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

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to 3-substituted 4-(phenyl-N-alkyl)piperidines of the general formula (1):

wherein R1 represents -OSO2CF3, -OSO2CH3, -SOR3, -SO2R3, -COR3; R2 represents (C1-C4)-alkyl, allyl, -CH2CH2OCH3, -CH2CH2CH2F, -CH2CF3, 3,3,3-trifluoropropyl, 4,4,4,-trifluorobutyl group; R3 represents (C1-C3)-alkyl, -CF3, and their pharmaceutically acceptable salts also. Also, invention discloses pharmaceutical compositions of abovementioned compounds and methods wherein abovementioned compounds are used in treatment of the central nervous system disturbances.

EFFECT: improved methods for treatment, valuable medicinal properties of compounds and compositions.

31 cl, 47 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 act on 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 E. strparameters 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/dopaminergic pharmacological profile, while some are partial or full agonists or antagonists of dopamine is eceptor with relatively high affinity 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:C, discloses disubstituted piperazines. The connections are represented as adrenolytic, hypotensive, potentiator barbiturates and depressants of the Central nervous system.

There are publications about a variety of substituted piperazines, such as ligands of 5-HT1Areceptors, 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. international is atenth 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).

In addition, WO 93/04684 and GB 2027703 also describe specific substituted piperazines, suitable for treatment of diseases of the Central nervous system.

Summary of the invention

The present invention is the creation of new pharmacologically active compounds, particularly suitable for the treatment of diseases 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. Compounds in accordance with the present invention have an amazing and interesting Dua is eticheskim profile dopaminergic activity with antagonist-like effects on the neurochemistry of the brain and moderate agonist-like effects on normal behavior, but they cause suppression of conduct for the state of hyperactivity.

Thus the present invention relates to new 3-substituted 4-(phenyl-N-alkyl)piperazines and 3-substituted 4-(phenyl-N-alkyl)piperidine in free base form or their pharmaceutically acceptable salts, pharmaceutical compositions containing these compounds, and use of these compounds in therapy.

One object of the invention is to provide new compounds for use in therapy, and more precisely, the compounds for modulation of dopaminergic systems in the brain of a mammal, including a human brain.

Another object of the present invention is to provide compounds having a therapeutic effect after oral administration.

More precisely, the present invention relates to compounds 3-substituted 4-(phenyl-N-alkyl)piperazine and 4-(phenyl-N-alkyl)piperidine of formula 1:

and their pharmaceutically acceptable salts,

where

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

R1selected from the group consisting of OSO2CF3, OSO2CH3, SOR3, SO2R3, COR3, NO2and CONHR3g is e R 3such as defined above, and when X represents CH or C, R1can also be selected from the group consisting of CF3, CN, F, Cl, Br and I;

R2selected from the group consisting of C1-C4Akilov, Halilov, CH2SCH3CH2CH2OCH3CH2CH2CH2F, CH2CF3, 3,3,3-cryptochrome, 4,4,4-trifloromethyl and -(CH2)-R4where R4as defined below;

R3selected from the group consisting of C1-C3Akilov, CF3and N(R2)2where R2the same as defined above;

R4selected from the group consisting of C3-C6cycloalkyl, 2-tetrahydrofuran and 3-tetrahydrofuran.

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 its modulatory action on the dopaminergic system, are diseases related to aging, to prevent bradykinesia and depression and improve mental functions. They can also be used to improve cognitive functions and related emotional disorders in neurodegenerative diseases is the third and developmental disabilities, and after brain damage.

Compounds of the present invention can also be used to improve all symptoms of psychosis, including schizophrenia and schizophrenia-like psychosis of the disease, and psychotic disorders caused by drugs.

Compounds of the present invention can also be used for violations of conduct, usually for the first time diagnosciousness in infancy, childhood or adolescence, and disorders of impulse control. Can also be improved speech disorders such as stuttering. They can also be used to treat substance abuse, as well as diseases characterized by misuse of food.

Mood disorders and anxiety, personality change and conversiona hysteria can also be treated with compounds of the present invention.

Neurological indications include the treatment of Huntington's disease and other movement disorders, and movement disorders caused by drugs. "Restless legs" and related diseases, as well as narcolepsy can also be treated by the compounds of the present invention. They can also improve mental and motor function in Parkinson's disease and related parkinsonopodobnyh symptoms. They can also be used to improve tremo the and of different origin. They can be used in the treatment of headaches and to improve brain function after vascular or traumatic brain damage. In addition, they can be used for relief of pain in conditions characterized by increased muscle tone.

It has been unexpectedly found that the compounds of the present invention is specifically affect the dopaminergic system of the brain. They have effects on biochemical impulses in the brain are characteristic features of selected dopamine antagonists, for example, causing an increase in the concentration of metabolites of dopamine.

In addition, antagonists of dopamine receptors specifically inhibit behavioral activity and cause catalepsy, while the compounds according to the invention show no or only limited inhibitory effects on spontaneous locomotor activity. On the contrary, they can cause a mild behavioral activation with a concomitant strengthening of small-scale movements, for example, stopping in the center of the field of registration of conduct, such as those that cause dopaminergic antagonists. Behavioral activation is limited, not reaching the same full activity increase, what cause direct or indirect dopaminergic antagonists. On the other hand, preferred to reduce substance p is increasing activity, caused by the direct or indirect dopaminergic agonists, that is, d-amphetamine and substances similar actions.

Thus, the compounds of the present invention unexpectedly showed an interesting dualistic profile of dopaminergic activity with antagonist-like effects on the neurochemistry of the brain and moderate agonist-like effects on normal behavior, but suppression of behavior in a state of hyperactivity. The activity profile offers a modulatory effect on dopaminergic function, is clearly different from known compounds belonging to these chemical classes or effects expected from typical antagonists or agonists of dopamine receptors of these or other chemical classes.

Given the involvement of dopamine in a wide variety of CNS functions and clinical disadvantages of currently available pharmaceutical drugs that affect the dopamine system, it is possible to prove the superiority of new classes of dopaminergic modulators present in this invention over 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 a surprise is the super 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 previous prior art there is no guidance for producing compounds such effects on the dopamine system in the brain.

