2,3-transvaalense troyanovo derivative, process for its production and pharmaceutical composition

 

(57) Abstract:

Describes the new 2,3-transvaalense Troyanovo derivative of General formula I

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or any of their mixture, or their pharmaceutically acceptable salt, where R represents hydrogen, methyl, ethyl or propyl; R3represents-CH2-X-R', where X represents O or S, and R' represents methyl, ethyl, propyl or cyclopropylmethyl; and R4represents phenyl which may be substituted once or more than once, by substituents selected from the group consisting of halogen, CF3and CN. New Troyanova derivatives are strong inhibitors of reuptake of neurotransmitter monoamines, i.e. dopamine, serotonin and norepinephrine, and the application of new troyanovich derivatives for the treatment of disorders or diseases which are influenced by inhibition of neurotransmitter reuptake of monoamines, such as Parkinson's disease, depression, obsessive-compulsive disorder, panic States, dementia, memory impairment, hyperactivity with attention deficit, obesity, anxiety, disturbances of appetite and substance abuse or the abuse of cocaine. Also describes the way oobrajenie relates to new tropaeolum derivative, which are strong inhibitors of reuptake of neurotransmitter monoamines, i.e. dopamine, serotonin and norepinephrine, and the application of new troyanovich derivatives for the treatment of disorders or diseases which are influenced by inhibition of neurotransmitter reuptake of monoamines, such as Parkinson's disease, depression, obsessive-compulsive disorder, panic States, dementia, memory impairment, hyperactivity with attention deficit, obesity, anxiety, disturbances of appetite and substance abuse or drug abuse, including the abuse of cocaine.

The brain consists of many neurons, which are in contact with each other through chemical carriers. Each neuron generates neurochemical substances, or neurotransmitters, which act to sites on the cell membrane of the neuron-specific receptors. One group of neurotransmitters, which refers to the neurotransmitter monoamines, includes serotonin, dopamine and norepinephrine.

Neurotransmitter monoamines are released into the synaptic gap between neurons to stimulate the activity of the postsynaptic receptor. Destruction (which in presynaptic endings. When reuptake inhibition has heightened physiological activity of neurotransmitter monoamines.

It is shown that serotonergically neural system of the brain affects a variety of physiological functions, and predict that compounds with inhibiting the reuptake of serotonin activity, capable of treating mammals, including humans, a variety of disorders associated with the neural system, such as violations of appetite, depression, obsessive-compulsive disorder, panic States, alcoholism, pain, memory disorders and anxiety. In this group of disorders includes disorders associated with depression, such as pseudodementia or syndrome Ganzera, migraine, bulimia, obesity, premenstrual syndrome or syndrome, late luteal phase, tobacco dependence, panic condition, post-traumatic syndrome, memory loss, dementia of aging, dementia complex of acquired immunodeficiency syndrome, memory impairment during aging, social phobia, hyperactivity with attention deficit syndrome of chronic fatigue, premature ejaculation, erection difficulty, anorexia nervosa, disorders of sleep, autism is adopted, it was expected that in the pathogenesis of major depression involves several neurotransmitters.

Mixed reuptake inhibitors of norepinephrine and serotonin, such as Imipramine and Amitriptyline, and inhibitors of reuptake of norepinephrine, such as Desipramine, Nortriptyline, Protriptyline represent modern pharmaceutical drugs used in antidepressant therapy. Moreover, several series of preclinical and clinical data indicate that the increase in serotonin-mediated neurotransmission, possibly underlies therapeutic effect of most drugs of the past and modern drugs used in antidepressant therapy: Fluoxetine, Citalopram and Paroxetine.

Paradoxical modern inhibitors serotonin reuptake inhibit the vector of serotonin within minutes, while their antidepressant effect fully observed only after three to four weeks of treatment, which indicates that the reuptake inhibition per se is not responsible for the antidepressant response, but rather further adaptive changes underlie therapeutic effect and/or WESTCOM modern reuptake inhibitors monoamine.

Believe that a strong inhibitory activity reuptake of dopamine is associated with the risk of unwanted Central stimulating effects. On the other hand, believe that the activating effects on the mesolimbic dopamine system that underlies the common mechanism of modern antidepressant treatment by enhancing endogenous compensatory system. Compounds with strong inhibitory activity on serotonin reuptake in combination with a well balanced moderate inhibitory activity reuptake of dopamine can, therefore, produce agents with the rapid emergence of the antidepressant effect.

Compounds of the present invention are also potent inhibitors of reuptake of dopamine and, thus, applicable to the treatment of Parkinson's disease, depression, obesity, narcolepsy, drug dependence or abuse of drugs, including cocaine abuse, hyperactivity with attention deficit, disease, Gilles de La Tourette's and senile dementia. Inhibitors of reuptake of dopamine indirectly reinforce through dopamine neurons release acetylcholine and therefore also primenen aging and chronic fatigue syndrome. Inhibitors of reuptake of norepinephrine considered applicable to increase attention, improve anxiety, agitation, insomnia and for the treatment of depression.

The present invention is the creation of new troyanovich derivatives, which are inhibitors of reuptake of neurotransmitter monoamines and therefore applicable for the treatment of disorders such as Parkinson's disease, depression and related illness, obsessive-compulsive disorder, panic States, dementia, memory impairment, hyperactivity with attention deficit, obesity, anxiety, disturbance of the appetite, drug dependency or drug abuse, including zloupotreblenie cocaine.

Another objective of the present invention is to provide new pharmaceutical compositions containing the new Troyanova derivatives.

Another object of the invention is to provide a method for treating diseases or disorders that are affected by the inhibition of neurotransmitter reuptake of monoamines, such as Parkinson's disease, depression and related illness, obsessive-compulsive Russ anxiety, violations of appetite, drug dependency or drug abuse, including the abuse of cocaine.

Other objectives will become apparent to the specialist next.

Thus, the invention is, inter alia, includes the following, singly or in combination:

The connection formulas

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or any of their mixture, or their pharmaceutically acceptable salt;

where R represents hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl or 2-hydroxyethyl;

R3represents-CH2-X-R', where X represents O, S or NR" where R" is hydrogen or alkyl, and R' represents alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl or-CO-alkyl; and

R4represents a

phenyl which can be substituted once or more than once, by substituents selected from the group consisting of halogen, CF3, CN, alkoxy, cycloalkane, alkyl, cycloalkyl, alkenyl, quinil, amino, nitro, heteroaryl and aryl;

