Substituted 4-(phenyl-n-alkyl)piperidines, pharmaceutical composition based on thereof and methods for treatment

FIELD: organic chemistry, neurology, pharmacy.

SUBSTANCE: invention relates to substituted 4-(phenyl-N-alkyl)piperidines of the general formula (1):

wherein R1 represents CF3, -OSO2CF3, -OSO2CH3, -SOR7, -SO2R7, -CN, -CONHR3, F, Cl, Br or J atoms; R2 represents F, Cl, Br, J atoms, -CN, CF3, CH3, -OCH3, hydroxyl (OH) and -NH2; R3 and R4 represent independently hydrogen atom (H); R5 represents (C1-C4)-alkyl, allyl, -CH2CH2OCH3, -CH2CH2CH2F, -CH2CF3, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl; R7 represents (C1-C3)-alkyl, CF3, -NH2, -N(CH3)2 and its pharmaceutically acceptable salts. Also, invention discloses pharmaceutical compositions of abovementioned compounds and methods wherein abovementioned compounds are used in treatment of disturbances of the central nervous system.

EFFECT: improved method for treatment, valuable medicinal properties of compounds.

33 cl, 67 ex

 

The present invention relates to new modulators of dopamine neurotransmission, and more particularly to new substituted 4-(phenyl-N-alkyl)piperazines and 4-(phenyl-N-alkyl) piperidine, and to their use.

Dopamine is a neurotransmitter in the brain. Since its opening, the incident in 1950, the function of dopamine in the brain has been widely used. To date, it has been established that dopamine plays a significant role in various aspects of brain function, including motor, cognitive, sensitive, emotional and autonomic functions (e.g., regulation of appetite, body temperature, sleep). Thus, the modulation of dopamine function may be useful in the treatment of a wide range of diseases that affect brain function. In fact, as neurological and psychiatric diseases are treated with medication, based on the interaction of dopamine systems and dopamine receptors in the brain.

Drugs that directly or indirectly affect the Central dopamine receptors, usually used in the treatment of neurological and psychiatric diseases such as Parkinson's disease and schizophrenia. Currently available dopaminergic medicines have serious side effects such as ek is trapezoidally side effects and remote dyskinesia when using dopaminergic antagonists as antipsychotic agents and dyskinesia and psychosis when using dopaminergic antagonists as agents aimed at treating Parkinson's disease. Therapeutic action is unsatisfactory in many respects. The search continues for improving efficiency and reducing the side effects of dopaminergic ligands pharmaceuticals, new ligands of dopamine receptors with selectivity towards specific subtypes of dopamine receptors or regional selectivity. In this context, to achieve an optimal level of stimulation of dopamine receptors have also been developed to partial antagonists of dopamine receptors, i.e., the ligands of dopamine receptors with some, but not full intrinsic activity relative to dopamine receptors, thus avoiding the blockade of dopamine receptor or excessive stimulation.

Previously the message and the compounds belonging to the class of substituted 4-(phenyl-N-alkyl)piperazine and substituted 4-(phenyl-N-alkyl)piperidino. Among these compounds, some are inactive in the CNS, some show serotonergically or mixed serotonergically, pharmacological profile, while some are partial or full agonists or antagonists of dopamine receptor with high the kinship relative to dopamine receptors.

A number of derivatives of 4-phenylpiperazine and 4 phenylpiperidine known and described, for example, Costall et al. European J.Pharm. 31, 94, (1975), Newshaw et al. Bioorg. Med. Chem. Lett., 8, 295, (1998). The described compounds are substituted 4-phenylpiperazine, and most of them is 2-, 3 - or 4-HE phenylselenenyl and shows the properties of dopamine agonists (DA) autoreceptors.

Fuller R.W. et al., J. Pharmacol. Exp.Therapeut. 218, 636, (1981) discloses substituted piperazines (e.g., 1-(m-triptoreline)piperazine), which reportedly act as agonists of serotonin and inhibit the uptake of serotonin. Fuller R.W. et al.. Res. Commun. Chem. Pathol. Pharmacol. 17, 551, (1977) disclose the comparative impact 3.4-dihydroxyphenylalanine acid, and Res. Commun. Chem. Pathol. Pharmacol. 29, 201, (1980) reveals comparative impact on the concentration of 5-treated acid in the rat brain by 1-(parachlorophenyl)piperazine.

Boissier J. et al., Chem Abstr. 61:10691, discloses disubstituted piperazines. The connections are represented as adrenolytic, hypotensive, potentiators barbiturates and depressants of the Central nervous system. In addition, Akasaka et al. (EP 0675118) reveal biphenylene piperazines derivatives which exhibit antagonism to the dopamine D2receptor and/or antagonism to 5-HT2the receptor.

There are publications about a variety of substituted piperazines, such kaliganga on 5-HT 1Athe receptors, for example, R.A. Glennon et al., J. Med. Chem., 31, 1968, (1988), van Steen B.J., J. Med. Chem., 36, 2751, (1993), Mokrosz, J. et al., Arch. Pharm. (Weinheim) 328, 143-148 (1995), and Dukat M.-L., J. Med. Chem., 39, 4017, (1996). Glennon R.A. in international patent applications WO 93/00313 and WO 91/09594 discloses various amines, and among them substituted piperazines as ligands of Sigma receptors. Clinical work that explores the properties of the ligands of Sigma receptors in patients with schizophrenia, not make it obvious that antipsychotic activity or activity in relation to any other Central nervous system diseases. With both of the most studied selective antagonists of the Sigma receptors, BW234U (rimcazole) and BMY14802, clinical studies on patients with schizophrenia (Borison et al., 1991, Psychopharmacol Bull 27(2): 103-106; Gewirtz et al., 1994, Neuropsychopharmacology. 10:37-40).

Summary of the invention

Earlier it was reported that among the compounds belonging to the class of substituted 4-(phenyl-N-alkyl)piperazines and substituted 4-(phenyl-N-alkyl) piperidino some are inactive in the CNS, some show serotonergically and mixed serotonergically/dopaminergic pharmacological profile, while some are full or partial antagonists of dopamine receptors with high affinity for dopamine receptors.

The present invention is the creation of new pharmacologically active with the of dinani, particularly suitable in the treatment of disorders of the Central nervous system, which does not have the disadvantages videoblogging substances.

In the development of the present invention found that it is desirable to create substances with specific pharmacological properties, namely, substances that have a modulating effect on neurotransmission of dopamine. Similar properties were not previously discussed, and cannot be obtained with the previously known compounds.

The proposal was unexpectedly found that the compounds of the present invention preferably act on the dopaminergic system of the brain. They affect biochemical parameters in the brain, showing the characteristic features of dopamine antagonists, for example, causing an increase in the concentration of metabolites of dopamine.

Antagonists of dopamine receptor specifically inhibit behavioral activity in a number of experiments, including spontaneous locomotor activity induced by amphetamine hyperactivity. It is also known that they induce catalepsy in rodents. In contrast, the compounds of this invention either do not have or have limited inhibitory effect on locomotor activity. Although some of the compounds can reduce locomotor activity, they do not cause deep suppressed the I behavioral activity, typical antagonists of the D2 receptor. The compounds of this invention or may not have inhibitory effects on locomotor activity, or take a more moderate inhibitory effects on locomotor activity than one would expect from dopamine antagonists. In addition, they can even be mild stimulants behavioral activity. In spite of their properties stimulants behavioral activity of some compounds can decrease caused by d-amphetamine hyperactivity.

Thus, the compounds of this invention surprisingly show a profile of dopaminergic activity with a clear antagonist-like effects on the neurochemistry of the brain, but no or moderate antagonist-like effect on normal behavioral activity, they can activate animals with low baseline activity, but can also inhibit behavioral activity in a state of hyperactivity. Profile action offers modulatory effects on dopaminergic function, is clearly different from the known compounds belonging to the chemical classes or effects, opposite to the typical antagonists or agonists dopamine receptor these or other chemical classes.

Given the involvement of dopamine in a wide variety of functions CN and clinical deficiencies in currently available pharmaceuticals, acting on the dopamine system, it is possible to prove the superiority of new classes of dopaminergic modulators presented in this invention, compared with the currently known dopaminergic compounds in the treatment of certain diseases related to dysfunction of the CNS, from the point of view of effectiveness and side effects.

Found that some compounds of the present invention have surprisingly good pharmacokinetic properties, including a high degree of bioavailability for oral use. Thus, they are suitable for the production of pharmaceuticals for oral administration. In prior art not disclosed the way to obtain connection with such action on the dopamine system in the brain.

The present invention relates to novel disubstituted 4-(phenyl-N-alkyl)piperazines and disubstituted 4-(phenyl-N-alkyl)piperidine in free base form or their pharmaceutically acceptable salts, processes for their preparation, pharmaceutical compositions containing these compounds, and use of these compounds in therapy. The aim of the invention is to provide new compounds for use in therapy, and more specifically, compounds for modulation of dopaminergic systems in the brain of a mammal, the key human brain. The present invention is the creation of compounds with therapeutic effects after oral administration.

More precisely, the present invention relates to compounds of substituted 4-(phenyl-N-alkyl)piperazine and 4-(phenyl-N-alkyl)piperidine of formula 1:

where

X is selected from the group consisting of N, CH and C, but X can be a only if the compound contains a double bond in the area marked by the dotted line.