Detailed description of the invention

Pharmacology

Obviously, in psychiatric and neurological diseases violated neurotransmission in the CNS. In many cases, such as in 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 antagonists of dopamine receptor, the compounds of the present invention show no or limited who is actvie on spontaneous locomotor activity. They can cause behavioral activation with simultaneous increase of small-scale movements, for example, stopping in the center of the field of registration of behaviour, like stops, caused by dopamine antagonists. Behavioral activation is limited, not reaching the same full-strengthening activity, what cause direct or indirect dopamine antagonists. Surprisingly, the preferred substances can actually reduce the increased activity caused by the direct or indirect dopaminergic agonists, that is, d-amphetamine and substances similar actions.

Preferred patterns are substituted in the meta position on the aromatic ring. An example of such compound is 3-(1-propylpiperidine-4-yl)phenyl ether methanesulfonate acid, which is presented below in example 14. In rats, this compound increases 3,4-dihydroxyphenylalanine acid in the striatum from 1265±74 (controls) to 3208±236 ng/g tissue at 50 μmol/kg subcutaneously in combination with a slight increase in behavioral activity; 1485±328 cm/30 min (control) to 2126±240 cm/30 min at 50 µmol/kg subcutaneously, n=4. Another preferred example of the compounds according to the invention represents a 4-(3-methanesulfonyl)-1-propylpiperidine, further illustrated in example 6. In rats, this compound increases 3,4-Digi recipricating acid in the striatum from 914± 19 (controls) to 1703±19 ng/g tissue at 50 μmol/kg subcutaneously. This increased turnover of dopamine should trend toward increased motor activity with 2030±299 cm/60 min before 2879±398 cm/60 min R=0,14. In animals, accustomed to the box dimension of mobility, the compound in example 6, 4-(3-methanesulfonyl)-1-propylpiperidine, increases behavioral activity with 476±279 cm/60 min (control) to 1243±72 cm/60 min, p<0,05, n=4, and 4-dihydroxyphenylalanine acid in the striatum from 975±23 (controls) to 2074±144 ng/g tissue at 50 μmol/kg subcutaneously p<0,05, n=4.

In addition, the compound described in example 6, 4-(3-methanesulfonyl)-1-propylpiperidine, has preferred the ability to reduce behavioral activity, called as d-amphetamine (1.5 mg/kg subcutaneously)and desrcibing (Mk-801, 0.7 mg/kg administered intraperitoneally). d-Amphetamine hyperactivity decreases with 10694±2165 cm/60 min prior to 1839±344 cm/60 min, p<0,05 n=4, at 50 µmol/kg subcutaneously compounds described in example 6, and behavioral activity caused by desrcibing (Mk-801) decreases with 32580±4303 cm/60 min before 18197±1389 cm/60 min, p<0.05 at 50 µmol/kg subcutaneously. To the surprise of the compound described in example 6, is available in oral introduction (F) to 85% in rats.

Unlike similar compounds described in WO91/09594, the compounds of example 6, 4-(3-methanesulfonyl)-1-about repellin, no affinity for the Sigma receptor, <50% suppression of [3H]-DTG binding (in accordance with the method of measurement of Sigma binding described Shirayama Y. et al., 1993, Eur. J. Pharmacol. 237, R) at 10 μmol/l in the membranes of rat brain.

To demonstrate the surprising action of the compounds according to the invention, some of the compounds are compared with similar compounds of the prior art. Thus, compounds suitable for comparison with the compounds according to the invention in comparative examples not included in the scope of the present invention, since they do not show desired properties.

Comparative example 1: 4-(4-methanesulfonyl)-1-propylpiperidine illustrates that the substitution in the para-position gives an inactive connection. 4-(4-methanesulfonyl)-1-propylpiperidine has no effect on 3,4-dihydroxyphenylalanine acid in the striatum, as shown in the neurochemical experiment; 988±70 (controls) ng/g tissue and 928±51 ng/g tissue at 50 μmol/kg subcutaneously. 4-(4-methanesulfonyl)-1-propylpiperidine does not have desirable properties.

Comparative example 2: To further illustrate the importance of substitution of the aromatic ring to obtain the desired properties, 4-phenyl-1-propylpiperidine demonstrates the lack of activity in the study of behavioral activity of the rats, not affected by pre-treatment with 3661±494 cm/60 min, controls, before 2553±471 cm/60 min; p>0,05, n=4, 33 µmol/kg and no impact 3.4-dihydroxyphenylalanine acid in the striatum, as shown in the neurochemical experiment; 1027±31 (controls) ng/g tissue and 1190±70 ng/g tissue in 33 µmol/kg subcutaneously; p>0,05, 4-phenyl-1-propylpiperidine also does not provide the desired suppression of behavioral activity during stimulation of d-amphetamine (17295±4738 cm/60 min, d-amphetamine, to 13764±2919 cm/60 min, n=4, p≫0.05 at 33 µmol/kg

Comparative example 3; also found that 1-phenyl-4-propylpiperazine described in WO91/09594 as a connection linking the Sigma receptor, reduces behavioral activity have not pre-treated animals 3370±227, controls, until 1923±204 cm/60 min, n=4, p<0.05 at 33 µmol/kg subcutaneously, thus providing the desired properties.

Comparative example 4: Substitution in ortho-position, as illustrated in example 1-(2-methoxyphenyl)-4-propylpiperazine, network connection, which increases the content of 3,4-dihydroxyphenylacetic acid in the striatum from 1028±9 (controls) ng/g tissue to 3836±65 ng/g tissue at 50 μmol/kg subcutaneously, n=4, p<0,05. This is accompanied by the inhibition of behavioral activity, undesirable in the present invention; 1651±300 cm/0 min (control) to 67± 34 cm/60 min at 50 µmol/kg subcutaneously, p<0,05, n=4.

Comparative example 5: it is Very important properties of substituents in the meta position. 1-propyl-4-(3-triptoreline) piperazine increases the content 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, however, followed the suppression of the behavior 1244±341 cm/60 min (control) to 271±137 at 50 µmol/kg subcutaneously, p<0,05, n=4, thus not providing the desired properties.

