlorophenyl)-8-azatricyclo[5.4.0.04,8]undecane-11-he,

(1S,3S,4S,8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-ol,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Oct-5-ylacetic,

(1S, 3S, 4S,8R)-3-(3,4-icicle[5.3.0.04,8] Dean,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-5-ethoxy-7-azatricyclo[5.3.0.04,8] Dean,

(1S,3S,4S,8R)-3-(4-chlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he,

(1S,3S,4S,8R)-3-(4-chlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-ol,

(1S,3S,4S,8R)-3-(4-chlorophenyl)-5-ethoxy-7-azatricyclo[5.3.0.4,8]Dean,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he-benzyloxy,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he-allyloxy,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he oxime,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he-tributyltin,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he-acyloxy,

(1S, 3S,4S,8R)-5-allyloxy-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8] Dean,

ethyl (1S, 3S, 4S, 8R)-2-[3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8] Oct-5-ilidene]-acetate,

(1S,3S,4S,8R)-3-(4-chlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he oxime,

N1-[(1S, 3S, 4S, 8R)-3-(4-chlorophenyl)-7-azatricyclo[5.3.0.04,8] Oct-5-yl] ndimethylacetamide or

(1S,3S,4S,8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Oct-5-ylamine,

or its pharmaceutically acceptable salt of the merger.

3. Pharmaceutical composition having soilection amount of the active ingredient together with at least one pharmaceutically acceptable carrier and/or diluent, characterized in that as the active ingredient it contains the connection PP.1 - 2.

4. A method of manufacturing a pharmaceutical composition having a property to inhibit the reuptake of neurotransmitter monoamines in the Central nervous system, by mixing the active ingredient, carrier and/or diluent, wherein the active ingredient is used as a compound for PP.1 - 2.

5. The method according to p. 4, characterized in that the neurotransmitter monoamines is serotonin.

6. The method of manufacturing according to PP.4 to 6, characterized in that the connection is:

(1S, 2S,4S,7R)-2-(3,4-dichlorophenyl)-8-azatricyclo[5.4.0.04,8]undecane-11-he,

(1S, 2S,4S,7R)-2-(3,4-dichlorophenyl)-8-azatricyclo[5.4.0.04,8]undecane-11-ol,

(1S,3S,4S,8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he-methyloxime,

(1S,2S,4S,7R)-2-(4-chlorophenyl)-8-azatricyclo[5.4.0.04,8]undecane-11-he,

(1S,3S,4S,8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-ol,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Oct-5-ylacetic,

(1S, 3S, 4S,8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Oct-5-limitans enyl)-5-ethoxy-7-azatricyclo[5.3.0.04,8] Dean,

(1S,3S,4S,8R)-3-(4-chlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he,

(1S,3S,4S,8R)-3-(4-chlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-ol,

(1S,3S,4S,8R)-3-(4-chlorophenyl)-5-ethoxy-7-azatricyclo[5.3.0.4,8]Dean,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he-benzyloxy,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he-allyloxy,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he oxime,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he-tributyltin,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he-acyloxy,

(1S, 3S,4S,8R)-5-allyloxy-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8] Dean,

ethyl (1S, 3S, 4S, 8R)-2-[3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8] Oct-5-ilidene]-acetate,

(1S,3S,4S,8R)-3-(4-chlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he oxime,

N1-[(1S, 3S, 4S, 8R)-3-(4-chlorophenyl)-7-azatricyclo[5.3.0.04,8] Oct-5-yl] ndimethylacetamide

or

(1S,3S,4S,8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Oct-5-ylamine,

or its pharmaceutically acceptable salt of the merger.

7. The method of obtaining compounds under item 1, in which the formation of condensed tropenbos rings, imeneniya, those having the formula:

< / BR>
where n and R1such, as defined in paragraph 1,

and then is it possible to make the compound obtained in another connection on p. 1 using traditional methods and/or may carry out the formation of its pharmaceutically acceptable salts.

Priorities signs:

02.11.95 - X and Y together form =O, =S, =NOR2, =CR3R4, Z = H; R3and R4independently represent hydrogen, lower alkyl, lower alkenyl; R2, R5and R6independently represent hydrogen, lower alkyl, lower alkenyl, -CO- (lower alkyl); R1is lower alkyl or phenyl, and the phenyl group may be substituted by one or more than one Deputy, selected from the group consisting of halogen, CF3, CN, lower alkyl and nitro; n = 1 or 2 and q = 0;

13.02.96 when

(1S, 2S,4S,7R)-2-(3,4-dichlorophenyl)-8-azatricyclo[5.4.0.04,8]undecane-11-he,

(1S, 2S,4S,7R)-2-(3,4-dichlorophenyl)-8-azatricyclo[5.4.0.04,8]undecane-11-ol,

(1S,3S,4S,8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he-methyloxime,

(1S,2S,4S,7R)-2-(4-chlorophenyl)-8-azatricyclo[5.4.0.04,8]undecane-11-he,

(1S,3S,4S,8R)-3-(3,4-dichlorophenyl)-7-Estrelleta,

(1S, 3S, 4S,8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Oct-5-elmersolver,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-5-methoxy-7-azatricyclo[5.3.0.04,8] Dean,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-5-ethoxy-7-azatricyclo[5.3.0.04,8] Dean,

(1S,3S,4S,8R)-3-(4-chlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he,

(1S,3S,4S,8R)-3-(4-chlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-ol,

(1S,3S,4S,8R)-3-(4-chlorophenyl)-5-ethoxy-7-azatricyclo[5.3.0.4,8]Dean,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he-benzyloxy,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he-allyloxy,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he oxime,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he-tributyltin,

(1S, 3S, 4S, 8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he-acyloxy,

(1S, 3S,4S,8R)-5-allyloxy-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8] Dean,

ethyl (1S, 3S, 4S, 8R)-2-[3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8] Oct-5-ilidene]-acetate,

(1S,3S,4S,8R)-3-(4-chlorophenyl)-7-azatricyclo[5.3.0.04,8]Decan-5-he oxime,

N1-[(1S, 3S, 4S, 8R)-3-(4-chlorophenyl)-7-azatricyclo[5.3.0.04,8] Oct-5-yl] ndimethylacetamide or (1S, 3S, 4S,8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.04,8] on the Sabbath.