3,4-methylenedioxyphenyl;

benzyl which may be substituted once or more than once, by substituents selected from the group consisting of halogen, CF3, CN, alkoxy, cycloalkane, alkyl, cycloalkyl more than once substituents, selected from the group consisting of halogen, CF3, CN, alkoxy, cycloalkane, alkyl, cycloalkyl, alkenyl, quinil, amino, nitro, heteroaryl and aryl; or

naphthyl which may be substituted once or more than once, by substituents selected from the group consisting of halogen, CF3, CN, alkoxy, cycloalkane, alkyl, cycloalkyl, alkenyl, quinil, amino, nitro, heteroaryl and aryl;

connection on p. 1, which is a

2-methoxymethyl-3-(3,4-dichlorophenyl)-tropan,

2-isopropoxyphenyl-3-(3,4-dichlorophenyl)-tropan,

2-ethoxymethyl-3-(3,4-dichlorophenyl)-tropan,

2-cyclopropylmethoxy-3-(3,4-dichlorophenyl)-tropan,

2-methoxymethyl-3-(4-chlorophenyl)-tropan,

N-normetal-2-methoxymethyl-3-(4-chlorophenyl)-tropan,

2-ethoxymethyl-3-(4-chlorophenyl)-tropan,

N-normetal-2-methoxymethyl-3-(3,4-dichlorophenyl)-tropan,

N-normetal-2-ethoxymethyl-3-(3,4-dichlorophenyl)-tropan,

N-normetal-2-ethoxymethyl-3-(4-chlorophenyl)-tropan,

2-ethylthiomethyl-3-(3,4-dichlorophenyl)-tropan,

2-cyclopropylmethoxy-3-(4-chlorophenyl)-tropan, or

N-normetal-2-cyclopropylmethoxy-3-(4-chlorophenyl)-tropan,

or its pharmaceutically acceptable salt of the merger;

connection on p. 1, K3-(3,4-dichlorophenyl)-tropan,

(1R,2R,3S)-2-ethoxymethyl-3-(3,4-dichlorophenyl)-tropan,

(1R,2R,3S)-2-cyclopropylmethoxy-3-(3,4-dichlorophenyl)-tropan,

(1R,2R,3S)-2-methoxymethyl-3-(4-chlorophenyl)-tropan,

(1R,2R,3S)-N-normetal-2-methoxymethyl-3-(4-chlorophenyl)-tropan,

(1R,2R,3S)-2-ethoxymethyl-3-(4-chlorophenyl)-tropan,

(1R,2R,3S)-N-normetal-2-methoxymethyl-3-(3,4-dichlorophenyl)-tropan,

(1R,2R,3S)-N-normetal-2-ethoxymethyl-3-(3,4-dichlorophenyl)-tropan,

(1R,2R,3S)-N-normetal-2-ethoxymethyl-3-(4-chlorophenyl)-tropan,

(1R, 2R, 3S)-N-normetal-2-cyclopropylmethoxy-3-(4 - chlorophenyl)-tropan,

(1R,2R,3S)-2-cyclopropylmethoxy-3-(4-course)-tropan, or

(1R,2R,3S)-2-ethylthiomethyl-3-(3,4-dichlorophenyl)-tropan

or its pharmaceutically acceptable salt of the merger;

a pharmaceutical composition comprising a therapeutically effective amount of a compound, such as any of the above, or its pharmaceutically acceptable salt accession, 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 in a living organism, including humans, and disorders or zabolevaniem;

the use of compounds, such as any of the above, where the disorder or disease is a parkinsonism, depression, pseudodementia, obesity, narcolepsy, drug dependency and/or abuse of drugs, hyperactivity with attention deficit, senile dementia or memory impairment;

the method of obtaining compounds, such as described above that includes a stage in which the compound of the formula

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or any of its enantiomers or any mixture, where R and R4such, as defined in paragraph 1, is subjected to the interaction with the alcoholate R'-Z-Na, where R' is as defined in paragraph 1, and Z represents O or S, with the formation of compounds according to the invention, in which X represents O or S;

the connection formulas

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or any of its enantiomers or any mixture, where R and R4such, as defined in paragraph 1, is subjected to interaction with other amine"-R' with the formation of compounds according to the invention, in which X represents NR'; or

the connection formulas

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or any of its enantiomers or any mixture, where R and R4such, as defined in paragraph 1, is subjected to the interaction with sodium hydride and the compound of the formula R'-SO2
the method of treatment of a disorder or disease in a living organism, including man, with a disorder or disease responsive to the inhibition of neurotransmitter reuptake of monoamines containing stage in which in need of such treatment a living body, including a human, is administered a therapeutically effective amount of the compounds according to paragraphs. 1-3; and

the method as described above, characterized in that treat Parkinson's disease, depression, pseudodementia, obesity, narcolepsy, drug dependency and/or abuse of drugs, hyperactivity with attention deficit, impaired cognitive ability, senile dementia or memory impairment.

Examples of pharmaceutically acceptable salts of joining include salt accession of inorganic and organic acids, such as hydrochloride, hydrobromide, phosphate, nitrate, perchlorate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate, benzoate, ascorbate, cinnamate, bansilalpet, methanesulfonate, stearate, succinate, glutamate, glycolate, toluene-p-sulfonate, format, malonate, naphthalene-2-sulfonate, salicylate and acetate. Such salts receive by methods well known to the specialist.

Halogen represents fluorine, chlorine, bromine or iodine.

Alkyl means a normal or branched chain, containing 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, containing from three to seven carbon atoms, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Alkenyl means a group containing from two to six carbon atoms, containing at least one double bond, for example ethynyl, 1,2 - or 2,3-propenyl, 1,2-, 2,3 - or 3,4-butenyl, but not limited to these examples.

Quinil means a group containing from two to six carbon atoms, containing at least one triple bond, such as ethinyl, 2,3-PROPYNYL, 2,3 - or 3,4-butynyl.

Cycloalkenyl means cycloalkyl, as noted above, the de alkyl such as specified above.

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

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

Heteroaryl represents a 5 - or 6-membered monocyclic heterocyclic group. Such heteroaryl group includes, for example, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isooctanol-3-yl, isooctanol-4-yl, isooctanol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazole-3-yl, 1,2,4-thiadiazole-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,5-thiadiazole-3-yl, 1,2,5-thiadiazole-4-yl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl and 3-pyrazinyl and 1-pyrazolyl, 3-pyrazolyl and 4-pyrazolyl.

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

In addition, the compounds of the present invention can exist as in resolutional and usually it is believed that for assignments of the present invention solvated forms are equivalent nonsolvated.

Professionals need to take into account that the compounds of the present invention contain several chiral centers, and that such compounds exist in the form of isomers, i.e. enantiomers. The invention includes all such isomers and any mixtures thereof, including racemic mixtures.

The racemic forms can be separated into the optical antipodes by known methods, for example by separation of the diastereomeric salts with optically active acids and release of optically active amino compounds by treatment with a base. Another method of separation of racemates on the optical antipodes based on chromatography on optically active stationary phase. Racemic compounds of the present invention can, thus, be divided into the optical antipodes, for example by fractional crystallization of d - or l-salts, such as tartratami, mandelate or camphorsulfonate. Compounds of the present invention can also be divided by formation of diastereomeric amides by reaction of these compounds with optically active ACTIVIA fanboy acid, or through the formation of diastereomeric carbamates by the interaction of the compounds according to the present invention with an optically active chloroformate or similar substance.

You can use additional methods known separation of optical isomers which are obvious to a person skilled. Such methods are described in J. Jaques, A. Collet, S. Wilen ("Enantiomers, racemates and resolutions", John Wiley and Sons, New York, 1981).

Optically active compounds can also be obtained from the source optically active materials.

The following diagram illustrates the ways in which you can obtain compounds according to the invention:

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The processes in the reaction scheme above, carry out the traditional way. Deputy Z in the above scheme represents O or S.

Starting materials for the methods described in this patent application, are known or can be obtained by known methods from commercially available materials (see WO-95/28401).

The connection according to the invention can be converted into another compound of the invention using standard methods.

The products described herein reactions produce standard means, such as extraction, krnu were investigated for their ability to bind to the neurotransmitter dopamine by using the following tests in vitro inhibition of3H-WIN 35428.

Inhibition of in vitro binding3H-WIN 35428

Prerequisites

Dopamine mediators/sites capture on the nerve endings presumably function as terminators of neural impulse by removing dopamine from the synaptic cleft. Activity transport integral protein of dopamine can be measured in vitro by synaptosomal capture or membrane binding3H-dopamine using3H-ligands, which are known to bind to the carrier.