Comparative example 6: Further, the compound 3-(4-propylpiperazine-1-yl)benzonitrile increases the content of 3,4-dihydroxyecdysone acid in the striatum from 1432±57 (controls) ng/g tissue to 4498±234 ng/g tissue at 100 µmol subcutaneously p<0,05, n=4, and reduces the content of 5-treated acid with 630±16 (controls) ng/g tissue to 484±26 ng/g tissue in 100 µmol/kg, p<0,05, n=4. These effects should suppress behavioral activity with 3959±688 cm/60 min (control) to 634±266 at 100 µmol/kg subcutaneously, p<0,05, n=4, thus not providing properties that are desirable in the present invention. 3-(4-Propylpiperazine-1-yl) benzonitrile has the following properties: TPL 159° (fumarate). MS m/z (relative intensity, 70 eV) 229 (M+, 28), 200 (bp), 157 (27), 129 (22), 70 (25).

Comparative example 7: Another example of the value of the Deputy p is ecstasy a preparative example 14, which also has no effect on 3,4-dihydroxyphenylalanine acid in the striatum; 1121±36 (controls) ng/g tissue to 1169±42 ng/g tissue at 50 μmol/kg subcutaneously.

Comparative example 8: Physical and chemical properties provided by the Deputy on the main nitrogen is also important to obtain the desired profile. You cannot use any Deputy, for example, 1-phenethyl-4-(3-triptoreline) piperazine described as a ligand of the Sigma receptor in WO 91/09594 and WO 93/00313, which has some impact on 3,4-dihydroxyphenylalanine acid in the striatum;

with 852±33 (controls) to 1406±77 ng/g tissue at 50 μmol/kg subcutaneously, p<0,05, n=4, and decreases as the number of 5-treated acid in the striatum from 358±20 (controls) to 289±16 ng/g tissue at 50 μmol/kg subcutaneously p<0,05, n=4, and serotonin (5-HT) 379±10 (controls) to 282±6 ng/g tissue at 50 μmol/kg subcutaneously, p<0,05, n=4, which is an undesirable property in accordance with this invention, but it is reported IC50 20,3 when 5-HT1Athe receptor (WO 93/00313).

Comparative example 9: in Addition, 1-benzyl-4-(3-methanesulfonyl)piperidine, 3-(1-benzylpiperidine-4-yl) phenol, compounds with benzyl substitution on the primary nitrogen, both have undesirable properties for binding to serotonin systems in the brain. 1-Benzyl-4-(3-methanesulfonyl enyl)piperidine increases the level of 5-treated acid in the striatum from 428± 20 (controls) to 487±7 ng/g tissue at 50 μmol/kg subcutaneously, p<0,05, n=4, and reduces serotonin (5-HT) 442±15 (controls) to 345±18 ng/g tissue at 50 μmol/kg subcutaneously, p<0,05, n=4, and causes a syndrome of behavioral activity caused by serotonin syndrome behavioral activity caused by serotonin, for example, Tricklebank et al., 1985, Eur. J. Pharmacol, 106, pp.271-282). 3-(1-Benzylpiperidine-4-yl)phenol has the undesirable ability to increase the level of 5-treated acid in the striatum with 404±10 ng/g tissue to 492±26 ng/g tissue at 50 μmol subcutaneously, p<0,05, n=4, and reduces serotonin in the limbic region (5-HT) 734±8 (controls) to 677±20 ng/g tissue at 50 μmol/kg subcutaneously, p<0,05, n=4.

Comparative example 10: the Substitution on the primary nitrogen in accordance with 2-[4-(3-methanesulfonyl)piperazine-1-yl]-ethanol (described in GB 20277030), gives compounds that are inactive in the test behavioral activity; 3238±1089 cm/60 min (control) to 3782±962 cm/60 min at 33 µmol/kg, subcutaneously p<0,05, n=4, and neurochemical test; affects 3,4-dihydroxyphenylalanine acid in the striatum; 1158±126 (controls) to 1239±162 ng/g tissue in 33 µmol/kg subcutaneously, p<0,05, n=4.

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, oborudova is related to the 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 schizophrenia and schizophrenia-like psychosis diseases and other psychoses, to improve existing symptoms, and to prevent the manifestation 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:

- schizophrenia and other psychotic disorders, such as catatonic, hebephrenic, paranoid, residual or differential schizophrenia; schizophrenia-like psychosis disease; schizoaffective disease; delusional state; 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 resstr Ista, 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 obesity;

- 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;

- not classified disorders of impulse control, such as a disorder of impulse control characterized by multiple episodes of loss of control over aggressive impulses, glue Romania, 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 disorder, 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 the diversified chemicals), 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 young children, 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 and paroxysmal dyskinesia; syndrome Ekbom (restless legs), Wilson's disease, a disease Hallervorden-Spitze;

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 is any, 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 any 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°C to about 100°C.

Another convenient method of synthesis of these compounds involves the reductive amination of an amine of formula 2:

with aldehyde or ketone, or 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, in particular, 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 keys which the notes are conventional Foundation, 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 the 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 ligand complex and subject to oxidative connection. Typical Pd catalyst is a Pd2(dba)3where 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 saloon the earth metals, as 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 the 50°C 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=SN, also receive catalyzed by transition metal reactions of cross-linking, known to experts 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)2(the dotted line can before the presentation of a double bond) or trialkylamine (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 Pd 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, MgBr2, MgI2in accordance with known methods (Tetrahedron Lett., vol.33, 1992, 5373-5374, Tetrahedron Lett., vol.37, 1996, 5491-5494).

The catalyst, preferably Pd, 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, 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 known 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 of or without 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, 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, or 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 of from about -110°C to 60°C. Formed in a similar manner the intermediate lithium anions or anions magnesium can then further cooperation in order to Modestovich with a suitable electrophile of formula 12:

where a is defined as a 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).

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. Another alternative 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 the bound 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-chloritisation (J. Org. 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 is 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 here, the term C1-C4alkyl refers to alkyl containing 1-4 carbon atoms in any from the agreement 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 both acute and 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, nitric, 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.