R1selected from the group consisting of CF3, OSO2CF3, OSO2CH3, SOR7, SO2R7, COR7CN, OR3, NO2, CONHR3, 3-thiophene, 2-thiophene, 3-furan, 2-furan, F, Cl, Br and I, where R7as defined below;

R2selected from the group consisting of F, Cl, Br, I, CN, CF3CH3The co3HE and NH2;

R3and R4independently selected from the group consisting of N and C1-C4Akilov;

R5selected from the group consisting of C1-C4Akilov, Halilov, CH2SCH3CH2CH2OCH3CH2CH2CH2F, CH2CF3, 3,3, 3-cryptochrome, 4,4,4-trifloromethyl and -(CH2)-R6where R6as defined below;

R6selected from the group consisting of C3-C6cycloalkyl, 2-tetrahydrofur the Ana and 3-tetrahydrofuran;

R7selected from the group consisting of C1-C3Akilov,3F and N(R4)2where R4such as defined above,

and its pharmaceutically acceptable salts.

Compounds of the present invention possess dopamine-modulating properties and are suitable in the treatment of several diseases of the Central nervous system, including both psychiatric and neurological symptoms. Diseases which may be useful in connection with a modulating effect on the dopaminergic system, are age-related diseases, are used to prevent bradykinesia and depression and improve mental functions. They can also be used to improve the symptoms of mood disorders. They can be used in obesity, as anorectics agent, and other eating disorders. They can be used to improve cognitive functions and related emotional disorders in neurodegenerative diseases, as well as after brain damage caused by vascular or traumatic stroke. Similarly can improve cognitive and motor dysfunction associated with the disorder development in infancy, childhood and adolescence. They can be used to improve all symptoms of schizophrenia and shizofrenopodobnyy, to improve existing symptoms, and to prevent new psychotic episodes. You can also fix other psychotic disorders, not characterized as schizophrenia, schizoaffective syndromes, as well as psychotic symptoms, delusions and hallucinations caused by other drugs. Can also improve devastating disorders behavioral activity, such as hyperactivity, attention deficit (ADHD), a disorder of communication and oppositional defiance. They can also be used for ticks, such as the syndrome of Gilles de La Tourette's, and other ticks. Can also be improved speech disorders such as stuttering. They can also be used to regulate pathological disorders when drinking coffee, tea, tobacco, alcohol and addictive drugs, and to improve mental diseases associated with the intake of psychoactive substances (including alcohol), including hallucinogens, withdrawal symptoms, delirium, mood disorders, sexual and cognitive impairment.

Anxiety, obsessive-compulsive disorder and other disorders of impulse control, post-traumatic stress disorder, personality disorder and conversional hysteria can also be treated by the compounds according to the invention. Other indications is clucalc sleep disorders, disorder of the normal circadian rhythm and sexual dysfunction.

Neurological indications include the treatment of Huntington's disease, movement disorder, such as psoriasis, including other types of Horai, as well as primary, secondary, and paroxysmal dyskinesia, long-term movement disorders, such as remote dyskinesia and remote dystonia and other movement disorders caused by drugs. "Restless legs", intermittent claudication and narcolepsy can also be treated by the compounds included in the invention. They can also improve mental and motor function in Parkinson's disease, and related parkinsonopodobnyh symptoms, such as multiple system atrophy, progressive supranuclear palsy, diffuse disorder Levi and vascular parkinsonism. They can also be used to improve tremor of different origin.

Compounds according to the invention can also be used in the treatment of vascular headaches such as migraine and hemicrania as for treatment in the acute case, and for prevention. They can improve rehabilitation after vascular or traumatic brain damage. In addition, they can be used for relief of pain conditions characterized by increased muscle t is Noosa.

Detailed description of the invention

Pharmacology

Obviously, in psychiatric and neurological diseases violated neurotransmission in the CNS. In many cases, such as schizophrenia or Parkinson's disease, is applicable, but not optimal pharmacotherapy based on antagonism or agonism dopamine receptors. In recent years much effort has been placed on the discovery of new and selective ligands for substrates dopamine receptor (D1, D2, D3, D4, D5) with the aim of improving efficiency and reducing side effects.

The present invention offers other principles for new therapeutic agents based on the interaction with dopamine systems. Compounds of the present invention have effects on the neurochemistry of the brain, similar to the effect of antagonists of dopamine D2 receptors. In contrast to currently used by antagonists of dopamine receptor compounds of the present invention show no or limited effects on spontaneous locomotor activity. They can be moderately active. Surprisingly, the compounds according to the invention can also reduce the increased activity caused by the direct or indirect dopaminergic agonists, that is, d-amphetamine and substances similar actions. Cu is IU, some of the compounds show high oral bioavailability.

Below are discussed in detail some examples of preferred compounds according to the invention.

One of the preferred compounds is 4-(4-chloro-3-triptoreline)-1-propylpiperidine obtained in example 9. In rats 4-(4-chloro-3-triptoreline)-1-propylpiperidine increases the level of 3,4-hydroxyphenylarsonic acid in the striatum from 1089±102 (controls) to 1680±136 ng/g tissue, p<0,05, n=4, at 50 µmol/kg subcutaneously. Surprisingly, no significant inhibition of spontaneous behavior; 1287±272 cm/30 min (control) vs. 944±144 cm/30 min at 50 µmol/kg subcutaneously. It does not effect on locomotor activity domesticated rats, 1381±877 cm/60 min (control) to 1300±761 cm/60 min at 50 µmol subcutaneously.

Hyperactivity induced by d-amphetamine significantly reduced with 8376±2188 cm/30 min prior 3399±1247 cm/30 min at 50 µmol/kg subcutaneously, p<0,05, n=4, Fischer PLSD. Surprisingly, 4-(4-chloro-3-triptoreline)-1-propylpiperidine has oral availability (F) to 55% in rats.

Like 4-(4-chloro-3-triptoreline)-1-propylpiperidine, 4- (4-fluoro-3-triptoreline)-1-propylpiperidine, which is the compound of example 43, increases the level of 3,4-dihydroxyphenylacetic acid in the striatum from 974±39 (for controls) to 185± 100 ng/g tissue, p<0,05, n=4, at 100 μmol/kg subcutaneously. In accordance with the test on behavioral activity in previously treated rats was slightly increased locomotor activity with a 14±4 cm/30 min (control) to 540±128 cm/30 min, 30-60 min, p<0,05, n=4, at 100 μmol/kg subcutaneously. Thus, 4-(4-fluoro-3-triptoreline)-1-propylpiperidine shows properties that are desirable in accordance with this invention.

The importance of substitution in the para-position shows 1-propyl-4-(3-triptoreline)piperazine, which is not included in the scope of the present invention, which has the same substituents as 4-(4-chloro-3-triptoreline)-1-propylpiperidine (compound of example 9) in the meta-position, but not substituted in the para-position. Such changes effects remain, but the impact on behavioral activity is significantly attenuated. Thus, 1-propyl-4-(3-triptoreline)piperazine increases the level of 3,4-dihydroxyphenylacetic acid in the striatum from 1066±46 (controls) ng/g tissue to 3358±162 ng/g tissue at 50 μmol/kg subcutaneously p<0,05, n=4, with subsequent inhibition of behavioral activity with 1244±341 cm/60 min (control) to 271±137 at 50 µmol/kg subcutaneously p<0,05, n=4. These properties are undesirable in accordance with the present invention, and respectively, 1-propyl-4-(3-triptoreline piperazine is not included in the scope of the present invention. 1-Propyl-4-(3-triptoreline)piperazine has oral availability (F) 9.5% in rats.

1-(4-Chloro-3-nitrophenyl)-4-propylpiperazine obtained in example 19, increases the level of 3,4-dihydroxyphenylacetic acid in the striatum from 1074±42 (controls) to 1693±104 ng/g tissue, p<0,05, n=4, at 100 μmol/kg subcutaneously. In accordance with the test on behavioral activity it moderately increases locomotor activity with 56±25 cm/30 min (control) to 266±89 cm/30 min, 30-60 min, p=0.06, n=4, at 100 μmol/kg subcutaneously. 1-(4-Chloro-3-nitrophenyl)-4-propylpiperazine reduces the hyperactivity induced by d-amphetamine, with 29792±3212 cm/60 min (control d-amphetamine) to 3767±2332 cm/60 min, p<0,05, n=4, at 100 μmol/kg subcutaneously. Thus, 1-(4-chloro-3-nitrophenyl)-4-propylpiperazine shows the desired properties.

CIS-4-(4-fluoro-3-triptoreline)-2,6-dimethyl-1-propylpiperazine, which is a compound according to the invention from example 34, has the ability to increase spontaneous behavioral activity in domesticated rats; 415±214 cm/60 min (control) to 919±143 cm/60 min, p=0,056, n=4, 33 µmol/kg subcutaneously in combination with a slight increase of 3,4-dihydroxyphenylacetic acid in the striatum from 1015±61 (for controls) to 1278±143 ng/g tissue, p=0.13, n=4, 33 µmol/kg subcutaneously.

The ability to inhibit the hyperactivity induced by d-amphetam the nom, demonstrates CIS-4-(3,4-dichlorophenyl)-2,6-dimethyl-1-propylpiperazine, which is the compound of example 35. Hyperactivity induced by d-amphetamine decreases with 19595±2999 cm/60 min (for controls d-amphetamine) to 6514±3374 cm/60 min, p<0,05, n=4, at 100 μmol/kg subcutaneously.

Compounds according to the invention is particularly suitable for the treatment of diseases of the Central nervous system and in particular for the treatment of diseases mediated by dopamine. They may, for example, be used to reduce the symptoms of disorders of mood, obesity, as anorectics agent and other eating disorders, for improving cognitive functions and related emotional disorders, to improve cognitive and motor dysfunction associated with developmental disabilities, to fix all of the symptoms of psychosis, including schizophrenia and schizophrenia-like psychosis of the disease, to improve existing symptoms, and to prevent the emergence of new mental manifestations, for the regulation of pathological conditions associated with the use of food, coffee, tea, alcohol, drugs, addictive, etc.