Research associate in vitro cocaine has shown that it is associated with a vector of dopamine and inhibits seizure3H-dopamine. It was reported that numerous ligands of several structural types are linked on the site of the capture of dopamine, but remains in question, is identical whether these sites to those for cocaine. Structural analog of cocaine,3H-WIN 35428, selectively binds to a transport complex of dopamine with a high degree of affinity.

The tissue preparations: Preparations prepared at 0-4oC, unless otherwise noted. Striatum of male Wistar rats (150-200 g) homogenized for 5-10 sec in 10 ml NaH2PO4(50 mm, pH 7,4) homogenizer Ultr is jirout 50 mm NaH2PO4, a pH of 7.4 (1000 ml per g of original tissue) and used for analyses on binding.

Analysis: To 25 ml of the investigated solution and 25 ml3H-WIN 35428 (final concentration 1 nm) add an aliquot of tissue at 0.5 ml, mixed and incubated for 60 min when 2oC. non-specific binding determine using cocaine (final concentration 30 mm). After incubation the sample add 5 ml of chilled in ice buffer, pour them directly on the filters glass fiber Whatman GF/C under suction and immediately washed with 5 ml chilled in ice buffer. The amount of radioactivity on the filters define the standard account liquid scintillation. Specific binding is the total binding minus nonspecific.

Before you can calculate the IC50must be achieved 25-75% inhibition of specific binding. The test lead is in the form of the IC50(the concentration (μm) of the studied substance which inhibits the specific binding3H-WIN 35428 50%).

The results obtained by testing the compounds according to the invention, are shown in table 1.

The above test results show that the compounds according to the invention is associated is invested on their ability to inhibit the reuptake of dopamine (DA), noradrenaline (NA) and serotonin (5-HT) uptake.

Prerequisites

Dopamine mediators/sites capture on the nerve endings presumably function as terminators of neural impulse by removing the neurotransmitters dopamine, noradrenaline and serotonin from the synaptic cleft. Active transport of integral proteins can be measured in vitro synaptosomal capture3H-dopamine,3H-norepinephrine and3H-serotonin, respectively.

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

The tissue preparations: Preparations prepared at 0-4oC, unless otherwise noted. Corpi striati from male Wistar rats (150-200 g) homogenized for 5-10 sec in 100 volumes of the cooled in ice of 0.32 M sucrose containing 1 mm of pargyline, homogenizer Ultra-Turrax. The monoamine oxidase activity must be inhibited in the presence of pargyline. The homogenate was centrifuged at 1000 g for 10 minutes Obtained supernatant is then centrifuged at 27000 g for 50 min and the supernatant discarded. The remainder (P2) re-suspended in oxygendemand (balanced in an atmosphere of 96% O2: 4% CO2for 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: To 100 μl of test solution and 100 µl of the3H-DA (final concentration 1 nm) add aliquots at 4,0 ml tissue suspension are mixed and incubated for 25 min at 37oC. Nonspecific capture determined using benztropine (final concentration 10 μm). After incubation the sample is poured directly on the filters glass fiber Whatman GF/C under suction. Then the filters are washed three times with 5 ml chilled in ice with 0.9% (wt./about.) NaCl solution. The amount of radioactivity on the filters define the standard account liquid scintillation. Specific capture is calculated as the difference between total and nonspecific capture.

Before the calculation of the IC50must be received 25-75% inhibition of specific binding.

The test lead is in the form of the IC50(the concentration (μm) test substance which inhibits the specific binding3H-DA at 50%).

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

The tissue preparations: Preparations prepared at 0-4oC, Evo ice of 0.32 M sucrose, containing 1 mm of pargyline, homogenizer Ultra-Turrax. The monoamine oxidase activity must be inhibited in the presence of pargyline. The homogenate was centrifuged at 1000 g for 10 minutes Obtained supernatant is then centrifuged at 27000 g for 50 min, and the supernatant discarded. The remainder (P2) re-suspended in oxygendemand (balanced in an atmosphere of 96% O2: 4% CO2for at least 30 min) incubation buffer Krebs-ringer (2000 ml per g of original tissue) with 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: To 100 μl of test solution and 100 µl of the3H-NA (final concentration 1 nm) add aliquots at 4,0 ml tissue suspension are mixed and incubated for 90 min at 37oC. Nonspecific capture determined using desipramine (final concentration 1 μm). After incubation the sample is poured directly on the filters glass fiber Whatman GF/C under suction. Then the filters are washed three times with 5 ml chilled in ice with 0.9% (wt./about.) NaCl solution. The amount of radioactivity on the filters define a standard account with liquid is Before the calculation of the IC50must be received 25-75% inhibition of specific binding.

The test is lead as the IC50(the concentration (μm) of the studied substance which inhibits the specific binding3H-NA 50%).

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

The tissue preparations: Preparations prepared at 0-4oC, unless otherwise noted. The cerebral cortex of male Wistar rats (150-200 g) homogenized for 5-10 sec in 100 volumes of the cooled in ice of 0.32 M sucrose containing 1 mm of pargyline, homogenizer Ultra-Turrax. The monoamine oxidase activity must be inhibited in the presence of pargyline. The homogenate was centrifuged at 1000 g for 10 minutes Obtained supernatant is then centrifuged at 27000 g for 50 min and the supernatant discarded. The remainder (P2) re-suspended in oxygendemand (balanced in an atmosphere of 96% O2: 4% CO2during at least 30 min) incubation buffer Krebs-ringer (1000 ml per g of original tissue) with 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 Glu is I concentration 1 nm) add an aliquot on a 4.0 ml of tissue suspension, mix and incubated for 30 min at 37oC. Nonspecific capture is determined with the use of citalopram (final concentration 1 μm). After incubation the sample is poured directly on the filters glass fiber Whatman GF/C under suction. Then the filters are washed three times with 5 ml chilled in ice with 0.9% (wt./about.) NaCl solution. The amount of radioactivity on the filters define the standard account liquid scintillation. Specific capture is calculated as the difference between total and nonspecific capture.

Before the calculation of the IC50must be received 25-75% inhibition of specific binding.

The test lead is in the form of the IC50(the concentration (μm) of the studied substance which inhibits the specific binding3H-5-HT by 50%).

The results obtained by testing the compounds of the present invention, are shown in table 2.

The above results show that the tested compounds effectively inhibit the reuptake of dopamine, norepinephrine and serotonin in the uptake.

Pharmaceutical compositions

Although it is possible that, for use in therapy a compound according to the invention can be introduced in widescope of the drug.

In the invention, thus, further suggested that pharmaceutical preparations containing the compound of the invention or its pharmaceutically acceptable salt or a derivative thereof together with one or more pharmaceutically acceptable carrier for him, and possibly other therapeutic and/or prophylactic ingredients. The carrier(s) must be "acceptable", that is compatible with other ingredients of the drug and harmless for the recipient.

Pharmaceutical preparations include forms suitable for oral, rectal, nasal, local (including hominids and sublingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) or form suitable for administration by inhalation or insufflation.

Compounds according to the invention together with a standard adjuvant, carrier or diluent, thus, may be appropriate in the form of pharmaceutical compositions and standard doses, and in this form they can be used in the form of solid dosage forms such as tablets or capsules, or in liquid forms such as solutions, suspensions, emulsions, elixirs, or capsules filled with them, all for oral administration; in the form of applications (including subcutaneous). Such forms of pharmaceutical compositions and their standard doses may include common ingredients in standard proportions, with an additional active compounds or elements, or without them, and such forms of standard doses may contain any suitable effective amount of the active ingredient commensurate with the intended range of daily dosage, which should be applied. Drugs, containing 10 mg of active ingredient or, in a wider range, from 0.1 to 100 mg per tablet, are, therefore, suitable characteristic form of standard doses.