Pharma is iticheskie composition, containing 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 preparation 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 of the selected compound may be mixed with solid excipients, for example, lactose, saccharose, sorbitol, Manni is om, 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 or 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 AMI is pectin), derivatives of cellulose 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 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. And the use of and introduction to the patient, required treatment in the clinic, it is obvious to a person skilled 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 preferably is introduced into individual dosage of 1-4 times a day.

Specialists in this field it is known that substitution of hydrogen in the unsubstituted position in the aromatic ring by fluorine atom can block the ability of the enzymatic hydroxylation, which gives a compound with low oral bioavailability. This kind of exchange (N F) rarely changes the pharmacological profile. So, in some cases, to improve oral bioavailability, it is important to introduce the fluorine atom in the unsubstituted position in the aromatic ring of the compounds of formula 1.

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-(3-methanesulfonyl)-4-propylpiperazine

A suspension of 1-(3-methanesulfonyl)piperazine (350 mg) and milled To3CO3(403 mg) is stirred in CH3CN (25 ml) at room temperature is re. Add 1-jumprope (712 μl). The mixture is refluxed over night. The reaction mixture was filtered, and volatiles evaporated in vacuo. Oily residue chromatographic on a column of silica with Meon:CH2Cl2(1:30 (V/V)as eluent. Collection of the fractions containing pure product, and evaporation of solvent gives pure 1-(3-methanesulfonyl)-4-propylpiperazine (220 mg). Amin converted into the HCl salt and recrystallized from ethanol/diethyl ether: TPL 233°C. MS m/z (relative intensity, 70 eV) 282 (M+, 30), 254 (15), 253 (bp), 210 (17), 70 (21).

The following connections in accordance with examples 2-11 receive the same manner as described in example 1.

Example 2

1-propyl-4-(3-triftormetilfullerenov)piperazine

MS m/z (relative intensity, 70 eV) 336 (M+, 16), 307 (bp), 77 (18), 70 (38), 56 (23).

Example 3

1-[3-(4-propylpiperazine-1-yl)phenyl]alanon

On the basis of 1-(3-piperazine-1-yl-phenyl)ethanone and n-Pr-I: TPL 119° (oxalate), MS m/z (relative intensity, 70 eV) 246 (M+, 10), 217 (33), 132 (18), 70 (bp), 56 (41); Rf Of 0.23 (EtOAc).

Example 4

1-propyl-4-(3-triptoreline)piperidine

On the basis of 4-(3-triptoreline)piperidine and n-Pr-I: TPL 195°C (HCl), MS m/z (relative intensity, 70 eV) 271 (M+, 4), 243 (16), 242 (bp), 159 (13), 70(49).

Example 5

1-butyl-4-(3-triptoreline)piperidine

On the basis of 4-(3-trifluoromethyl who enyl)piperidine and n-Bu-Br: TPL 222°C (HCl), MS m/z (relative intensity, 70 eV) 285 (M+, 3), 243 (12), 242 (bp), 70 (51), 56 (17).

Example 6

4-(3-methanesulfonyl)-1-propylpiperidine

TPL 200°C (HCl), MS m/z (relative intensity, 70 eV) 281 (M+, 5), 252 (bp), 129 (20), 115 (20), 70 (25).

Example 7

4-(3-methanesulfonyl)-1-propyl-1,2,3,6-tetrahydropyridine

On the basis of 4-(3-methanesulfonyl)-1,2,3,6-tetrahydropyridine and jumprope: MS m/z (relative intensity, 70 eV) 279 (M+, 26), 250 (bp), 171 (6), 128 (12), 115 (8).

Example 8

4-(3-methanesulfonyl)-1-ethylpiperidine

On the basis of 4-(3-methanesulfonyl)of piperidine and iodata: TPL°C (HCl). MS m/z (relative intensity, 70 eV) 267 (M+, 20), 252 (bp), 130 (10), 115 (12), 84 (20).

Example 9

1-isopropyl-4-(3-methanesulfonyl)piperidine

On the basis of 4-(3-methanesulfonyl)of piperidine and Isopropylamine: TPL 220°C (HCl). MS m/z (relative intensity, 70 eV) 281 (M+, 4), 266 (bp), 187 (5), 129 (5), 115 (5).

Example 10

4-(3-methanesulfonyl)-1-butylpiperazine

On the basis of 4-(3-methanesulfonyl)piperidine and n-BuCl. MS m/z (relative intensity, 70 eV) 295 (M+, 3), 252 (bp), 130 (5), 115 (3), 70 (8).

Example 11

1-isobutyl-4-(3-methanesulfonyl)piperidine

On the basis of 4-(3-methanesulfonyl)of piperidine and isobutyramide: TPL 212°C (HCl). MS m/z (relative intensity, 70 eV) 295 (M+, 1), 252 (80), 129 (40), 115 (50), 70 (bp).

Example 12

3-(1-propylpiperidine-yl)benzonitrile

A solution of 3-(1-propylpiperidine-4-yl)benzamide (350 mg) and POCl3(326 μl) in dry DMF (6 ml) is heated at 80°C for 3 hours in argon atmosphere. Evaporation of solvent gives a dark oily residue which is dissolved in water. The solution is alkalinized and extracted with CH2Cl2. The combined organic phases are dried (MgSO4), filtered and evaporated. Oily residue chromatographic on a column of silica with MeOH:CH2Cl2(1:19 (V/V)as eluent. Collection of the fractions containing pure product, and evaporation of solvent gives pure 3-(1-propylpiperidine-4-yl)benzonitrile (127 mg). Amin converted into fumaric salt and precrystallizer from ethanol/diethylether: TPL 122°C; MS m/z (relative intensity, 70 eV) 228 (M+, 2), 199 (42), 129 (26), 70 (bp), 56 (53).