Thus, the compounds according to the invention can be used to treat symptoms when, for example, the following conditions:

- schizophrenia and other psychotic disorders, such to the to catatonic, hebephrenic, paranoid, residual or differential schizophrenia; schizophrenia-like psychosis disorder; schizoaffective disorder; delusional disorder; brief psychotic disorder, psychotic disorder in the General morbid condition with delusions and/or hallucinations;

- mood disorders such as, for example, estimatesa disorder and large depressive disorder; bipolar disorder, for example bipolar I disorder, bipolar II disorder and cyclothymic disorder; mood disorder in the General morbid condition with depressive and/or manic features; and mood disorder, caused by certain substances;

- anxiety disorders, such as acute stress disorder, agoraphobia without panic disorder in the epicrisis; anxiety disorder in the General morbid condition, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, specific phobia, social phobia and anxiety disorder, caused by certain substances;

- eating disorders such as anorexia nervosa, bulimia nervosa and air the tion;

- sleep disorders, such as dyssomnia, for example, a sleep disorder associated with breathing, sleep disorder with disturbance of circadian rhythm, hypersomnia, insomnia, narcolepsy and upset the normal circadian rhythm;

- unclassified disorders of impulse control, such as a disorder of impulse control characterized by multiple episodes of loss of control over aggressive impulses, kleptomania, pathological gambling, Pyromania and triacetone;

- personality disorders such as paranoid, schizoid or schizotypical disorder, antisocial, borderline, hypocrisy and narcissism; and avoidant, dependent, obsessive-compulsive disorder;

- caused by medication movement disorder, such as neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced and remote dystonia, neuroleptic-induced akathisia, neuroleptic-induced remote dyskinesia, drug-induced tremor and drug-induced dyskinesia;

- caused by substances disorders, such as abuse, addiction, anxiety disorders, intoxication, toxic delirium, psychotic disorders is, psychotic disorder with delusions, mood disorders, persistent amnestic disorder, persistent dementia, persistent disorder of perception, sexual dysfunction, sleep disorder, withdrawal, withdrawal delirium due to alcohol abuse, amphetamine (or amphetamine-like substances)caffeine, cannabis, cocaine, hallucinogens, volatile drugs, nicotine, drugs, opium, phencyclidine (or phencyclidine-like compounds), sedative agents, hypnotic agents, and/or tranquilizers;

disorders, for the first time diagnostirovanie in infancy, childhood or adolescence, such as mental retardation, learning disorder, a disorder of motor skills, for example, disorder development coordination; communication disorders, for example, the disorder expressive language, phonological disorder, disorder of perception of the expression language and stuttering; pervasive development disorder, for example, illness, Asperger's, autism, children disintegration, disease, rett, attention deficit and disruptive behavior, such as attention deficit/hyperactivity disorder, conduct disorder and oppositional defiance; eating disorders and feeding babies or young children, for example, disorders of infant feeding or children early is about age, pietism, disorder chewing; tics, for example, chronic motor or vocal TIC and Tourette's disorder; and other disorders of the infant, child or youth, for example, selective mutism and stereotypical movement disorder;

- delirium, dementia, amnestic and other related diseases such as Alzheimer's disease, Creutzfeldt-Jakob, dead trauma, Huntington's disease, HIV disease Peak, dementia and diffuse Lewy;

- conversiona hysteria;

States associated with normal aging, such as a disorder of motor functions and mental functions;

- Parkinson's disease and related diseases, such as multiple system atrophy, for example, industrial degeneration, olivopontocerebellar atrophy syndrome Shay-Geiger; progressive supranuclear paralysis; corticobasal degeneration; and vascular parkinsonism;

- tremors, such as significant orthostatic tremor at rest, cerebellaris and secondary tremor;

- headaches, such as migraine, hemicrania, headache voltage and paroxysmally headache;

- movement disorder, such as psoriasis, for example, General medical conditions, secondary post-traumatic or vascular stroke, hemiballism, acetosa, chorea of Sydenham, peroxy the normal dyskinesia; syndrome Ekbom (restless legs), Wilson's disease, a disease Hallervorden-Spitze;

- during the rehabilitation treatment, such as rehabilitation after vascular or traumatic brain damage;

- pain in conditions characterized by increased muscle tone, such as fibromyalgia, muscle-facial syndrome, dystonia and parkinsonism; and

state, related to the above, which fall within the broader class of diseases, but do not meet the criteria for any specific disease within the boundaries of these classes.

Synthesis

The synthesis of these compounds is carried out by methods conventional for the synthesis of related known compounds. The synthesis of compounds of formula 1, in General, includes the interaction of intermediate compounds containing alkyl group, with an intermediate piperidine or piperazine containing amino group of the formula 2:

The usual method of synthesis of these compounds is to use alkylated (for example, 1-propyl-iodide). Alternative, the alkyl group can of course use other leaving groups in addition to iodide, such as sulfonates, especially methanesulfonate or toluensulfonate, the group of bromine and the like. Alkyl intermediate compounds interact with the corresponding amine in the presence of either is of a suitable acid trap. Suitable traps acids are conventional bases, such as carbonates, bicarbonates and hydroxides of alkaline or alkaline earth metals, and some organic bases, such as trialkylamine and trialkanolamines. The reaction medium for such reactions can be any suitable organic solvent, inert under alkaline conditions; can be used acetonitrile, esters such as ethyl acetate and the like, and halogenated alcamovia solvents. Usually the reaction is conducted at elevated temperatures of the reaction mixture, for example, from ambient temperature to the boiling temperature under reflux, in particular from 50 to about 100°C.

Another convenient method of synthesis of these compounds involves the reductive amination of an amine of the formula:

with aldehyde or ketone in the presence of a reducing agent, such as cyanoborohydride sodium or triacetoxyborohydride sodium, or with the subsequent recovery, for example, using catalytic hydrogenation, receiving a corresponding compound of formula 1.

The compound of formula 3

where X=N, is produced by interaction of the compounds of formula 4

with compounds of formula 5:

where Z represents a leaving group such as iodide. Of course, the alkyl group can be used and other leaving groups, in addition to iodide, such as sulfonates, especially methanesulfonate or toluensulfonate, the group of bromine and the like. Alkyl intermediate substance interacts with a corresponding amine in the presence of any suitable acid trap. Suitable traps acids are conventional bases, such as carbonates, bicarbonates and hydroxides of alkaline or alkaline earth metals, and organic bases, such as trialkylamine and trialkanolamines. The reaction is carried out in a suitable solvent, such as n-butanol, heated at about 50-150°C.

The compounds of formula 1 where X=N, also produced by interaction of the compounds of formula 6:

with aryl, substituted leaving group of formula 7:

where Z is a halide, such as chlorine, bromine, iodine, or a sulfonate, for example, -OSO2CF3or-OSO2F in the presence of base and catalyst in the form of a transition metal with zero valency, such as Pb or Ni, in accordance with the known method (Tetrahedron Letters, vol.37, 1996, 4463-4466, J. Org. Chem., vol.61, 1996, 1133-1135).

The catalyst, preferably Pd, has the ability to form l is handy complex and subject to oxidative connection. Typical Pd catalyst is a Pd2(dba)3(where dba refers to dibenzylideneacetone), Pd(PPh3)4Pd(OAc)2or PdCl2[P(o-tol)3]2and the typical phosphine ligands are BINAP, P(o-tol)3, dppf and the like. Suitable traps acids are conventional bases, such as carbonates, bicarbonates and alkyloxy alkaline or alkaline earth metals, and some organic bases, such as trialkylamine and trialkanolamines. The reaction medium for such reactions may be any conventional organic solvent, inert under alkaline conditions; suitable solvents are acetonitrile, toluene, dioxane, NRM (N-methyl-2-pyrrolidone), DMA (dimethoxyethane), DMF (N,N-dimethylformamide), DMSO (dimethylsulfoxide), and THF (tetrahydrofuran).

Usually the reaction is carried out at an elevated temperature of the reaction mixture, for example, from ambient temperature to the boiling temperature under reflux, especially from 50 to about 120°C.

The compounds of formula 1 where X=N, also produced by interaction of the compounds of formula 6 with aryl, substituted leaving group (for example, F or Cl), by reaction of nucleophilic aromatic substitution in the presence of a base, as explained above.

The compounds of formula 1 where X=CH or C, also produces the t catalyzed by transition metal reactions of cross-linking, well-known specialists in the art as, for example, reaction of Suzuki and Stille.

The reaction can be conducted between the compounds of formula 8:

where Y represents, for example, valcivir, dialkanolamine or Bronevoy acid (e.g., Bet2In(OH)2or triamcinolone (for example, SnMe3, SnBu3), and the aryl, substituted leaving group of formula 7:

(definition Z see above) in the presence of base and catalyst in the form of a transition metal with zero valency, such as Pb or Ni, in accordance with known methods (Chem. Pharm. Bull., vol.33, 1985, 4755-4763, J. Am. Chem. Soc., vol.109, 1987, 5478-5486, Tetrahedron Lett., vol.33, 1992, 2199-2202). In addition, Y may be a zinc - or mineralogico group (e.g., ZnCl2, ZnBr2, ZnI2, MgBr, MgI) in accordance with known methods (Tetrahedron Lett., vol.33, 1992, 5373-5374, Tetrahedron Lett., vol.37, 1996, 5491-5494).

The catalyst, preferably Pb has the ability to form ligand complex and subject to oxidative connection. Determination of ligands, bases and solvents listed above.