Compounds of the present invention can be introduced in a wide variety of oral and parenteral dosage forms. The specialist should be obvious that these dose forms may comprise as the active component, either a compound according to the invention, or its pharmaceutically acceptable salt.

To obtain pharmaceutical compositions of the compounds according to the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid dosage forms include powders, tablets, coated tablets, capsules, pills, suppositories and dejstvovatj as diluents, the corrigentov, soljubilizatory, lubricants, suspendresume agents, binders, preservatives, loosening agents of tablets or encapsulating material.

In powders, the carrier is a finely powdered solid substance that is mixed with finely ground active ingredient.

In tablets, the active ingredient is mixed with carrier having the necessary binding capacity in suitable proportions and compacted in the shape desired 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 carboxymethylcellulose, low melting wax, cocoa butter and the like. The term "drug" shall include the preparation of the active compound with encapsulating material as a carrier, forming a capsule, where the active ingredient with the carriers, or without them, is surrounded by carrier, which is thus connected with it. This includes a wafer and pellet. Tablets, powders, capsules, pills, wafers and Le the suppositories low-melting wax, such as a mixture of glycerides of fatty acids or cocoa butter, is first melted and the active component is homogeneous dispersed therein by stirring. The molten homogeneous mixture is then poured into molds of suitable size, allow to cool and then solidify.

Drugs suitable for vaginal insertion, can be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient associated media, well-known specialists.

Liquid dosage forms include solutions, suspensions and emulsions, such as solutions in water or in water with propylene glycol. For example, liquid preparations for parenteral administration can be prepared as solutions in aqueous solution of polyethylene glycol.

Compounds of the present invention, thus, can be prepared in the form of a preparation for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and presented in the form of a single dose in ampoules, pre-filled syringes, small volume infusion or in containers for reusable doses with the addition of preservative. The composition can have a t is drousie, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic selection of sterile solid or by lyophilization from solution, for the preparation of the composition with a suitable solvent, such as sterile pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, corrigentov, stabilizing and thickening agents as desired.

Aqueous solutions suitable for oral use can be prepared by dispersing finely ground active component in water with viscous material, such as natural and synthetic resins, methylcellulose, sodium carboxymethylcellulose or other well-known suspendresume agents.

Also included are solid dosage forms that are designed to turn immediately before use in liquid dosage forms for oral administration. Such liquid forms include solutions, suspensions and emulsions. These preparations may contain augmented Italy, dispersing agents, thickeners, solubilizing agents and the like.

For local insertion through the skin of the compounds according to the invention can be presented in the form of ointments, creams or lotions, or as a transdermal patch. Ointments and creams can be prepared, for example, aqueous or oily base with the addition of suitable thickening or gelling agents. Lotions can be prepared in water or oil-based, and, as a rule, they must also contain one or more than one emulsifying, stabilizing, dispersing, suspendisse, thickening agent or dye.

Drugs suitable for local insertion through the mouth include cakes, which include an active agent on the basis of corrigenda, usually sucrose and Arabian gum or tragakant; lozenges, which is the active ingredient in an inert basis such as gelatin and glycerin or sucrose and Arabian gum; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Solutions and suspensions are injected directly into the nasal cavity using standard means, for example, a dropper, pipette or spray. Drugs m the, what then is the introduction of the patient corresponding to a certain volume of solution or suspension. In the case of spray this is achieved, for example, by using a metering valve.

Introduction to the respiratory tract is also achieved with the help of aerosol preparations in which the active ingredient is in a sealed package with a suitable propellant such as a chlorofluorocarbon (CFC), for example DICHLORODIFLUOROMETHANE, Trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. Aerosol acceptable may also contain a surfactant such as lecithin. The dose can be controlled using a metering valve.

Alternatively, the active ingredients can be represented in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives, for example, hypromellose and polyvinylpyrrolidone (PVP). For convenience powder carrier must form a gel in the nasal cavity. The powder composition may be presented in the form of a standard dose of, for example, capsules or cartridges, for example, from gelatin or blister packs from the cat who atelinae path, including intranasal drugs, the connection should generally have a small particle size, for example about 5 μm or less. Particles of this size can be obtained by methods known in the art, for example by micronization.

Optionally, you can use the products, adapted to the gradual release of the active ingredient.

The pharmaceutical preparations are preferably in the form of standard dosage. In such form the preparation is divided into single standard doses containing appropriate quantities of the active component. Form single standard doses can be a drug in the package containing discrete quantities of preparation, such as packaging of tablets, capsules, and powders in vials or ampoules. The standard dosage may be itself a capsule, a tablet, wafer or cake, or the appropriate number of any of them in the package.

Tablets or capsules for oral administration and liquids for intravenous administration are the preferred compositions.

Treatment

Compounds of the present invention are useful for the treatment of disorders and diseases that affect the spine of the compounds according to the invention makes them particularly useful for the treatment of parkinsonism, depression, obesity, narcolepsy, drug abuse, such as cocaine abuse, hyperactivity with attention deficit, senile dementia and disorders of cognitive activity, as well as other disorders sensitive to the inhibitory neurotransmitter reuptake of monoamine activity of these compounds. Compounds according to this invention can, accordingly, to enter a living organism, including humans, in need of treatment, reduction or elimination of a symptom associated with or sensitive to the inhibitory neurotransmitter reuptake of monoamine activity. This applies in particular to Parkinson's disease, depression, obesity, narcolepsy, cocaine abuse, hyperactivity disorders attention, senile dementia and memory loss in aging. A suitable dosage range is 0.1 to 500 mg per day, and especially 10-70 mg per day, which is administered once or twice daily, depending, usually, the exact way of introduction, forms of administration, symptom, which directed the introduction of the patient and his or her body weight and, finally, preferences and experience of the attending physician or veterinarian.

I. p. means "intraperitoneal" that a well-known method of administration.

The following examples illustrate the invention, but should not be considered as limiting.

Example 1

Methyl ester (-)anhydroecgonine

< / BR>
(1R, 2R, 3S)-2-Carbomethoxy-3-benzoxazolone hydrochloride (100 g, 0.29 mol) was boiled under reflux in 1000 ml of 1M hydrochloric acid for 18 hours, and the solution was cooled in ice. Benzoic acid was collected by filtration, and the filtrate was concentrated in vacuo. Rubbing the residue with ethanol and filtration was obtained (1R,2R,3S)-3-hydroxy - tropan-2 - carboxylate hydrochloride as a white crystalline substance, which without further purification was dried and boiled under reflux in phosphorus oxychloride (50 ml) for two hours. The solution was concentrated in vacuo and was slowly added to absolute methanol (150 ml) under cooling in ice. The solution was stirred at ambient temperature for 16 hours and concentrated in vacuo. The residue was cooled in ice, made alkaline by adding sodium hydroxide solution (10 M, approximately 100 ml) and was extracted 5 times with diethyl ether. The combined organic phase was dried and concentrated in vacuo to obtain oil that person to distil in vacuo (70-74oC, 1 mbar) to obtain the soy is Nina was prepared as follows:

To 103 g (3.05 EQ.) sodium 3.25 l of absolute ethanol was added 3 l of ethyl acetate (HPLC (high performance liquid chromatography) grade) and 500 g of cocaine hydrochloride. The reaction mixture is boiled under reflux for 2.5 hours. Added 150 ml of acetic acid, pH 8, then 1.5 l of toluene. 2 l solvent evaporated under reduced pressure. Was added 2 l of toluene and 2 l of the evaporated solvents. This processing is repeated again. The total number of added toluene was 5.5 l, and about 6 liters of solvents evaporated. The reaction mixture was filtered and the salts washed with a total number of 1 liter of toluene, the Solvent is evaporated under reduced pressure and the residue 570 g person to distil using a Vigreux column 15 see Ethylbenzoic person to distil under pressure 12 mm RT. Art., TKip80-95oC, and the connection specified in the header, person to distil without Vigreux column at 0.2-0.4 mbar, TKip56-80oC. the Product was a clear yellow liquid.