Example 13

1-sec-butyl-4-(3-methanesulfonyl)piperidine

4-(3-methanesulfonyl)piperidine hydrochloride (20 mg), glacial acetic acid (4.4 mg) and 2-butanone (5.1 mg) is mixed in 1,2-dichloroethane (5 ml). To the solution add triacetoxyborohydride (23,5 mg)and the reaction mixture stirred at room temperature under nitrogen atmosphere for 5 hours (G.L.C. analysis indicates complete reaction). The reaction is quenched with saturated aqueous NaHCO3and the product extracted with CH2Cl2. The combined organic phases are dried (MgSO4), filtered, the solvent is evaporated, getting 1-sec-butyl-(3-methanesulfonyl)piperidine in the form of an oily residue. Product chromatografic on a column of silica with CH2Cl2:MeOH (9:1 (V/V)as eluent. Collection of the fractions containing pure product, and evaporating the solvent to give the pure amine (15 mg, 71%); MS m/z (relative intensity, 70 eV) 295 (M+, 1), 280 (7), 266 (bp), 187 (4), 129 (4).

Example 14

3-(1-propylpiperidine-4-yl)phenyl ester methanesulfonic acid

A solution of 3-(1-propylpiperidine-4-yl)phenol (340 mg) and triethylamine (187 mg) in 20 ml of CH2Cl2cooled to 0°C. and Then added dropwise to methanesulfonanilide (194 mg), dissolved in 10 ml of CH2Cl2. The reaction mixture was allowed to warm to room temperature and then stirred for 2.5 hours at 25°C. Finally, the reaction quenched with water. The organic layers separated and washed with 10% HCl and then with 10% Na2CO3.

After drying (MgSO4) the solvent is removed under reduced pressure. The remainder chromatographic on a column of silica using MeOH:CH2Cl2(1:9 (V/V)as eluent. The fractions containing pure 3-(1-propylpiperidine-4-yl)phenyl ether methanesulfonate acid, is collected, and the solvent is removed in vacuum, getting 206 mg specified in the connection header. (MS m/z (relative intensity, 70 eV) 297 (M+, 3), 268 (bp), 189 (24), 131 (13), 79 (16)

The following compounds in examples 15-19 receive the same manner as described in example 14.

Example 15

3-(1-ethylpiperazin-4-yl)phenyl ester methanesulfonic acid

On the basis of 3-(1-ethylpiperazin-4-yl)phenol and methanesulfonanilide: MS m/z (relative intensity, 70 eV) 283 (M+, 6), 268 (bp), 189 (54), 131 (20), 79 (70).

Example 16

3-(1-butylpiperazine-4-yl)phenyl ester methanesulfonic acid

On the basis of 3-(1-butylpiperazine-4-yl)phenol and methanesulfonanilide: MS m/z (relative intensity, 70 eV) 311 (M+, 3), 268 (bp), 189 (20), 131 (18), 79 (12).

Example 17

3-(4-propylpiperazine-1-yl)phenyl ester methanesulfonic acid

On the basis of 3-(4-propylpiperazine-1-yl)phenol and methanesulfonanilide: TPL 143-144° (fumarate); MS m/z (relative intensity, 70 eV) 298 (M+, 35), 269 (95), 121 (25), 84 (30), 70 (bp).

Example 18

3-(1-propylpiperidine-4-yl)phenyl ester triftormetilfullerenov acid

On the basis of 3-(1-propylpiperidine-4-yl)phenol and triflate anhydride: MS m/z (relative intensity, 70 eV) 351 (M+, 4), 322 (65), 189 (30), 131 (20), 69 (bp).

Example 19

3-(1-ethylpiperazin-4-yl)phenyl ester triftormetilfullerenov acid

On the basis of 3-(1-ethylpiperazin-4-yl)phenol and triflate anhydride: MS m/z (relative intensity, 70 eV) 337 (M+, 4), 322 (65), 189 (30), 131 (20), 69 (bp).

Example 20

1-[3-(1-propylpiperidine-4-yl)FeNi is]alanon

To a stirred solution of 3-(1-propylpiperidine-4-yl) phenyl ether complex triftormetilfullerenov acid (300 mg) in DMF (4 ml) in an argon atmosphere at room temperature successively added NEt3(356 μl), butylvinyl ether (823 μl) of 1,3-bis(diphenylphosphino)propane (50 mg) and Pd(OAc)2(19 mg). The resulting mixture was then heated to 80°and after 2 hours the reaction is stopped. Add 5% solution of hydrochloric acid (6 ml)and the combined mixture is stirred for 45 minutes. Then add CH2Cl2and the phases are separated. The aqueous layer was then extracted with CH2Cl2. The combined organic phases are dried (MgSO4), filtered and evaporated to dryness. The crude product was purified flash chromatography (MeOH:CH2Cl2(1:9 (V/V)). Collection of the fractions containing pure product, and evaporation of solvent gives pure 1-[3-(1-propylpiperidine-4-yl)phenyl]alanon (35 mg). MS m/z (relative intensity, 70 eV) 245 (M+, 4), 216 (bp), 100 (19), 70 (36), 57 (13).

Example 21

1-propyl-4-(3-triftormetilfullerenov)-1,2,3,6-tetrahydropyridine

4-(3-triftormetilfullerenov)pyridine (0.3 g) dissolved in 1-jumprope (2 ml) and heated to 100°C for 2 hours. Then volatiles are evaporated and the residue is dissolved in abs. EtOH (20 ml), and NaBH4(340 mg) is added in portions at -20°C. the Mixture then give magnetised room temperature and stirred over night. To the mixture is added 10% solution of Na2CO3(20 ml). The aqueous layer was extracted with CH2Cl2, and the combined organic phases are dried (MgSO4), filtered and evaporated to dryness. The crude product was purified flash chromatography (Meon:CH2Cl2(1:9 (V/V)). Collection of the fractions containing pure product, and evaporation of solvent gives pure 1-propyl-4-(3-triftormetilfullerenov)-1,2,3,6-tetrahydropyridine (150 mg). MS m/z (relative intensity, 70 eV) 333 (M+, 21), 305 (16), 304 (bp), 171 (14), 128 (14). Rf Of 0.55 (Meon).

Example 22

1-propyl-4-(3-triftormetilfullerenov)piperidine

On the basis of 1-propyl-4-(3-triftormetilfullerenov)-1,2,3,6-tetrahydropyridine, 1-propyl-4-(3-triftormetilfullerenov) piperidine allocate the same manner as described in preparative example 9. MS m/z (relative intensity, 70 eV) 335 (M+, 3), 307 (17), 306 (bp), 173 (26), 70 (10).