Alternative catalyzed by transition metal reactions of cross-linking are carried out with the opposite pattern substitution:

heteroaryl/alkenyl is m, substituted leaving group of formula 10:

in the presence of base and catalyst in the form of a transition metal with zero valency, such as Pd and Ni, in accordance with the new methods discussed in the previous section.

The compounds of formula 11:

can be obtained by catalytic hydrogenation tetrahydropyridine or pyridine in the previous section, using a standard technique known in the prior art, usually with palladium on carbon, PtO2or Raney Nickel as catalyst. The reaction is carried out in an inert solvent, such as ethanol or ethyl acetate, in the presence or in the absence of a proton acid, such as acetic acid or HCl. When the pyridine ring is quaternion alkyl group, the ring may be partially restored NaBH4or NaCNBH4giving tetrahydropyridine similar, which can then be restored by catalytic hydrogenation.

Another convenient method of synthesis of compounds of formula 1, where X=CH or C, is also carried out by treatment of aryl halides of formula 7:

where Z represents Cl, Br or I, with alkyllithium reagents, for example, butyllithium, second-butyllithium or tert-butyllithium, preferably by butyllithium, is whether Mg (reaction of the Grignard reagent) in an inert solvent. Suitable solvents include, for example, ether or tetrahydrofuran, preferably tetrahydrofuran. The reaction temperature is in the range from about to about -110 0°C. Formed in a similar manner the intermediate lithium anions or anions magnesium can then continue to interact with a suitable electrophile of formula 12:

where And is defined as the protective group, such t-Boc (tert-butoxycarbonyl), Fmoc (fluorenylmethoxycarbonyl)/ Cbz (benzyloxycarbonyl) or an alkyl group such as benzyl.

It is necessary that the hydroxy-group formed intermediate compounds of the formula 13:

has been removed so that the result is a compound of formula 1 (X=CH or C).

This stage can be one of several standard methods known in the art. For example, thiocarbonyl derivative (for example, xantac) can be obtained and removed free radical method known in the art. Alternatively, the hydroxy group can be removed by restoring a source of hydride, such as triethylsilane, in acidic conditions using, for example, triperoxonane acid or mortified. The reduction can be carried out without dilution or in a solvent such as methylene chloride. the school, one alternative method is to first transform the hydroxyl group into a suitable leaving group, such as tosylate or chloride using standard methods. This group is then removed using a nucleophilic hydride, such as lithium aluminum hydride. This latter reaction is carried out usually in an inert solvent such as ether or tetrahydrofuran.

Another alternative method of removing the hydroxyl group is first in the dehydrogenation of the alcohol to olefin such reagents as salt Burgess (J. Org. Chem., vol.38, 1973, 26), with subsequent catalytic hydrogenation of the double bond under standard conditions with the same catalyst as palladium on carbon. Alcohol can also be digidrirovanny to olefin by treatment with an acid, such as para-toluensulfonate or triperoxonane acid.

The protective group is removed under standard conditions known to specialists in this field. For example, t-Boc cleavage is usually done with triperoxonane acid, or pure, or combined with methylene chloride. F-moc usually cleaved by a simple base, such as ammonia, piperidine or morpholine, typically in a polar solvent such as DMF and acetonitrile. When And represents Cbz or benzyl, they usually hatshepsuts under conditions of catalytic hydrogenation. The benzyl group can also be chipped off in terms of N-dealkylation, such as processing α-chloroethyl chloroformate (J. rg. Chem., vol.49, 1984, 2081-2082).

In addition, it is possible to turn the radical R1in the compound of formula 1 in the other radical R1for example, the oxidation of metilsulfate in methylsulfone (for example, m-chloroperoxybenzoic acid), substitution triflate or halide group, a cyano (e.g., catalyzed by palladium cyanidation), substitution triflate or halide group, a ketone (e.g., catalyzed by palladium Heck reaction butylvinyl ether), substitution triflate or halide group carboxamides (for example, catalyzed by palladium-carbonyliron) or splitting or, for example, the transformation of the methoxy group into the corresponding hydroxyl derivative, which can be further transformed into the corresponding mesilate or triflate. Terms mesilate, triplet refer to OSO2CH3CH3SO3or OSO2CF3, CF3SO3respectively.

In General we can say that the overall process of obtaining these compounds has six main options, which can be briefly described as follows:

in accordance with scheme 1:

or in accordance with scheme 2:

or in accordance with scheme 3:

or in accordance with scheme 4:

or in accordance with scheme 5:

or in accordance with scheme 6:

As used herein, the term " C1-C4alkyl refers to alkyl containing 1-4 carbon atoms in any isomeric form. Various carbon fragments are defined as follows: alkyl refers to an aliphatic hydrocarbon radical and includes the forms of branched and non-branched chain such as methyl, ethyl, n-propyl, ISO-propyl, n-butyl, ISO-butyl, sec-butyl, tert-butyl. The term cycloalkyl refers to the radical of saturated cyclic hydrocarbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The term "patient"as used here, refers to the individual in need of treatment in accordance with the invention.

The term "treatment"used herein refers to treatment aimed at cure or alleviate disease or condition and to treatment to prevent development of the disease or condition. The treatment may be carried out in the acute and in the chronic form of the disease.

Both organic and inorganic acids can be used to form non-toxic pharmaceutically acceptable additive salts of acid compounds according to the invention. Examples of acids are sulfuric, who Satna, phosphoric, hydrochloric, citric, acetic, lactic, tartaric, palm, ethicality, Sultanova, succinea, cyclohexylsulfamate, fumaric, maleic and benzoic acid. These salts can easily be obtained by methods known in the field of engineering.

Pharmaceutical compositions containing a compound according to the invention can also contain substances that are used to facilitate the production of a pharmaceutical preparation or administration of drugs. Such substances are well known to specialists in this field and can, for example, be pharmaceutically acceptable adjuvants, carriers and preservatives.

In clinical practice the compounds used in accordance with the present invention, usually given orally, rectally or by injection, or in the form of pharmaceutical preparations comprising the active ingredient, or in free base form or in the form of a pharmaceutically acceptable non-toxic additive salts of acids such as hydrochloric, lactic, acetic, sulphamate salt, in combination with a pharmaceutically acceptable carrier. The carrier may be solid, semi-solid or liquid. Usually the active substance is from 0.1 to 99% by weight of the weight of the drug, more usually from 0.5 to 20% by weight of the drug intended for injection and between 0.2 and 50% by weight of the drug, etc is suitable for oral administration.

To obtain pharmaceutical preparations containing the compound according to the invention, in the form of a unit dosage forms for oral administration, the selected compound may be mixed with solid excipients, for example, lactose, saccharose, sorbitol, mannitol, starch, such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatin or polyvinylpyrrolidine, and a lubricating agent such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin and the like, and then compressed into tablets. If you require coated tablets, content, obtained as described above, may be coated with a concentrated sugar solution which may contain, for example, gum Arabic, gelatin, talc, titanium dioxide and the like. Alternatively, tablets can be coated with polymer, known to specialists in this field, dissolved in a readily volatile organic solvent or mixed organic solvents. Dyes can be added to this covering substances to facilitate the distinction between tablets containing different active substances or different number of active connections.

To obtain soft gelatin capsules, the active substance can be mixed with, for example, vegetable oil is whether polyethylene glycol. Hard gelatin capsules may contain granules of the active substance using or mentioned excipients for tablets, for example, lactose, saccharin, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatin. Liquid or semi-liquid dosage forms can fill hard gelatin capsules.

Dosage units for rectal injection can be solutions or suspensions, or may be obtained in the form of suppositories containing the active substance in a mixture with a neutral fat base, or gelatin rectal capsules that contain the active substance in a mixture with vegetable oil or paraffin oil. Liquid preparations for oral administration can be in the form of syrups or suspensions, for example solutions containing from 0.2 to about 20% by weight of the active substances described here, the rest is sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thickening agent or other excipients known to specialists in this field.

Solutions for parenteral administration by injection can be obtained in an aqueous solution of water-soluble pharmaceutically acceptable the x salts of the active substance, preferably in a concentration of from 0.5 to about 10% by weight. These solutions may also contain stabilizing agents and/or buffering agents and can be easily provided in the ampoule in the form of various dosage units. The use and introduction to the patient in need of treatment in the clinic, it is obvious to a person skilled in this field.

Additionally it should be considered that the present invention also includes stereoisomers and optical isomers, e.g. mixtures of enantiomers as well as individual enantiomers and diastereoisomers, which arise due to structural asymmetry in certain compounds of the current line. The separation of the various isomers is carried out using various methods, well known to specialists in this field.

When therapeutic treatment an effective amount or therapeutic amount of the compounds according to the invention is from about 0.01 to about 500 mg/kg body weight per day, preferably 0.1 to 10 mg/kg of body weight per day. The compounds can be administered by any suitable route, such as orally or parenterally. Daily dose is preferably introduced in a separate doses 1-4 times a day.

Further, the invention is illustrated in the following examples which are in no way intended to limit the scope of the invention.

Example 1

1-(4-chloro-3-t is iformatter)-4-propylpiperazine

A mixture of 5-bromo-2-chlorobenzotrifluoride (0.2 g, 0.85 mmol), n-propylpiperazine (0.15 g, 1,17 mmol), tert-butoxide sodium (0,134 g), dppf (14 mg) and [Pd2(dba)]3(10 mg) in dioxane (5 ml) is heated in argon at 100°C for 24 hours. After cooling to room temperature the reaction mixture is transferred in Et2O (40-50 ml) and washed with salt solution (15-20 ml). The organic fractions are dried (MgSO4), filtered and evaporated to dryness. The crude material is purified flash chromatography on silica gel using CH2Cl2:MeOH (9:1 (obob.). Amin turned into HCl-salt and subjected to recrystallization from ethanol/diethyl ether: other 268°C (HCl); MS m/z (relative intensity, 70 eV) 307 (M+, 6), 279 (33), 277 (98), 70 (bp), 56 (40). Rf=0.35 In (EtOAc).