 

Same patents:

The invention relates to the field of medicine and is an aqueous solution of risperidone for oral and parenteral administration

The invention relates to compounds of the formula I, their pharmaceutically acceptable salts and stereoisomeric forms, where R is hydrogen or C1-6-alkyl; R2is hydrogen; C1-6-alkyl; trihalomethanes; C1-6-alkyl, substituted carboxyla,1-6-alkylcarboxylic,1-6-allyloxycarbonyl, or R1and R2taken together with the nitrogen atom to which they are attached, may form a ring morpholinyl or optionally substituted heterocyclic radical; R3- R10each independently represents hydrogen; R8, R9independently represent hydrogen or halogen; R11and R12is hydrogen; n= 1, 2, 3, 4, 5 or 6; X Is O, S, S(=O)
Neurotropic drug // 2156621
The invention relates to medicine and can be used for the correction of impaired immune homeostasis accompanied by changes psychosomatic functions and/or biological reactions, through a multifaceted impact on the integrative activity of the brain

The invention relates to compounds of General formula I

< / BR>
in which X represents a hydrogen atom or halogen, (C1-C3)alkyl group, one or two (C1-C3)alkoxy group, or triptorelin group, Y is a hydrogen atom or halogen, (C1-C3)alkyl or (C1-C3)alkoxygroup, R represents a hydroxy group, a methoxy group, or a group of the General formula NR2R3in which R2and R3each independently represents a hydrogen atom, (C1-C4)alkyl group, 2-methoxyaniline group, 3-methoxyaniline group, 3-aminopropyl group, group 2-(dimethylamino)ethyl group, 3-(dimethylamino)propyl or 2-piperidine-2-retil, or R2and R3form together with the nitrogen atom to which they are connected, morpholine, pyrolidine or pieperazinove ring which may have in position 4 Deputy in the form of a methyl group or groups (1,1-dimethylmethoxy)carbonyl, in the form of free bases or salts formed by the addition of acid

The invention relates to medicine, namely to addiction
The invention relates to medicine, namely to urology, andrology, and can be used in the treatment of infertility in men
The invention relates to medicine, namely to ophthalmology, and can be used for abdominal eye operations (extraction [phacoemulsification] cataract with IOL implantation, vitrectomy, etc
The invention relates to medicine, namely to addiction, and can be used to treat various types of drug addiction

The invention relates to the field of pharmaceutical industry and relates to a liquid pharmaceutical composition in the form of an aerosol

FIELD: pharmaceutical industry.

SUBSTANCE: invention is characterized by that system contains underlayer, therapeutical substance storage layer, and agent attaching the system on the person's skin and allowing access of nicotine to skin. System is transparent (opacity factor below 48.6%).

EFFECT: facilitated transcutaneous transport of nicotine.

8 cl, 1 tbl

FIELD: medicine, gynecology, anesthesiology.

SUBSTANCE: invention concerns to a method for carrying out the anesthesiology assistance for woman in childbirth with accompanying bronchial asthma. Method involves administration of atropine, dimedrol, analgin and clophelin. Method involves additional intravenous administration of transamine for 5-7 min. Transamine is administrated in doses 12-14 and 15-17 mg/kg in woman in childbirth with body mass 75 kg and above and 74 kg and less, respectively. Method provides enhancing quality and safety of anesthesia in this class of woman in childbirth.

EFFECT: improved assistance method.

7 tbl, 4 ex

FIELD: medicine, ophthalmology.

SUBSTANCE: a patient should be alternately and separately instillated with 0.1-1%-atropine solution per 1 drop twice daily, both in the morning and in the evening into conjunctival sac. Instillation into one eye should be carried out for 1-3 d followed by 8-9-d-long interval. The same procedure should be repeated for the second eye.

EFFECT: higher efficiency of therapy.

1 cl, 2 ex

FIELD: medicine, narcology.

SUBSTANCE: method involves alternating comatose therapy and electroshock therapy every other day. In day carrying out the comatose therapy eserine ointment is placed in conjunctival sacs to patient and in 30 min 2-2.5 mg scopolamine hydrobromide solution is administrated as its 0.5% solution. Then in 3-5 h of comatose state patient is recovered from coma and 15-30 mg of physostigmine, 6 g of pyracetam, 7.5 g of magnesium sulfate and 400 ml of sodium hypochlorite are administrated by intravenous drops. In each next séance of comatose therapy dose of scopolamine hydrobromide is increased by 0.5 mg and brought about to 5-6 mg. In day carrying out electroshock therapy 1 ml of 0.1% solution of atropine sulfate and 2 ml of cordiamine are administrated and preliminary narcosis is carried out by intravenous administration of 200-300 mg of sodium thiopental or 100 mg of ketamine with simultaneous administration of 3-4 ml 2% ditiline solution and electroshock therapy is carried out followed by artificial lungs ventilation. Method provides enhancing effectiveness of treatment and to prolong the remission period.

EFFECT: enhanced effectiveness of treatment.

3 ex

Up!