Example 23

1-allyl-4-(3-methanesulfonyl)piperidine

On the basis of 4-(3-methanesulfonyl)of piperidine and allylbromide named in the title compound are described in example 1. MS m/z (relative intensity, 70 eV) 279 (M+, 74), 96 (bp), 82 (98), 68 (74), 55 (93). Rf=0,42 (Meon, 0,08 EtOAc).

Example 24

4-(3-methanesulfonyl)-1-tetrahydrofuran-2-ylmethyl)piperidine

On the basis of 4-(3-methanesulfonyl)of piperidine and tetrahydrofurfurylamine named in the title compound distinguish the way, is written in example 1. MS m/z (relative intensity, 70 eV) 323 (M+, 1), 252 (bp), 129 (9), 115 (6), 70 (17). Rf=0,3 (MeOH, 0,03 EtOAc).

The synthesis of intermediates used in the above examples, are described in the preparative examples.

Preparative example 1

Tert-butyl ester 4-hydroxy-4-(3-methylsulfinylphenyl)piperidine-1-carboxylic acid

1-bromo-3-methylsulfonylbenzoyl (5.0 g, 24.6 mmol) dissolved in dry THF (40 ml) and cooled to -78°in a stream of argon (g). n-BuLi (12,8 ml, 2.5 M in hexane, to 31.9 mol) is added dropwise via syringe and the reaction mixture is stirred for further 30 minutes at -78°C, then the temperature was raised to 0°C for 5 minutes and then lowered to -78°C. Via a syringe was added 1-tert-butoxycarbonyl-4-piperidone (5,4 g, 27,06 mmol)dissolved in dry THF (30 ml). The reaction mixture is brought to room temperature and then stirred for 1 hour, and finally quenched with a saturated solution of ammonium chloride (30 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 CH2Cl2:Meon (19:1 (V/V)as eluent, obtaining tert-butyl ester 4-hydroxy-4-(3-methylsulfinylphenyl) piperidine-1-carboxylic acid (6 g, 76%). MS m/z (relative intensity, 70 eV) 323,1 (M+,6), 223,0 (11), 178,0 (7), 152 (3), 57,0 (bp), 56 (30).

Preparative example 2

1-benzyl-4-(3-methoxyphenyl)piperidine-4-ol

Based on 3-bromoanisole (5 g) and 1-benzyl-4-piperidone (5.5 g), allocate 4,58 g of 1-benzyl-4-(3-methoxyphenyl)piperidine-4-ol by the method described in example 1. MS m/z (relative intensity, 70 eV) 297 (M+, 8), 279 (13), 206 (28), 146 (17), 91 (bp).

Preparative example 3

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

Based on 3-cryptomaterial (3 g) and 1-benzyl-4-piperidone (2.1 g) was isolated 1,75 g named in the title compound by the method described in example 1. MS m/z (relative intensity, 70 eV) 335 (M+, 29), 244 (22), 146 (19), 91 (bp), 56 (19).

Preparative example 4

4-(3-methylsulfinylphenyl)-1,2,3,6-tetrahydropyridine

Tert-butyl ester 4-hydroxy-4-(3-methylsulfinylphenyl)piperidine-1-carboxylic acid (of 3.97 g) was dissolved in CH2Cl2(500 ml), and one portion add triperoxonane acid (80 ml). The mixture is refluxed for 1 hour and then washed with two portions of 10% Na2CO3, dried (MgSO4), filtered and evaporated to dryness. Output 2,07, MS m/z (relative intensity, 70 eV) 205 (M+, 73), 158 (44), 129 (95), 128 (80), 82 (bp).

Preparative example 5

1-benzyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine

On the basis of 1-benzyl-4-(3-methoxyphenyl)piperidine-4-ol (4.5 g) and triperoxonane acid (80 ml), 3.5 g of 1-benzo is l-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine allocate way described in preparative example 4. MS m/z (relative intensity, 70 eV) 279 (M+, 35), 145 (13), 115 (15), 91 (bp), 65 (22).

Preparative example 6

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

On the basis of 1-benzyl-4-(3-triptoreline)piperidine-4-ol (1,74 g) allocate 1.44 g named in the title compound by the method described in preparative example 4 (net CF3COOH). MS m/z (relative intensity, 70 eV) 317 (M+, 71), 226 (13), 172 (15), 91 (bp), 65 (17).

Preparative example 7

Methyl ester of 4-(3-methylsulfinylphenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid

4-(3-methylsulfinylphenyl)-1,2,3,6-tetrahydropyridine (2 g) and NEt3(1 g) dissolved in CH2Cl2(75 ml) and cooled to 0°C. added dropwise methylchloroform (0.96 g), dissolved in CH2Cl2(20 ml)and the reaction mixture is allowed to warm to room temperature. After another two hours at room temperature, the reaction mixture was washed with 10% solution of Na2CO3, dried (MgSO4), filtered and concentrated by evaporation.

Oily residue chromatographic on a column of silica, using CH2Cl2:Meon (19:1 (V/V)as eluent, obtaining the methyl ester of 4-(3-methylsulfinylphenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid (1.4 g). MS m/z (relative intensity, 70 eV) 263 (M+, 45), 248 (89), 129 (83), 128 (bp), 59 (96)

Preparative example 8

Methyl ester of 4-(3-methanesulfonyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid

Methyl ester of 4-(3-methylsulfinylphenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid (1.4 g) was dissolved in CH2Cl2(150 ml) and cooled to 0°C. In portions add m-chloroperoxybenzoic acid (2,48 g), and the mixture is stirred at room temperature for three hours. The resulting clear solution was washed with a 10% solution of Na2CO3, dried (MgSO4), filtered and concentrated by evaporation, and get an oily residue (1.3 g). MS m/z (relative intensity, 70 eV) 295 (M+, 19), 280 (56), 129 (70), 128 (89), 59 (bp).