Example 2

1-(3-chloro-5-triptoreline)-4-propylpiperazine

A suspension of 1-(3-chloro-5-triptoreline)piperazine (100 mg) and milled To2CO3(200 ml) is stirred in CH3CN (30 ml) at room temperature. Added dropwise a solution of 1-bromopropene (52 mg) in CH3CN (5 ml). The mixture was stirred at 50°With during the night. The reaction mixture was filtered, and volatiles evaporated in vacuo. Oily residue chromatographic on a column of silica with MeOH:CH2Cl2(1:9 (vol./about.) as eluent. Collection of the fractions containing pure product,and evaporation of solvent gives named in segaloviciene (85 mg). MS m/z (relative intensity, 70 eV) 306 (M+, 25), 277 (bp), 234 (23), 206 (23), 179 (23).

Example 3

1-(3-chloro-5-triptoreline)-4-ethylpiperazin

On the basis of 1-(3-chloro-5-triptoreline)piperazine and iodata named in the title compound are described in example 2. MS m/z (relative intensity, 70 eV) 292 (M+, bp), 277 (88), 234 (33), 206 (55), 179 (49).

Example 4

1-(3-chloro-5-triptoreline)-4-isopropylpiperazine

On the basis of 1-(3-chloro-5-triptoreline)piperazine and Isopropylamine allocate named in the title compound by the method described in example 2. MS m/z (relative intensity, 70 eV) 306 (M+, 30), 291 (bp), 206 (25), 193 (15), 179 (20).

Example 5

1-(4-chloro-3-triptoreline)-4-ethylpiperazin

On the basis of 1-(4-chloro-3-triptoreline)piperazine and brometane named the title compound is obtained by a method described in example 2. MS m/z (relative intensity, 70 eV) 293 (M+, 6), 292 (30), 277 (29), 57 (bp), 56 (41).

Example 6

1-(3,5-bis-triptoreline)-4-propylpiperazine

On the basis of 1-(3,5-bis-triptoreline)-4-piperazine and 1-propyliodide named the title compound is obtained by a method described in example 2. So 266,1 (HCl), MS m/z (relative intensity, 70 eV) 340 (M+, 20), 311 (95), 240 (30), 70 (bp), 56 (46).

Example 7

1-(3,5-bis-triptoreline)-4-ethylpiperazin

On the basis of 1-(3,5-bis-triptoreline)-4-piperazine and iodata n is called the title compound is obtained by way described in example 2. MS m/z (relative intensity, 70 eV) 326 (M+, 65), 311 (bp), 268 (35), 240 (70), 213 (65).

Example 8

4-(4-chloro-3-triptoreline)-1-butylpiperazine

On the basis of 4-(4-chloro-3-triptoreline)piperidine and 1-butylbromide named the title compound is obtained by a method described in example 2. MS m/z (relative intensity, 70 eV) 319 (M+, 6), 278 (31), 277 (19), 276 (bp), 70 (30).

Example 9

4-(4-chloro-3-triptoreline)-1-propylpiperidine

On the basis of 4-(4-chloro-3-triptoreline)piperidine and 1-propyliodide named the title compound is obtained by a method described in example 2. So 218-220°C (HCl), MS m/z (relative intensity, 70 eV) 305 (M+, 4), 278 (35), 277 (13), 276 (bp), 70 (40).

Example 10

4-(4-chloro-3-triptoreline)-1-ethylpiperidine

On the basis of 4-(4-chloro-3-triptoreline)of piperidine and iodata named the title compound is obtained by a method described in example 2. MS m/z (relative intensity, 70 eV) 291 (M+, 6), 278 (29), 277 (11), 276 (bp), 70 (50).

Example 11

1-(3,4-dichlorophenyl)-4-propylpiperazine

On the basis of 1-(3,4-dichlorophenyl)-4-piperazine and jumproping named the title compound is obtained by a method described in example 2. MS m/z (relative intensity, 70 eV) 273 (M+, 7), 272 (37), 245 (64), 243 (bp), 70 (48).

Example 12

1-(2-chloro-5-triptoreline)-4-propylpiperazine

On the basis of 1-(2-chloro-5-triptoreline)piperazine and 1-iodine is Rapana named the title compound is obtained by way described in example 2. So 234°C (HCl), MS m/z (relative intensity, 70 eV) 306 (M+, 20), 279 (34), 277 (bp), 70 (99), 56 (48).

Example 13

2-fluoro-5-(4-propylpiperazine-1-yl)benzonitrile

On the basis of 2-fluoro-5-piperazine-1-yl-benzonitrile and 1-jumprope named the title compound is obtained by a method described in example 2. MS m/z (relative intensity, 70 eV) 247 (M+, 25), 218 (bp), 175 (28), 147 (33), 70 (65).

Example 14

1-(4-methyl-3-nitrophenyl)-4-propylpiperazine

On the basis of 1-(4-methyl-3-nitrophenyl)piperazine and 1-bromopropane named the title compound is obtained by a method described in example 2. MS m/z (relative intensity, 70 eV) 263 (M+, 26), 234 (bp), 191 (19), 70 (84), 56 (40).

Example 15

1-ethyl-4-(4-methyl-3-nitrophenyl)piperazine

On the basis of 1-(4-methyl-3-nitrophenyl)piperazine and 1-brometane named the title compound is obtained by a method described in example 2. MS m/z (relative intensity, 70 eV) 249 (M+, 53), 234 (47), 84 (36), 57 (bp), 56 (46).

Example 16

1-allyl-4-(4-methyl-3-nitrophenyl)piperazine

On the basis of 1-(4-methyl-3-nitrophenyl)piperazine and allylbromide named the title compound is obtained by a method described in example 2. MS m/z (relative intensity, 70 eV) 261 (M+, 60), 96 (70), 69 (bp), 68 (48), 56 (73).

Example 17

1-isopropyl-4-(4-methyl-3-nitrophenyl)piperazine

On the basis of 1-(4-methyl-3-nitrophenyl)piperazine and 1-isopropylamino named in the header with the unity gain method, described in example 2. MS m/z (relative intensity, 70 eV) 263 (M+, 31), 249 (15), 248 (bp), 84 (15), 56 (42).

Example 18

1-butyl-4-(4-methyl-3-nitrophenyl)piperazine

On the basis of 1-(4-methyl-3-nitrophenyl)piperazine and 1-butylbromide named the title compound is obtained by a method described in example 2. MS m/z (relative intensity, 70 eV) 277 (M+, 23), 234 (bp), 191 (17), 70 (64), 56 (33).

Example 19

1-(4-chloro-3-nitrophenyl)-4-propylpiperazine

On the basis of 1-(4-chloro-3-nitrophenyl)piperazine and 1-bromopropane named the title compound is obtained by a method described in example 2. So 249°C (HCl); MS m/z (relative intensity, 70 eV) 283 (M+, 27), 254 (87), 165 (bp), 153 (78), 56 (90).

Example 20

1-(4-fluoro-3-triptoreline)-4-propyl)piperazine

On the basis of 1-(4-fluoro-3-triptoreline)piperazine and 1-bromopropane named the title compound is obtained by a method described in example 2. So 238°C (HCl); MS m/z (relative intensity, 70 eV) 290 (M+, 17), 261 (70), 190 (34), 70 (bp), 56 (44).

Example 21

1-(3-fluoro-5-triptoreline)-4-propylpiperazine

On the basis of 1-(3-fluoro-5-triptoreline)piperazine and 1-bromopropane named the title compound is obtained by a method described in example 2. So 242°C (HCl); MS m/z (relative intensity, 70 eV) 290 (M+, 34), 261 (bp), 218 (22), 190 (20), 70 (37).

Example 22

1-ethyl-4-(3-fluoro-5-triptoreline)piperazine

On the basis of 1-(3-fluoro-5-tripto who were)piperazine and 1-iodata named the title compound is obtained by way described in example 2. MS m/z (relative intensity, 70 eV) 276 (M+, 46), 261 (41), 190 (30), 84 (30), 57 (bp).

Example 23

1-butyl-4-(3-fluoro-5-triptoreline)piperazine

On the basis of 1-(3-fluoro-5-triptoreline)piperazine and 1-bromobutane named the title compound is obtained by a method described in example 2. MS m/z (relative intensity, 70 eV) 304 (M+, 22), 261 (bp), 218 (22), 190 (21), 70 (46).

Example 24

1-isopropyl-4-(3-fluoro-5-triptoreline)piperazine

On the basis of 1-(3-fluoro-5-triptoreline)piperazine and Isopropylamine named the title compound is obtained by a method described in example 2; MS m/z (relative intensity, 70 eV) 290 (M+, 30), 257 (bp), 190 (20), 84 (23), 56 (64).

Example 25

1-(3-methanesulfonyl-4-methoxyphenyl)-4-propylpiperazine

On the basis of 1-(3-methanesulfonyl-4-methoxyphenyl)piperazine and n-Pr-I named the title compound is obtained by a method described in example 2; MS m/z (relative intensity, 70 eV) 312 (M+, 38), 284 (17), 283 (bp), 70 (49), 56 (17).

Example 26

1-butyl-4-(3-methanesulfonyl-4-methoxyphenyl)piperazine

On the basis of 1-(3-methanesulfonyl-4-methoxyphenyl)piperazine and n-Bu-Br named the title compound is obtained by a method described in example 2; MS m/z (relative intensity, 70 eV) 326 (M+, 32) 284 (16), 283 (bp), 70 (58), 56 (23).