Output: 218 g (76%).

Example 2

(1R, 2S, 3S)-2-Carbomethoxy-3-(4-forfinal)tropan and (1R,2R,3S)-2-carbomethoxy-3-(4-forfinal)tropan

< / BR>
The Grignard reagent was obtained in a three-neck reaction flask equipped with a mechanical stirrer, intensivnymi (6.3 g, 260 mmol) in 250 ml of absolute diethyl ether. The solution of Grignard reagent was cooled to -20oC was added a solution of methyl ester (-)anhydroecgonine (21,7 g, 120 mmol) in 100 ml of absolute diethyl ether for 1/2 hour. The reaction mixture was stirred for one hour at -20oC, and the reaction extinguished one of the following two ways:

1. The reaction mixture was stirred with 250 ml of crushed ice, and the aqueous phase was acidified by adding approximately 100 ml of 4M hydrochloric acid. The organic phase was decanted, and the aqueous phase was washed with 100 ml of diethyl ether. The aqueous phase was podslushivaet addition of 25% ammonium hydroxide solution, and then saturated with sodium chloride and, finally, was extracted three times with diethyl ether. The combined organic phase was dried and concentrated in vacuo to obtain oil that person to distil in vacuo (150-160oC, 2 mbar). In this way received a mixture of two stereoisomers (2S/2R - 1/3), which were divided by column chromatography using a mixture of diethyl ether and pentane (1+1)+1% triethylamine as eluent. The crude products triturated in pentane to obtain (1R,2S,3S)-2-carbomethoxy-3-(4-forfinal)tropane, white crystals with TPL91-92oC and (1R,2R,3S)-2-carbomethoxy-3-(4-ftoh C and the solution was added triperoxonane acid (20 ml, 250 mmol) in 50 ml of diethyl ether for 10 minutes. The cooling bath was removed and when the temperature reached 0oC, the mixture was stirred with 700 ml of water. the pH of the aqueous phase was brought to pH 1 by adding concentrated hydrochloric acid, followed by water treatment and purification in the same manner as described above. In this way received a mixture of two stereoisomers (2S/2R - 2/1).

In this way received the following connections:

(1R, 2R, 3S)-2-Carbomethoxy-3-besitran and (1R,2S,3S)-2-carbomethoxy-3-besitran, mode 2, only the (1R,2S,3S)-2-carbomethoxy-3-besitran received without contamination of other isomers, in the form of an oil which crystallizes upon standing, TPL53-54oC. (1R,2R,3S)-2-Carbomethoxy-3-besitran was obtained by isomerization of the mixture as described in example 3.

(1R, 2R,3S)-2-Carbomethoxy-3-(4-chlorophenyl)tropan and (1R,2S,3S)-2-carbomethoxy-3-(4-chlorophenyl)tropan, method 2. Two isomers are not separated, but the mixture isomerically as described in example 3.

(1R, 2R, 3S)-2-Carbomethoxy-3-(4-chlorophenyl)tropan, (1R,2S,3S)-2-carbomethoxy-3-(4-chlorophenyl)tropan, (1S,2S,3R)-2-carbomethoxy-3-(4-chlorophenyl)tropan and (1S, 2R, 3R)-2-carbomethoxy-3-(4-chlorophenyl)tropan, method 2. Two series of enantiomeric pairs are not separated, but the mixture isomerically, Kail)tropan, method 2. Two isomers are not separated, but the mixture isomerically as described in example 3.

(1R, 2S, 3S)-2-Carbomethoxy-3-(2-naphthyl)tropan and (1R,2R,3S)-2-carbomethoxy-3-(2-naphthyl)tropan, method 2. The Grignard reagent was obtained by addition of a mixture of one equivalent of 2-bromonaphthalene and 1,2-dibromethane in diethyl ether to boiling under reflux the suspension of two equivalents of magnesium. Both product was a white crystalline compounds with TPL79-80oC and 86-87oC, respectively.

(1R, 2R, 3S)-2-Carbomethoxy-3-(1-naphthyl)tropan and (1R,2S,3S)-2-carbomethoxy-3-(1-naphthyl)tropane hydrochloride, method 2. The Grignard reagent was obtained by addition of a mixture of one equivalent of 2-bromonaphthalene and 1,2-dibromethane in diethyl ether to boiling under reflux the suspension of two equivalents of magnesium. The connections defined in the header, identified, respectively, as a white crystalline compound, TPL133-135oC and amorphous compound.

(1R, 2S,3S)-2-Carbomethoxy-3-(3,4-dichlorophenyl)tropan and (1R,2R,3S)-2-carbomethoxy-3-(3,4-dichlorophenyl)tropan, method 2. Both product was a white crystalline compounds with TPL69-70oC and 61-63oC, respectively.

Racemic were sociolegal using methyl ether ()-anhydroecgonine as source material, method 2, followed by isomerization as described in example 3.

(1S, 2S, 3R)-2-Carbomethoxy-3-(3,4-dichlorophenyl)tropan received, using method 2. The connection was not identified, but was isomerically as described in example 3.

(1R, 2S,3S)-2-Carbomethoxy-3-(4-phenyl-phenyl)tropan and (1R,2R,3S)-2-carbomethoxy-3-(4-phenyl-phenyl)tropan, method 2. Both product was a white crystalline compounds with TPL130-132oC and 95-96oC, respectively.

(1R, 2S,3S)-2-Carbomethoxy-3-(4-tert-butyl-phenyl)tropan and (1R,2R,3S)-2-carbomethoxy-3-(4-tert-butyl-phenyl)tropan, method 2. Both product was a white crystalline compounds with TPL84-85oC and 83-84oC, respectively.

Example 3

(1R,2R,3S)-2-carbomethoxy-3-besitran, hydrochloride

< / BR>
To a solution of (1R,2S,3S)-2-carbomethoxy-3-benzyltoluene (5.6 g, 20,5 mmol) in absolute methanol (100 ml) solution was added methanolate in methanol (2 M, 2 ml) and the mixture is boiled under reflux for 16 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in diethyl ether and washed with water. The organic phase was dried and concentrated in vacuo. The crude product was purified column chromatography using a mixture of Dyatlovo is, hydrochloride, in the form of oil. By dissolving this product in diethyl ether and subsequent addition of a solution of hydrochloric acid in diethyl ether compound indicated in the title, besieged in the form of white crystals, TPL188-190oC.