Preparative example 9

Methyl ester of 4-(3-methanesulfonyl) piperidine-1-carboxylic acid

Methyl ester of 4-(3-methanesulfonyl)-3,6-dihydro-3H-pyridine-1-carboxylic acid (2.0 g) dissolved in methanol (40 ml). Add concentrated hydrochloric acid (2 ml) and Pd/C (500 mg). The resulting mixture hydronaut under pressure generated gaseous hydrogen (50 psi) for 8 hours, and then filtered through a layer of celite. The solvent is evaporated in vacuo, and the residue purified flash chromatography (CH2Cl2:Meon, 3:1 (V/V)). The output of 0.92, MS m/z (relative intensity, 70 eV) 297 (M+, 54), 282 (62), 238 (bp), 15 (92), 56 (93).

Preparative example 10

4-(3-methoxyphenyl)piperidine

On the basis of 1-benzyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine (5,1 g) and 900 mg of Pd/C, 1.7 g of 4-(3-methoxyphenyl)piperidine allocate the same manner as described in preparative example 9. The oily residue is purified flash chromatography (SiO2CH2Cl2:MeOH, 3:1 (V/V) with 1% NEt3)to give a pure compound named in the heading. MS m/z (relative intensity, 70 eV) 191 (M+, 75), 160 (60), 83 (55), 57 (80), 56 (bp).

Preparative example 11

4-(3-triptoreline)piperidine

On the basis of 1-benzyl-4-(3-triptoreline)-1,2,3,6-tetrahydropyridine (1.44 g), 1 g named the title compound as a salt model HC1 receive the same manner as described in preparative example 9. TPL 202°C (HCl), MS m/z (relative intensity, 70 eV) 229 (M+, 44), 228 (33), 83 (12), 57 (54), 56 (bp).

Preparative example 12

Methyl ester of 4-(3-methanesulfonyl)piperidine-1-carboxylic acid (0,92 g) dissolved in ethanol (15 ml) and 8 M HCl (40 ml) and refluxed for 12 hours. The mixture was then evaporated in vacuum to dryness. The output of 0.85, MS m/z (relative intensity, 70 eV) 239 (M+, 59), 238 (50), 69 (20), 57 (79), 56 (bp).

Preparative example 13

3-piperidine-4-yl-phenol

4-(3-methoxyphenyl)piperidine (1.7 g) is dissolved in 48% HBr (60 ml) and stirred at 120°C in argon atmosphere for 3 hours. Excess is to HBr then evaporated, add absolute ethane ethanol and evaporated. This procedure is repeated several times, getting dry crystals of 3-piperidine-4-yl-phenol × HBr (2.3 g). MS m/z (relative intensity, 70 eV) 177 (M+, bp), 176 (23), 91 (14), 57 (44), 56 (60).

Preparative example 14

3-(1-propylpiperidine-4-yl)phenol × HBr

Based on 3-piperidine-4-yl-phenol × HBr (300 mg) and p-propyliodide (200 mg), allocate 340 mg of 3-(1-propylpiperidine-4-yl)phenol by the method described in example 1. Get HBr salt to ensure that named the title compound. MS m/z (relative intensity, 70 eV) 219 (M+, 21), 190 (bp), 119 (22), 91 (30), 70 (63); TPL 181-184° (HBr).

Preparative example 15

3-(1-ethylpiperazin-4-yl)phenol

Based on 3-piperidine-4-yl-phenol × HBr (200 mg) and ethyliodide (121 mg), allocate 120 mg 3-(1-ethylpiperazin-4-yl)phenol by the method described in example 1. MS m/z (relative intensity, 70 eV) 205 (M+, 12), 190 (bp), 119 (36), 91 (22), 70 (87).

Preparative example 16

3-(1-butylpiperazine-4-yl)phenol

Based on 3-piperidine-4-yl-phenol × HBr (200 mg) and n-butyl chloride (73 mg), allocate 118 mg of 3-(1-butylpiperazine-4-yl)phenol by the method described in example 1. MS m/z (relative intensity, 70 eV) 233 (M+, 6), 190 (bp), 119 (42), 91 (26), 70 (45).

Preparative example 17

1-(3-methanesulfonyl)piperazine

A mixture of 1-bromo-3-methanesulfonate (0.8 g), piperazine (1 g), tert-butoxide sodium (0.5 g), BINAP (42 mg, and [Pd 2(dba)]3(38 mg) in toluene (7 ml) is heated in an argon atmosphere at 80°C for 24 hours. After cooling to room temperature the solvent is evaporated until dry. The crude material is purified flash chromatography on silica gel using EtOAc. The output is 0.48 g: MS m/z (relative intensity, 70 eV) 240 (M+, 17), 199 (12), 198 (bp), 119 (9), 56 (7).

Preparative example 18

1-(3-triftormetilfullerenov)piperazine

Based on 3-BROMOTRIFLUOROETHYLENE and piperazine named the title compound is obtained by a method described in preparative example 17. MS m/z (relative intensity, 70 eV) 294 (M+, 22), 252 (bp), 119 (32), 104 (10), 56 (15). (45).

Preparative example 19

1-(3-piperazine-1-ylphenyl)alanon

Based on 3-bromoacetophenone and piperazine named the title compound is obtained by a method described in preparative example 17. MS m/z (relative intensity, 70 eV) 204 (M+, 5), 162 (35), 77 (30), 57 (35), 56 (bp).

Preparative example 20

Methyl ester 3-(1-propylpiperidine-4-yl)benzoic acid

The mixture triftormetilfullerenov acid 3-(1-propylpiperidine-4-yl)phenyl ether complex (1.2 g), triethylamine (0.9 g), Meon (5,4 ml), Pd(OAc)2(25 mg) and 1,3-bis(diphenylphosphino)propane (45 mg) in 15 ml of DMSO is stirred at room temperature for 15 minutes. The flow of CO (g) is bubbled through the solution for the tion for 4-5 minutes, and then the reaction vessel is placed under a slightly positive pressure of CO (g). The temperature was raised to 70°C. After 6 hours the reaction mixture is allowed to cool to room temperature. Then add water, and the aqueous solution extracted with five portions of ethyl acetate, and the combined organic phases are dried (MgSO4) and evaporated. The remainder chromatographic on a column of silica using MeOH:CH2Cl2(1:9 (V/V)as eluent. The fractions containing pure named in the title compound, collected, and the solvent is removed in vacuum, obtaining 650 mg specified in the connection header. MS m/z (relative intensity, 70 eV) 261 (M+, 5), 233 (16), 232 (bp), 161 (5), 70 (20).