Example 27

1-ethyl-4-(3-methanesulfonyl-4-methoxyphenyl)piperazine

On the basis of 1-(3-methanesulfonyl-4-meth is xifei)piperazine and Et-I named the title compound is obtained by way described in example 2; MS m/z (relative intensity, 70 eV) 298 (M+, 81), 283 (45), 84 (36), 57 (bp), 56 (41).

Example 28

1-isopropyl-4-(3-methanesulfonyl-4-methoxyphenyl)piperazine

On the basis of 1-(3-methanesulfonyl-4-methoxyphenyl)piperazine and Isopropylamine named the title compound is obtained by a method described in example 2; MS m/z (relative intensity, 70 eV) 312 (M+, 43), 297 (bp), 84 (35), 71 (33), 56 (73).

Example 29

1-allyl-4-(3-methanesulfonyl-4-methoxyphenyl)piperazine

On the basis of 1-(3-methanesulfonyl-4-methoxyphenyl)piperazine and allylbromide named the title compound is obtained by a method described in example 2; MS m/z (relative intensity, 70 eV) 310 (M+, 91), 214 (73), 96 (86), 69(80), 56 (bp).

Example 30

2-methanesulfonyl-4-(4-propylpiperazine-1-yl)phenol

1-(3-methanesulfonyl-4-methoxyphenyl)-4-propylpiperazine (30 mg) was dissolved in 48% HBr (2 ml) and stirred at 120°C in argon atmosphere for 3 hours. Excess HBr then evaporated and absolute ethanol is added and evaporated. This procedure is repeated several times, receiving the remainder of the 2-methanesulfonyl-4-(4-propylpiperazine-1-yl)phenol ×HBr. MS m/z (relative intensity, 70 eV) 298 (M+, 35), 269 (bp), 226 (15), 199 (12), 70 (62).

Example 31

4-(4-butylpiperazine-1-yl)-2-methanesulfonyl

Based on 1-butyl-4-(3-methanesulfonyl-4-methoxyphenyl) piperazine named in the title compound get JV the way described in example 30; MS m/z (relative intensity, 70 eV) 312 (M+, 29), 270 (15), 269 (bp), 226 (13), 70 (29).

Example 32

4-(4-isopropylpiperazine-1-yl)-2-methanesulfonyl

On the basis of 1-isopropyl-4-(3-methanesulfonyl-4-methoxyphenyl) piperazine named the title compound is obtained by a method described in example 30; MS m/z (relative intensity, 70 eV) 298 (M+, 39), 284 (18), 283 (bp), 84 (23), 56 (51).

Example 33

CIS-4-(4-chloro-3-tetrafluorethylene)-2,6-dimethyl-1-propylpiperazine Based on 5-bromo-2-chlorobenzotrifluoride and CIS-2,3-dimethyl-1-propylpiperazine named the title compound is obtained by a method described in preparative example 9; etc. 256°C (HCl), MS m/z (relative intensity, 70 eV) 335 (M+, 5), 305 (55), 112 (bp), 70 (67), 56 (82).

Example 34

CIS-4-(4-fluoro-3-tetrafluorethylene)-2,6-dimethyl-1-propylpiperazine

Starting from 5-bromo-2-fermentatively and CIS-2,3-dimethyl-1-propylpiperazine named the title compound is obtained by a method described in preparative example 9; etc. 221°C (HCl), MS m/z (relative intensity, 70 eV) 318 (M+, 32), 289 (74), 112 (bp), 70 (71), 56 (84).

Example 35

CIS-4-(3,4-dichlorophenyl)-2,6-dimethyl-1-propylpiperazine

On the basis of 4-bromo-1,2-dichlorobenzene, CIS-2,3-dimethyl-1-propylpiperazine named the title compound is obtained by a method described in preparative example 9; etc. 225°C (HCl), MS m/z (relative intensively is th 70 eV) 301 (M+, 24), 271 (64), 112 (bp), 70 (47), 56 (53).

Example 36

4-(4-fluoro-3-triptoreline)-1-propyl-1,2,3,6-tetrahydropyridine

On the basis of 4-(4-fluoro-3-triptoreline)-1-propylpiperidine-4-ol named the title compound is obtained by a method described in preparative example 5; MS m/z (relative intensity, 70 eV) 287 (M+, 20), 259 (15), 258 (bp), 177 (17), 147 (21).

Example 37

4-(3-fluoro-5-triptoreline)-1-propyl-1,2,3,6-tetrahydropyridine

On the basis of 4-(3-fluoro-5-triptoreline)-1-propylpiperidine-4-ol named the title compound is obtained by a method described in preparative example 5; MS m/z (relative intensity, 70 eV) 287 (M+, 27), 259 (14), 258 (bp), 177 (6), 146 (7).

Example 38

4-(2-chloro-5-triptoreline)-1-propyl-1,2,3,6-tetrahydropyridine

On the basis of 4-(2-chloro-5-triptoreline)-1-propylpiperidine-4-ol named the title compound is obtained by a method described in preparative example 5; MS m/z (relative intensity, 70 eV) 303 (M+, 18), 2.76 (32), 274 (bp), 177 (6), 128 (5).

Example 39

4-(1-propyl-1,2,3,6-tetrahydropyridine-4-yl)-2-triptorelin

4-pyridin-4-yl-2-triptorelin (270 mg) was dissolved in 1-jumprope (2 ml) and heated to 100°C for 2 hours. Then the volatiles evaporated and the residue is dissolved in abs. EtOH (20 ml) and added in portions NaBH4(800 mg) at 20°C. the Mixture is allowed to warm to room temperature and peremeshivayte during the night. To the mixture is added 10% solution of Na2CO3(20 ml). The aqueous layer was extracted with CH2Cl2, and the combined organic phase is dried (MgSO4, filtered and evaporated to dryness. The crude product was purified flash chromatography (Meon: CH2Cl2(1:9 (vol./vol.)). Collection of the fractions containing pure product, and evaporation of solvent gives pure 4-(1-propyl-1,2,3,6-tetrahydropyridine-4-yl)-2-triptorelin (200 mg). MS m/z (relative intensity, 70 eV) 284 (M+, 53), 255 (bp), 144 (40), 127 (39), 70 (39). Rf 0.28 In (Meon).

Example 40

2,4-debtor-N,N-dimethyl-5-(1-propyl-1,2,3,6-tetrahydropyridine-4-yl)benzosulfimide

Based on 2,4-debtor-N,N-dimethyl-5-pyridin-4-yl-benzosulfimide named the title compound is obtained by a method described in example 39; MS m/z (relative intensity, 70 eV) 344 (M+, 22), 316 (18), 315 (bp), 207 (10), 164 (9). Rf 0,27 (Meon).

Example 41

4-(3-methanesulfonyl-4-methoxyphenyl)-1-propyl-1,2,3,6-Tetra hydropyridine

On the basis of 4-(3-methanesulfonyl-4-methoxyphenyl)pyridine named the title compound is obtained by a method described in example 39; MS m/z (relative intensity, 70 eV) 309 (M+, 31), 281 (12), 280 (bp), 128 (20), 115 (30).

Example 42

2-fluoro-5-(1-propyl-1,2,3,6-tetrahydropyridine-4-yl)benzonitrile

On the basis of 2-fluoro-5-pyridin-4-yl-benzonitrile named the title compound is obtained by a method described in example 39; MS m/z (relative and tensively, 70 eV) 244 (M+, 24), 217 (16), 216 (bp), 158 (11), 134 (10).

Example 43

4-(4-fluoro-3-triptoreline)-1-propylpiperidine

On the basis of 4-(4-fluoro-3-triptoreline)-1-propyl-1,2,3,6-tetrahydropyridine named the title compound is obtained by a method described in preparative example 6; etc. 195-197°C (HCl), MS m/z (relative intensity, 70 eV) 289 (M+, 4), 261 (15), 260 (bp), 177 (7), 70 (13).

Example 44

4-(3-fluoro-5-triptoreline)-1-propylpiperidine

On the basis of 4-(3-fluoro-5-triptoreline)-1-propyl-1,2,3,6-tetrahydropyridine named the title compound is obtained by a method described in preparative example 6; etc. 215°S, MS m/z (relative intensity, 70 eV) 289 (M+, 4), 261 (15), 260 (bp), 177 (6), 70 (11).

Example 45

4-(2-chloro-5-triptoreline)-1-propylpiperidine

On the basis of 4-(2-chloro-5-triptoreline)-1-propyl-1,2,3,6-tetrahydropyridine named the title compound is obtained by a method described in preparative example 6; MS m/z (relative intensity, 70 eV) 305 (M+, 4), 290 (3), 278 (32), 277 (15), 276 (bp).

Example 46

4-(1-propylpiperidine-4-yl)-2-triptorelin

On the basis of 4-(1-propyl-1,2,3,6-tetrahydropyridine-4-yl)-2-triptoreline named the title compound is obtained by a method described in preparative example 6; MS m/z (relative intensity, 70 eV) 286 (M+, 2), 257 (17), 98 (10), 96 (8), 70 (bp), Rf=0.28 In (MeOH).

Example 47

2,4-debtor-N,N-dimethyl-5-(1-PR is preparedin-4-yl)-benzosulfimide

Based on 2,4-debtor-N,N-dimethyl-5-(1-propyl-1,2,3,6-tetrahydropyridine-4-yl)benzosulfimide named the title compound is obtained by a method described in preparative example 6; MS m/z (relative intensity, 70 eV) 346 (M+, 2), 318 (19), 317 (IR), 209 (10), 70 (13).