Example 4

2 Carbomethoxy-3-tropane

< / BR>
To a suspension of sodium hydride (3.2 g 80%, 107 mmol, pre-washed in cyclohexane) and dimethylcarbonate (9,13 ml, 108 mmol) in absolute cyclohexane is heated to a temperature of reflux distilled, was added a solution of ()-3-tropinone (6.9 g, 50 mmol) in 50 ml of absolute cyclohexane for 15 minutes. When it was not observed the formation of hydrogen, was added 0.2 ml of methanol. The reaction mixture was stirred overnight at a temperature of reflux distilled, and after cooling to ambient temperature was carefully added 75 ml of water. To the aqueous phase was added 40 g of ammonium chloride, and the resulting mixture was extracted 8 times with methylene chloride. Combined methylenchloride the organic phase was dried and concentrated in vacuo and subsequent column chromatography of the crude product using methylene chloride with increasing amounts (up to 10%) of methanol as eluent. The fractions containing the product were concentrated in vacu is the head, in the form of orange crystals, TPL104-107oC.

Example 5

2 Carbomethoxy-3-hydroxychromone, hydrochloride

< / BR>
To a solution of 2-carbomethoxy-3-tropinone obtained in example 4 (17 g, 85 mmol) in 750 ml of methanol, cooled to -35oC, was added sodium borohydride (17 g, 450 mmol) and the mixture was stirred for 4 hours. The cooled solution was suppressed by slow addition of concentrated hydrochloric acid (40 ml) and the mixture was concentrated in vacuo. Was added water (400 ml) and brought the pH to 3 by addition of concentrated hydrochloric acid. After the aqueous phase was washed three times with diethyl ether, the pH was brought to 11 by addition of concentrated ammonium hydroxide, and the aqueous phase was extracted three times with methylene chloride. Concentration in vacuo was obtained an oil which was dissolved in ethanol, was added concentrated hydrochloric acid, followed by concentration in vacuo. Drying, freezing the remainder received the connection specified in the header, in the form of an amorphous product.

(1S)-Carbomethoxy-3-hydroxychromone, amorphous solid, was obtained in a similar way, using as source material (1S)-2-carbomethoxy-3-tropinone obtained by the section of the Il - (1RS)-anhydroecgonine

< / BR>
A mixture of 2-carbomethoxy-3-hydroxy-tropane, hydrochloride, obtained in example 5 (0.5 g, 2.1 mmol), and thionyl chloride (0.4 ml, 5.3 mmol) was stirred at 60oC for two hours, resulting in a net solution. After cooling to ambient temperature was added crushed ice and brought the pH to 11 by addition of concentrated ammonium hydroxide. The mixture was twice extracted with methylene chloride and the solvent was removed in vacuo obtaining the connection specified in the header, in the form of oil, which person to distil at 1 mbar 70-85oC.

Methyl ester of (1S)-anhydroecgonine, oil, was obtained in a similar way, using (1S)-carbomethoxy-3-hydroxy-tropane, hydrochloride, obtained in example 5 as starting material.

Example 7

(1R,2R,3S)-N-Normetal-2-carbomethoxy-3-(3,4-dichlorophenyl)tropan

< / BR>
A mixture of (1R, 2R, 3S)-2-carbomethoxy-3-(3,4-dichlorophenyl)tropane (8.7 g, 27 mmol) and 2,2,2-trichlorethylphosphate (14.6 ml, 106 mmol) in dry toluene (100 ml) was boiled under reflux for 18 hours. The reaction mixture was concentrated in vacuo and to the residue was added methylene chloride, which was then washed with water. The organic phase was dried and concentrated in vacuo. The remainder R is the ROI then

was stirred at ambient temperature for 18 hours. Added concentrated ammonium hydroxide solution (pH>7), and the mixture was twice extracted with diethyl ether. The combined organic phase was dried and concentrated in vacuo to obtain the connection specified in the header, in the form of oil, which was used without further purification.

Example 8

(1R, 2R,3S)-N-Normetal-N-(tert-butoxycarbonyl)-2-carbomethoxy - 3-(3,4-dichlorophenyl)tropan

< / BR>
A solution of (1R,2R,3S)-N-normetal-2-carbomethoxy-3-(3,4-dichlorophenyl)tropane (7 g, of 22.3 mmol) and di-tert-butyl-dicarbonate (7.7 ml, 33.6 mmol) in dry tetrahydrofuran (50 ml) was stirred at room temperature for one hour. The reaction was suppressed by the addition of ice (100 ml) and the mixture was twice extracted with titilation, which was dried and concentrated in vacuo to obtain the connection specified in the header, in the form of oil, which was used without further purification.

Example 9

(1R,2S,3S)-2-Hydroxymethyl-3-(4-forfinal)tropan

< / BR>
To a suspension of sociallyengaged (0.8 g, 21 mmol) in diethyl ether (30 ml) at room temperature was slowly added a solution of (1R,2S,3S)-2-carbomethoxy-3-(4-forfinal)tropane (5 g, 18 mmol) in 100 ml diethyl ether. Re (15%) and 2 ml of water. Aluminum salts were removed by filtration and the solvent was removed in vacuo to obtain an oil. The connection specified in the header, besieged with rubbing with pentane in the form of white crystals, TPL79-80oC.

In this way received the following connections:

(1R, 2R,3S)-2-hydroxymethyl-3-(4-forfinal)-tropan, white crystals, TPL169-170oC;

(1R, 2R,3S)-2-hydroxymethyl-3-(3,4-dichlorophenyl)-tropan, white crystals, TPL145-150oC;

(1R, 2R, 3S)-N-normetal-N-(tert-butoxycarbonyl)-2-hydroxymethyl - 3-(3,4-dichlorophenyl)-tropan, oil;

(1R, 2S,3S)-2-hydroxymethyl-3-(3,4-dichlorophenyl)-tropan, white crystals, TPL83-89oC;

the racemic mixture of (1R,2R,3S)-2-hydroxymethyl-3-(3,4-dichlorophenyl)-tropane and its enantiomer (1S,2S,3R)-2-hydroxymethyl-3-(3,4-dichlorophenyl)-tropane, TPL186-187oC:

(1S,2S,3R)-2-hydroxymethyl-3-(3,4-dichlorophenyl)-tropan, TPL179-184oC;

(1R, 2R,3S)-2-hydroxymethyl-3-(3,4-dichlorophenyl)-tropan, white crystals, TPL200-202oC.

Example 10

(1R,2R,3S)-2-Hydroxymethyl-3-(3,4-dichlorophenyl)tropane toilet

To a suspension of (1R,2R,3S)-2-hydroxymethyl-3-(3,4-dichlorophenyl)tropane (15 g, 0.05 mol) in methylene chloride (250 ml) was added triethylamine (8 ml) and taillored (10,5 g 0,06 mo is realy in the air. The ether phase is washed with sodium hydroxide (1 BC) and twice washed with water. Drying over magnesium sulfate and evaporation of the solvent was 21.1 g (93%) of the corresponding tosilata.

Another way toilet received:

To a cold (5oC) suspension of (1R,2R,3S)-2-hydroxymethyl-3-(3,4-dichlorophenyl)tropane (1.5 g, 5 mmol) in pyridine (5 ml) was added taillored (to 1.15 g, 6 mmol). The reaction mixture was stirred at room temperature for one hour. Was added water (50 ml) at a temperature < 10oC, and the mixture was stirred for 15 minutes

Added 4 N. NaOH (2.5 ml). The product was isolated, washed with water and dried. Output 2,12 g (93%).

Recrystallization from 100 ml of heptane gave to 1.61 g of pure tosilata. TPL124-125oC.