Example 48

4-(3-methanesulfonyl-4-methoxyphenyl)-1-propylpiperidine

On the basis of 4-(3-methanesulfonyl-4-methoxyphenyl)-1-propylpiperidine named the title compound is obtained by a method described in preparative example 6; MS m/z (relative intensity, 70 eV) 311 (M+, 6), 283 (17), 282 (bp), 280 (11), 70 (22), Rf=0,3 (MeOH).

Example 49

1-(4-chloro-3-methanesulfonyl)-4-propylpiperazine

On the basis of 1-(4-chloro-3-methanesulfonyl)piperazine and 1-jumprope named the title compound is obtained by a method described in example 2; MS m/z (relative intensity, 70 eV) 316 (M+, 25), 289 (41), 287 (bp), 70 (59), 56 (23).

Example 50

1-allyl-4-(3-chloro-5-triptoreline)piperazine

On the basis of 1-(3-chloro-5-triptoreline)piperazine and allylbromide named the title compound is obtained by a method described in example 2; MS m/z (relative intensity, 70 eV) 305 (M+, 7), 96 (57), 69 (bp), 68 (48), 56 (69).

Example 51

2-fluoro-5-(1-propylpiperidine-4-yl)benzonitrile

On the basis of 2-fluoro-5-(1-propellerdriven-4-yl) benzonitrile named the title compound is obtained by a method described in preparation the m example 6; MS m/z (relative intensity, 70 eV) 246 (M+, 6), 217 (bp), 174 (5), 146 (6), 134 (7).

The synthesis of intermediates used in the above examples, discussed below in the preparative examples.

Preparative example 1

1-(3-chloro-5-triptoreline)piperazine

Based on 3,5-dichlorobenzotrifluoride (500 mg, 2.32 mmol) and piperazine (1 g, 11.6 mmol) 320 mg named in the title compound are described in example 1.

Preparative example 2

1-(4-chloro-3-triptoreline)piperazine

Starting from 5-bromo-2-chlorobenzotrifluoride (602 mg) and piperazine (1 g) 480 mg named in the title compound are described in example 1.

Preparative example 3

1-(3,5-bis-triptoreline)-4-piperazine

On the basis of 1-iodine-3,5-bis(trifluoromethyl)benzene and piperazine named in the title compound are described in example 1.

Preparative example 4

1-benzyl-4-(4-chloro-3-triptoreline)piperidine-4-ol

(Get in line with the Collection Czechoslav. Chem. Commun. 1973, 38, 3879)

A solution of 5-bromo-2-chlorobenzotrifluoride (5 g, 19.2 mmol) in dry diethyl ether (40 ml) is added dropwise at room temperature to a mixture of Mg (470 mg) in dry diethyl ether (20 ml) in an argon flow (g). The reaction mixture is transferred into a solution of the Grignard reagent. Dropwise via syringe add a solution of 1-benzyl-4-piperidone (1.3 g, 6,88 the mol) in dry diethyl ether (30 ml) at room temperature. The combined mixture is stirred for 1 hour and finally quenched with a saturated solution of ammonium chloride (40 ml). The mixture is extracted with EtOAc several times and the combined organic phases are dried (MgSO4), filtered and evaporated to dryness. Oily residue chromatographic on a column of silica using EtOAc:toluene (1:1 (vol./about.)) as eluent, getting named the title compound (1.6 g, 64%). MS m/z (relative intensity, 70 eV) 369 (M+, 23), 278 (15), 91 (bp), 65 (16), 56 (21).

Preparative example 5

1-benzyl-4-(4-chloro-3-triptoreline)-1,2,3,6-tetrahydropyridine

1-benzyl-4-(4-chloro-3-triptoreline)piperidine-4-ol (1.5 g) is dissolved in triperoxonane acid (35 ml) and refluxed for 24 hours, and then add CH2Cl2(200 ml). The phases are separated and then the organic phase is washed with two portions of 10% Na2CO3, dried (MgSO4), filtered and evaporated to dryness. The output is 1.5, MS m/z (relative intensity, 70 eV) 351 (M+, 27), 172 (9), 92 (11), 91 (bp), 65 (21).

Preparative example 6

1-benzyl-4-(4-chloro-3-triptoreline)piperidine

1-benzyl-4-(4-chloro-3-triptoreline)-1,2,3,6-tetrahydropyridine (1.45 g) was dissolved in methanol (40 ml). Add concentrated hydrochloric acid (0.2 ml) and 50 mg of Pd/C. the resulting mixture hydronaut under the pressure created by hazoor the EIT hydrogen (40 lb/in 2) for 1 hour and then filtered through a layer of celite. The solvent is evaporated in vacuo and the residue purified flash chromatography (SiO2CH2Cl2:MeOH, 9:1 (vol./vol.), getting clean, named the title compound (1.2 g). MS m/z (relative intensity, 70 eV) 353 (M+, 16), 262 (20), 91 (bp), 65 (18), 56 (14).

Preparative example 7

4-(4-chloro-3-triptoreline)piperidine

A solution of 1-benzyl-4-(4-chloro-3-triptoreline)piperidine (1.1 g) in 1,2-dichloroethane (50 ml) cooled to 0°C. Then added dropwise α-chloroethylphosphonic (1.5 g)dissolved in 1,2-dichloroethane (30 ml) at 0°C. Then the reaction mixture was refluxed for 2 days. Volatile matter is evaporated in vacuo and the residue triturated with methanol. The mixture is refluxed for 4 hours. The solvent is evaporated, getting named the title compound as HCl salt (light brown crystals 1.0 g). MS m/z (relative intensity, 70 eV) 263 (M+, 34), 262 (22), 83 (22), 57 (60), 56 (bp).

Preparative example 8

1-(3,4-dichlorophenyl)piperazine

On the basis of 4-bromo-1,2-dichlorobenzene (200 mg, 0.88 mmol) and piperazine (91 mg, 1.06 mmol), 98 mg named in the title compound are described in example 1.

Preparative example 9

1-(3-methanesulfonyl-4-methoxyphenyl)piperazine

A mixture of 4-bromo-2-methanesulfonyl-1-methoxybenzo the La (0.65 g), piperazine (0,43 g), tert-butoxide sodium (0,13 g), BINAP (19 mg) and [Pd2(dba)]3(27 mg) in dioxane (5 ml) is heated in argon at 100°C for 24 hours. After cooling to room temperature the reaction mixture is transferred in Et2O (40-50 ml) and washed with saturated salt solution (15-20 ml). The organic fractions are dried (MgSO4), filtered and evaporated to dryness. The crude material is purified flash chromatography on silica gel using CH2Cl2:MeOH (9:1 (vol./vol.)). The output is 0.14 g: MS m/z (relative intensity, 70 eV) 270 (M+, 23), 229 (11), 228 (bp), 148 (7), 56 (17).

Preparative example 10

4-(4-fluoro-3-triptoreline)-1-propylpiperidine-2-ol

On the basis of 4-bromo-1-fluoro-2-cryptomelane and 1-propyl-4-piperidone named in the title compound are described in preparative example 4.

MS m/z (relative intensity, 70 eV) 305 (M+, 5), 276 (bp), 258 (50), 191 (13), 185 (33).

Preparative example 11

4-(3-fluoro-5-triptoreline)-1-propylpiperidine-2-ol

On the basis of 1-bromo-3-fluoro-5-cryptomelane and 1-propyl-4-piperidone named in the title compound are described in preparative example 4.

MS m/z (relative intensity, 70 eV) 305 (M+, 6), 276 (bp), 258 (34), 258 (34), 185 (14).

Preparative example 12

2,4-debtor-N,N-dimethyl-5-pyridin-4-yl-benzosulfimide

5-Bromo-2,4-debtor-N,N-dimethylbenzamide the amide (400 mg) and 4-pyridineboronic acid (165 mg) was dissolved in toluene (5 ml) and abs. EtOH (5 ml). Then added to the mixture of Na2CO3(200 mg) and Pd(PPh3)4(79 mg) in an argon atmosphere. The resulting mixture is heated to 90°C for 18 hours. Then add CH2Cl2and the organic phase is washed with water and dried (MgSO4), filtered and evaporated to dryness. The residue is then used without further purification. (MS m/z (relative intensity, 70 eV) 298 (M+, 77), 256 (36), 191 (bp), 190 (98), 143 (74).

Preparative example 13

4-pyridin-4-yl-2-triptorelin

On the basis of 4-bromo-2-triptoreline named in the title compound are described in preparative example 12; MS m/z (relative intensity, 70 eV) 238 (M+, 52), 218 (44), 191 (27), 75 (41), 51 (bp).

Preparative example 14

4-(3-methanesulfonyl-4-methoxyphenyl)pyridine

On the basis of 4-bromo-2-methanesulfonyl-1-methoxybenzene named in the title compound are described in preparative example 12; MS m/z (relative intensity, 70 eV) 263 (M+, bp), 182 (36), 169 (18), 154 (32), 127 (18).

Preparative example 15

4-(2-chloro-5-triptoreline)-1-propylpiperidine-4-ol

On the basis of 4-chloro-3-identified and 1-propyl-4-piperidone named in the title compound are described in preparative example 4, MS m/z (relative intensity, 70 eV) 321 (M+, 8), 294 (38), 292 (bp), 274 (52), 56 (35).

Preparative examples is 16

1-(4-chloro-3-methanesulfonyl)piperazine

Starting from 5-bromo-2-chloromethylthiazole and piperazine named in the title compound are described in example 1. MS m/z (relative intensity, 70 eV) 274 (M+, 20), 234 (40), 232 (bp), 153 (9), 56 (12).

The following tests were used to evaluate the compounds according to the invention.

In vivo test: Behavior

To test the behavioral activity of animals were placed in individual boxes measure mobility 50×50×50 cm, equipped with many potaczek 16×16 (Digiscan activity monitor, RXYZM (16) TAG, Omnitech Electronics, USA), connected to the analyzer Omnitech Digiscan and Apple Macintosh computer equipped with a digital control panel (NB-DIO-24, National Instruments, USA). Data behavioral activity of each carton dimension of mobility that represents the position (center of gravity) of the animal at each time point, were recorded with the selected frequency of 25 Hz and collected using specially made written LABView™ applicator. The data for each cycle was analyzed from the point of view of distance and small-scale movements, such as a stop in the center of the area registration behavior during the cycle of the Desk. To define a stop in the center of the speed at each time point was calculated as the distance from the previous m is the moment of measurement, divided by the time elapsed since the previous measurement. Then counted the number of stops as the number of cases of change of speed from zero to zero. The number of stops in the center of the field of registration of conduct was calculated as the number of stops that occurred at least at a distance of ten inches from the edges of registration. To test the behavior of the trained rats, animals were placed in a box measuring mobility for 30 minutes before injection of the tested compounds. Each cycle check the behavior lasted 60 or 30 minutes, starting immediately after injection of the tested compounds. Similar to the registration procedure of conduct were untamed rats, domesticated rats and from rats pre-treated with the medication. Pre-treated d-amphetamine rats received a dose of 1.5 mg/kg subcutaneously for 5 minutes to cycle registration measurement of mobility.

In vivo test; neurochemistry

After cycles determine the behavioral activity of rats subjected decapitate and their brains were rapidly isolated and placed on ice Petri dishes. The limbic forebrain, striatum, cortex of the frontal lobe and the remaining portion of the hemisphere of each rat was dissected and frozen. Each part of the brain consistently analyzed from the point of view of the content of the project it monoamines and their metabolites. Defined monoaminergic stimulants represented dopamine (DA), 3,4-dihydroxyphenylacetic acid (DO RACES), HVA acid (HVA), 3-methoxytyramine (3-MT), serotonin (5-HT), 5-treated acid (5-HIAA) and noradrenaline (NA). All monoaminergic stimulants in esecanna tissues was analyzed using HPLC with electrochemical determination as described Svensson K, et al., 1986, Naunyn-Schmiedeberg''s Arch Pharmacol 334: 234-245 and these links.

In vivo test: Farmacocinetica in rats

To determine the oral bioavailability (F) and plasma time-life (t1/2} was carried out experiments on rats with the test compounds according to the invention. On the first day, rats were implanted one catheter in the jugular vein, and the second catheter in the carotid artery under ketamine anesthesia. On the third day was administered to test the connection, or orally, or through a catheter in the jugular vein. Blood samples were collected within 8 hours from the arterial catheter. Blood samples were Gaprindashvili and centrifuged. After centrifugation of the samples of plasma collected and frozen. The levels of the tested compounds were consistently identified in each sample by gas chromatography - mass spectroscopy (Hewlett-Packard 5972MSD). Plasma samples taken from rats Sprague-Dawley, (0.5 ml), diluted with water (0.5 ml), was added 30 pmol (50 is CL) ((-)-S-3-(3-ethylsulfonyl)-N-n-propylpiperidine as internal standard. the pH was brought to 11.0 by addition of 25 μl of saturated Na2CO3. After mixing, the samples were extracted with 4 ml dichloromethane by shaking for 20 minutes. The organic layer after centrifugation was transferred to a small test tube and evaporated to dryness in a stream of nitrogen and consistently was dissolved in 40 ml of toluene for analysis GC-MS. Received a standard curve in the range of 1-500 pmol adding more test compounds to free plasma samples. GC was performed on capillary columns HP-Ultra 2 (12 m×0.2 mm ID), and 2 µl was injected in a continuous way. The temperature of the GC was supported by 90°within 1 minute after injection and then increased by 30°C/min to a final temperature of 290°C. Each sample was duplicated. In General, it is found that the lowest detectable concentration of the tested compounds was 1 pmol/ml

1. The connection of substituted 4-(phenyl-N-alkyl)piperidine of the formula 1

where R1selected from the group consisting of CF3, OSO2CF3, OSO2CH3, SOR7, SO2R7, COR7CN, CONHR3, F, Cl, Br and I, where R7defined below;

R2selected from the group consisting of F, Cl, Br, I, CN, CF3CH3The co3HE and NH2;

R3and R4regardless both are the Xia H;

R5selected from the group consisting of C1-C4of alkyl, allyl, CH2CH2Och3CH2CH2CH2F, CH2CF3, 3,3,3-cryptochrome and 4,4,4-trifloromethyl;

R7selected from the group consisting of C1-C3of alkyl, CF3, NH2and N(CH3)2,

and its pharmaceutically acceptable salt.

2. The compound or its pharmaceutically acceptable salt according to claim 1, where R1selected out of SO2CH3, SO2CF3The PINES3CN or CF3.

3. The compound or its pharmaceutically acceptable salt according to claim 1 or 2, where R2represents CH3, F or Cl.

4. The compound according to any one of claims 1 to 3, where R5selected from the group consisting of n-propyl and ethyl.

5. The compound according to any one of claims 1 to 4, where R1is a CF3, R2represents Cl and R5represents n-propyl.

6. The compound according to any one of claims 1 to 5, where the specified connection is a 4-(4-chloro-3-triptoreline)-1-propylpiperidine.

7. Pharmaceutical composition having dopamine-modulating the property containing the compound or its pharmaceutically acceptable salt according to any one of claims 1 to 6 and one or more pharmaceutically acceptable carriers or diluents.

8. The pharmaceutical composition according to claim 7 for the treatment of the condition is, selected from the group consisting of iatrogenic and not iatrogenic parkinsonism, dyskinesia, dystonia or disease Tourette's.

9. The pharmaceutical composition according to claim 7, suitable for the treatment of Parkinson's disease.

10. The pharmaceutical composition according to claim 7, suitable for the treatment of a condition selected from the group consisting of iatrogenic and not iatrogenic psychoses and Galluzzo.

11. The pharmaceutical composition according to claim 7 suitable for treatment of a condition selected from schizophrenia and schizophrenia-like psychosis diseases.

12. The pharmaceutical composition according to claim 7, suitable for the treatment of a condition selected from the group consisting of mood disorders and anxiety.

13. The pharmaceutical composition according to item 12, where a condition selected from mood disorders and anxiety, is manic-depressive illness, depression, or obsessive-compulsive disease.

14. The pharmaceutical composition according to claim 7, suitable for the treatment of a condition selected from the group consisting of disorders related to attention deficit, autism, and cognitive dysfunction.

15. The pharmaceutical composition according to claim 7, suitable for the treatment of Huntington's disease.

16. The pharmaceutical composition according to claim 7, suitable for the treatment of diseases associated with the sleep disorder.

17. The pharmaceutical composition according to claim 7, PR is suitable for treatment of disorders caused by substances, which include alcohol abuse, or addiction to medicine.

18. The pharmaceutical composition according to any one of claims 7 to 17, prepared for oral administration.

19. The pharmaceutical composition according p prepared in tablet form.

20. The pharmaceutical composition according p prepared in the form of capsules.

21. The pharmaceutical composition according to any one of claims 7 to 17, prepared for administration by injection.

22. Method of treating conditions selected from the group consisting of iatrogenic and not iatrogenic parkinsonism, dyskinesia, dystonia or disease, Tourette's, including the introduction of the patient pharmaceutically effective amount of a compound or pharmaceutically acceptable salt according to any one of claims 1 to 6.

23. A method of treating Parkinson's disease comprising the administration to a patient pharmaceutically effective amount of a compound or pharmaceutically acceptable salt according to any one of claims 1 to 6.

24. Method of treating conditions selected from the group consisting of iatrogenic and not iatrogenic psychoses and hallucinosis, including the introduction of the patient pharmaceutically effective amount of a compound or pharmaceutically acceptable salt according to any one of claim 1 to 6.

25. Method of treating conditions selected from the group consisting of schizophrenia and schizophrenia-like psychosis of diseases, including the introduction of the patient is pharmaceutically effective amount of a compound or pharmaceutically acceptable salt according to any one of claim 1 to 6.

26. Method of treating conditions selected from the group consisting of mood disorders and anxiety, including the introduction of the patient pharmaceutically effective amount of a compound or pharmaceutically acceptable salt according to any one of claim 1 to 6.

27. The method according to p, where the specified condition selected from the group consisting of manic-depressive illness, depression and obsessive-compulsive disease.

28. Method of treating conditions selected from the group consisting of disorders related to attention deficit, autism, and cognitive dysfunction, including the introduction of the patient pharmaceutically effective amount of a compound or pharmaceutically acceptable salt according to any one of claim 1 to 6.

29. A method of treating Huntington's disease, comprising the administration to a patient pharmaceutically effective amount of a compound or pharmaceutically acceptable salt according to any one of claim 1 to 6.

30. A method of treating sleep disorders comprising the administration to a patient pharmaceutically effective amount of a compound or pharmaceutically acceptable salt according to any one of claim 1 to 6.

31. A method of treating disorders caused by substances, which include alcohol abuse, or addiction to medicine, including the introduction of the patient pharmaceutically effective amount of a compound or pharmaceutically acceptable with is whether according to any one of claim 1 to 6.

32. The method according to any of item 22-31, in which the substance is administered orally.

33. The method according to any of item 22-31, in which the substance is administered by injection.



 

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1 ex, 2 tbl

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