Example 11

(1R,2R,3S)-2-Methoxymethyl-3-(3,4-dichlorophenyl)tropan

(1R, 2R, 3S)-2-Hydroxymethyl-3-(3,4-dichlorophenyl)tropane toilet (9.2 grams, 0.02 mol) was dissolved in anhydrous methanol (100 ml). Was added sodium methoxide in methanol (15 ml, 2H, 30 mmol) and the reaction mixture is boiled under reflux for 96 hours. The solvent is evaporated, and the residue was dissolved in ether. The ether phase was washed three times with water and dried over magnesium sulfate. Evaporation of the solvent prochlorper)tropane citrate was prepared as follows:

To a solution of (1R,2R,3S)-2-methoxymethyl-3-(3,4-dichlorophenyl)-tropane (16 g, 50 mmol) in 96% ethanol (200 ml) was added citric acid (10.5 g, 55 mmol). The mixture was heated to obtain a pure solution. The solution was cooled, the precipitate was filtered and washed h ml of ethanol. Output 21,0 g (83%). TPL159-160oC.

(1R, 2R, 3S)-2-Methoxymethyl-3-(3,4-dichlorophenyl)tropane sulfate was prepared as follows:

To a solution of (1R,2R,3S)-2-methoxymethyl-3-(3,4-dichlorophenyl)tropane (2.2 g, 7 mmol) was added sulfuric acid in isopropanol (2M, 3.6 ml). Sulfate crystallizes upon cooling and persecution by the crystals. The crystals were filtered off, washed with cold isopropanol and dried. The output of 1.61, TPL171-172oC.

The following compounds were obtained analogously:

(1R, 2R, 3S)-2-isopropoxyphenyl-3-(3,4-dichlorophenyl)-tropane fumarate,PL154-155oC:

(1R, 2R, 3S)-2-cyclopropylmethoxy-3-(3,4-dichlorophenyl)-tropane sulfate, TPL66-75oC;

(1R,2R,3S)-2-methoxymethyl-3-(4-chlorophenyl)-tropane citrate, TPL165-166oC;

(1R,2R,3S)-2-ethoxymethyl-3-(4-chlorophenyl)-tropane citrate, TPL166-167oC;

(1R,2R,3S)-N-normetal-2-ethoxymethyl-3-(4-chlorophenyl)-tropane fumarate, TPL184-186oC;

(1R,2R,3S)-N-normetal-2-mylarfoil)-tropane citrate, TPL155-157oC;

(1R, 2R, 3S)-N-normetal-2-cyclopropylmethoxy-3-(4 - chlorophenyl)-tropane fumarate, TPL176-178oC;

Example 13

(1R,2R,3S)-2-Ethoxymethyl-3-(3,4-dichlorophenyl)tropan

(1R, 2R, 3S)-2-Hydroxymethyl-3-(3,4-dichlorophenyl)tropane tosylate (2.5 g, 5.5 mmol) was dissolved in anhydrous ethanol (20 ml). Added ethoxide sodium in ethanol (2.4 ml, 2.5 M, 6 mmol) and the reaction mixture is boiled under reflux for 72 hours. The solvent is evaporated. The residue was stirred with water and the ether was extracted three times with ether (CH ml) and dried over MgSO4. Evaporation of the solvent was received of 1.75 g of compound indicated in the title. The product was purified column chromatography on silica gel using EtOAc:Et3N (99:1). The output of 1.24 g

Salt of fumaric acid the above compound was prepared as follows:

To a solution of (1R,2R,3S)-2-ethoxymethyl-3-(3,4-dichlorophenyl)tropane (450 mg, 1.38 mmol) in ether was added fumaric acid (160 mg, 1.38 mmol) suspended in MeOH and heated the mixture to obtain a pure solution. The solution is evaporated and the residue triturated in ether, was made fun of crystals and stirred over night. The precipitate was filtered, washed with ether and dried with receipt shall arvanil)tropan

To (1R, 2R, 3S)-2-hydroxymethyl-3-(3,4-dichlorophenyl)tropane (26,9 g, 0.09 mol) in THF (200 ml) was added 60% sodium hydride in oil (4.6 g, 0.12 mol) and ethyl sulfate (15.7 ml, 0.12 mol) and was heated to 30-40oC on an oil bath for 1/2 hour. The reaction mixture was stirred at ambient temperature overnight. Then the reaction mixture was heated to 30-40oC in an oil bath for one hour and poured into water (500 ml). The mixture was extracted twice tert-butylmethylamine ether, the organic phase was washed with water, dried over MgSO4and evaporated to obtain 32,82 g of compound indicated in the heading.

(1R, 2R, 3S)-2-Ethoxymethyl-3-(3,4-dichlorophenyl)tropane citrate was prepared as follows:

To a solution of (1R, 2R, 3S)-2-ethoxymethyl-3-(3,4-dichlorophenyl)tropane in 96% ethanol (275 ml) was added citric acid (19.2 g, 0.1 mol). The solution was heated to the temperature of reflux distilled. Leave the solution at ambient temperature for 3 hours, which led to its crystallization. The mixture was left in an ice bath for 1/2 hour, the crystalline product was filtered and washed with 96% ethanol (50 ml and 25 ml). The crystalline product was dried. Output 32,85 mg (70%). TPL153 to 155,5oC.

Example 15

(1R,2R,3S)-N-Normetal-2-methoxymethyl-3-(3,4-dichlo in dichloroethane (50 ml) was added claritinclaritin (2.7 ml, 25 mmol). The reaction mixture is boiled under reflux during the night. The solvent is evaporated and the residue is boiled under reflux in methanol for 30 minutes. The solvent is evaporated, and the residue was dissolved in water. The solution was made alkaline with aqueous ammonia and extracted with ether. The ether phase is washed with water, dried over magnesium sulfate and evaporated to dryness with the release of 5.4, the Residue was purified column chromatography on silica gel using CH2Cl2/MeOH/NH3(aq.) (40:9:1). Received 2.64 g of purified material. This material was dissolved in ethanol (20 ml, 96%) was added citric acid (1.7 g) in ethanol (20 ml, 96%). Standing at 5oC gave 3,82 g (41%) of crystalline solid, TPL118-120oC.

(1R,2R,3S)-N-Normetal-2-ethoxymethyl-3-(3,4-dichlorophenyl)tropane citrate

To a solution of (1R, 2R, 3S)-N-normetal-2-ethoxymethyl-3-(3,4-dichlorophenyl)-tropane (4,85 g of 14.8 mmol) in dichloroethane (50 ml) was added claritinclaritin (2.4 ml, 22 mmol). The reaction mixture is boiled under reflux during the night. The solvent is evaporated, and the residue was boiled under reflux in methanol (50 ml) for 30 minutes. The solvent is evaporated, and the residue was dissolved in water. gSO4and evaporated to obtain 4.35 g of the crude product. The product was purified column chromatography on silica gel using CH2Cl2/MeOH/NH3(VOD.) (40:9: 1) as eluent. Output 2,49,

Salt of fumaric acid was obtained by dissolving the product in ethanol and adding fumaric acid in ethanol (0.25 M). Salt was filtered, washed with ethanol and dried. TPL220-222oC.

Example 16

(1R,2R,3S)-2-ethylthiomethyl-3-(3,4-dichlorophenyl)tropan

To a cold (0oC) the solution ethanthiol (0.5 ml) in dimethylformamide (30 ml) was added sodium hydride (60%, 0.27 g). When stopped the formation of hydrogen was added (1R, 2R,3S)-2-toiletr-3-(3,4-dichlorophenyl)tropan (2.0 g, 4.4 mmol) in dimethylformamide (20 ml). The mixture was stirred at 0oC for 25 minutes. The reaction mixture was heated at 100oC for 5 days. The reaction mixture was cooled to ambient temperature and was poured into a mixture of water (500 ml) and ether (100 ml). The phases were separated, and the aqueous phase was extracted again with ether (100 ml). The ether phase is evaporated and the residue was dissolved in ether (75 ml) and washed with water (I ml), dried over MgSO4and evaporated to dryness. Yield: 1.4 g of the compound indicated in the title. The crude product of cleansing 3
(VOD.). 0.6 g of the compound indicated in the title, was received in the form of butter.

To a suspension of (1R,2R,3S)-2-ethylthiomethyl-3-(3,4-dichlorophenyl)tropane (0.3 g) in ether (3-4 ml) was added fumaric acid (1,02 EQ.) in warm MeOH (4 ml). The solution was made fun of crystals and left overnight at ambient temperature. The crystalline product was isolated by filtration. Crystals suspended in petroleum ether, stirred for 30 min, were isolated by filtration and dried. The output of 0.38, TPL69-71oC.

Examples of pharmaceutical compositions

Chemical compound according to the invention can be embodied in any desired dosage form and may be dosed in any desired quantity. The following is a common drug in the form of a capsule, a standard drug in tablet form and the standard preparation in the form of solution for injection, respectively.

The standard drug in the form of a capsule

Capsules containing 1 mg of active pharmaceutical ingredient (API) to capsule, can be obtained using the following composition (see table. A).

The calculated amount of drug and filler corresponding to 1 mg of active drug substances the number of capsules (size 4).

The standard drug in tablet form

Tablets containing 1,585 mg of active ingredient per tablet, get, using the following composition (see table. B).

The active ingredient is dissolved in a solvent for granulation, which consists of methyl cellulose and water, and then used for granulation of microcrystalline cellulose. The granulate is allowed to dry on the pallet. The obtained granulate containing the active pharmaceutical ingredient (API), microcrystalline cellulose, lactose and sodium crosscarmelose weigh, sift in the mixer and mix. Give magnesium stearate and sift it into the mixer together with the mixture obtained earlier, and mix. The resulting mixture is then pressed into tablets.

Standard preparation in the form of solution for injection

Solution for injection containing 1 mg/ml of the active ingredient, get, using the following composition (see table. B).

The calculated amount of active ingredient is weighed, dissolved in sterile purified water, add the prescribed amount of sodium chloride and sodium citrate, then the pH of the solution was adjusted to the desired value, typically in the range of from about pH 6.5 to about pH 8.


where R represents hydrogen, methyl, ethyl or propyl,

R3represents-CH2-X-R', where X represents O or S, and R' represents methyl, ethyl, propyl or cyclopropylmethyl;

R4represents phenyl which may be substituted once or more than once, by substituents selected from the group consisting of a halogen.

2. 2,3-transvaalense Troyanovo derived under item 1, in which R represents hydrogen or methyl; R3represents-CH2-O-R', where R' represents methyl, ethyl, isopropyl or cyclopropylmethyl; and R4represents phenyl which may be substituted once or more than once by halogen.

3. 2,3-TRANS disubstituted Troyanovo derived under item 1, in which R represents hydrogen or methyl; R3represents-CH2-O-R', where R' represents methyl, ethyl; and R4represents 3,4-dichlorophenyl.

4. 2,3-transvaalense Troyanovo derived under item 1, which is a 2-methoxymethyl-3-(3,4-dichlorophenyl)-tropan, 2-isopropoxyphenyl-3-(3,4-dichlorophenyl)-tropan, 2-ethoxymethyl-3-(3,4-dichlorophenyl)-tropan, 2-cyclopropylmethoxy-3-(3,4-dichlorophenyl)-tropan, 2-methox N-normetal-2-methoxymethyl-3-(3,4-dichlorophenyl)-tropan, N-normetal-2-ethoxymethyl-3-(3,4-dichlorophenyl)-tropan, N-normetal-2-ethoxymethyl-3-(4-chlorophenyl)-tropan, 2-ethylthiomethyl-3-(3,4-dichlorophenyl)-tropan, 2-cyclopropylmethoxy-3-(4-chlorophenyl)-tropan or N-normetal-2-cyclopropylmethoxy-3-(4-chlorophenyl)-tropan, or their pharmaceutically acceptable salt of the merger.

5. 2,3-transvaalense Troyanovo derived under item 1, which is (1R,2R,3S)-2-methoxymethyl-3-(3,4-dichlorophenyl)-tropan, (1R,2R, 3S)-2-isopropoxyphenyl-3-(3,4-dichlorophenyl)-tropan, (1R, 2R,3S)-2-ethoxymethyl-3-(3,4-dichlorophenyl)-tropan, (1R,2R,3S)-2-cyclopropylmethoxy-3-(3,4-dichlorophenyl)-tropan, (1R,2R,3S)-2-methoxymethyl-3-(4-chlorophenyl)-tropan, (1R, 2R,3S)-N-normetal-2-methoxymethyl-3-(4-chlorophenyl)-tropan, (1R,2R,3S)-2-ethoxymethyl-3-(4-chlorophenyl)-tropan, (1R,2R,3S)-N-normetal-2-methoxymethyl-3-(3,4-dichlorophenyl)-tropan, (1R, 2R, 3S)-N-normetal-2-ethoxymethyl-3-(3,4-dichlorophenyl)-tropan, (1R,2R,3S)-N-normetal-2-ethoxymethyl-3-(4-chlorophenyl)-tropan, (1R,2R,3S)-N-normetal-2-cyclopropylmethoxy-3-(4-chlorophenyl)-tropan, (1R, 2R, 3S)-2-cyclopropylmethoxy-3-(4-chlorophenyl)-tropan or (1R,2R,3S)-2-ethylthiomethyl-3-(3,4-dichlorophenyl)-tropan, or their pharmaceutically acceptable salt of the merger.

6. 2,3-transvaalense Troyanovo derived under item 1, which represents oxymethyl-3-(3,4-dichlorophenyl)-tropan, (1R, 2R, 3S)-N-normetal-2-methoxymethyl-3-(3,4-dichlorophenyl)-tropan or (1R, 2R,3S)-N-normetal-2-ethoxymethyl-3-(3,4-dichlorophenyl)-tropan, or their pharmaceutically acceptable salt of the merger.

7. A pharmaceutical composition comprising a therapeutically effective amount tropenbos derived by PP. 1 - 6 or its pharmaceutically acceptable salt accession, together with at least one pharmaceutically acceptable carrier or diluent.

8. Connection PP.1 to 6 for use in the manufacture of medicinal products for the treatment of a disorder or disease in a living organism, including man, with a disorder or disease responsive to the inhibition of neurotransmitter reuptake of monoamines in the Central nervous system.

9. Connection for use under item 8, wherein the disorder or disease is a parkinsonism, depression, pseudodementia, obesity, narcolepsy, drug dependency and/or abuse of drugs, hyperactivity with attention deficit, senile dementia or memory impairment.

10. The method of obtaining tropenbos derivative according to any one of paragraphs.1 to 6, comprising the steps, to R4such, as defined in paragraph 1,

subjected to interaction with the alcoholate R'-Z-Na, where R' is as defined in paragraph 1, a Z represents O or S, with the formation of tripanosoma derivative having the formula I.

11. The method of obtaining tropenbos derivative according to any one of paragraphs.1 - 6, including the stage at which the compound having the formula III

< / BR>
or any of its enantiomers or any mixture of those

where R and R4such, as defined in paragraph 1,

subjected to interaction with sodium hydride and a compound having the formula

R'-SO2,

where R' is as defined in paragraph 1,

with the formation of tripanosoma derivative having the formula I, where X represents O.

 

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