Preparative example 21

3-(1-propylpiperidine-4-yl)benzamid

A solution of ester methyl 3-(propylpiperidine-4-yl)benzoic acid (0.6 g) and formamide (320 ml) in DMF (9 ml) was heated to 100°C under argon. Added dropwise sodium methoxide in methanol (30%, 770 μl), and after 1 hour GC analysis reveals a complete absence of the original substance and shows named in the title compound in the form of a single product. After cooling, add CH2Cl2and the resulting solution is filtered through a layer of celite and evaporated until dry. The remainder chromatographic on a column of silica using MeOH:CH2Cl2(:3 (V/V)as eluent. The fractions containing pure named in the title compound, collected, and the solvent is removed in vacuum, receiving 400 mg specified in the connection header. So 182° (oxalate). MS m/z (relative intensity, 70 eV) 246 (M+, 4), 217 (bp), 131 (19), 100 (22), 70 (63).

Preparative example 22

4-(3-triftormetilfullerenov)pyridine

1-Bromo-3-triftormetilfullerenov (580 mg) and 4-pyridineboronic acid (275 mg) was dissolved in toluene (5 ml) and abs. EtOH (5 ml). To the mixture then add Na2CO3(424 mg) and Pd(PPh3)4(119 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) 287 (M+, 33), 218 (22), 154 (bp), 127 (56), 69 (27).

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

In vivo test: Behavior

To test the behavioral activity of animals, they were placed in separate boxes measuring the mobility of the 50×50×50 cm, equipped with many potaczek 16×16 (Digiscan activity monitor, RXYZM (16) TAO, 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). The data surface is Enesco activity of each carton dimensions mobility, 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, the speed at each time point was calculated as the distance from the previous point measurements 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 rats, seeing what Ino processed drug. Pre-treated d-amphetamine rats received a dose of 1.5 mg/kg subcutaneously for 5 minutes to cycle registration measurement of mobility. Rats pretreated with desrcibing (Mk-801), received a dose of 0.7 mg/kg administered intraperitoneally 90 minutes before measuring cycle mobility.

In vivo test: neurochemistry

After cycles determine the behavioral activity of rats, they were subjected to 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 monoamines and their metabolites. Defined monoaminergic stimulants represented dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), 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 those who together with the 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 25 μl of 30 pmol (50 µl) ((-)-S-3-(3-ethylsulfonyl)-N-n-propylpiperidine as internal standard. the pH was brought to 11.0 by the addition 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 until dry 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 continuous is a diversified 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. 3-Substituted 4-(phenyl-N-alkyl)-piperidine formula 1

where R1selected from the group consisting of OSO2CF3, OSO2CH3, SOR3, SO2R3The PINES3The PINES2CH3where R3as defined below;

R2selected from the group consisting of linear or branched C2-C4of alkyl, terminal allyl, CH2CH2OCH3CH2CH2CH2F, CH2CF3, 3,3,3-cryptochrome, 4,4,4-trifloromethyl;

R3selected from the group consisting of C1-C3of alkyl, CF3,

or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where R1selected from the group consisting of OSO2CF3, OSO2CH3, SO2CH3, SO2CF3The PINES3.

3. The compound according to any one of claim 1 or 2, where R2selected from n-propyl and ethyl.

4. The compound according to any one of claims 1 to 3, where the specified connection is a 4-(3-methanesulfonyl)-1-propylpiperidine the N.

5. Pharmaceutical composition having diaminotoluene the property containing the compound according to any one of claims 1 to 4 and one or more pharmaceutically acceptable carriers or diluents.

6. The pharmaceutical composition according to claim 5, suitable for treatment of a condition selected from the group consisting of such as iatrogenic and petrogenic parkinsonism, dyskinesia and dystonia, a disease Tourette's.

7. The pharmaceutical composition according to claim 5, suitable for the treatment of Parkinson's disease.

8. The pharmaceutical composition according to claim 5, suitable for treating conditions selected from the group consisting of iatrogenic and petrogenic psychosis and hallucinogen.

9. The pharmaceutical composition according to claim 5, suitable for treating conditions selected from schizophrenia and schizophrenia-like psychosis diseases.

10. The pharmaceutical composition according to claim 5, suitable for treating conditions selected from the group consisting of mood disorders and anxiety.

11. The pharmaceutical composition of claim 10, where these mood disorders and anxiety is selected from manic-depressive illness, depression and obsessive-compulsive diseases.

12. The pharmaceutical composition according to claim 5, suitable for treating conditions selected from the group consisting of disorders related to attention deficit, autism, cognitive di the functions.

13. The pharmaceutical composition according to claim 5, suitable for the treatment of Huntington's disease.

14. The pharmaceutical composition according to claim 5, suitable for the treatment of sleep disorders.

15. The pharmaceutical composition according to claim 5, suitable for the treatment of disorders caused by substances, which include alcohol abuse, or addiction to medicine.

16. The pharmaceutical composition according to any one of pp.5-15, prepared for oral administration.

17. The pharmaceutical composition according to item 16, prepared in tablet form.

18. The pharmaceutical composition according to item 16, prepared in the form of capsules.

19. The pharmaceutical composition according to any one of pp.5-15, prepared for administration by injection.

20. Method of treating conditions selected from the group consisting of iatrogenic and nitrogenase parkinsonism, dyskinesia and dystonia, 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 4.

21. 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 4.

22. Method of treating conditions selected from the group consisting of iatrogenic and petrogenic psychosis and Galluzzo, including the introduction paragraph what they pharmaceutically effective amount of a compound or pharmaceutically acceptable salt according to any one of claims 1 to 4.

23. Method of treating conditions selected from the group consisting of schizophrenia and schizophrenia-like psychosis diseases, comprising the administration to a patient pharmaceutically effective amount of a compound or pharmaceutically acceptable salt according to any one of claims 1 to 4.

24. 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 claims 1 to 4.

25. The method according to paragraph 24, where the specified mood disorder and anxiety is selected from the group consisting of manic-depressive illness, depression and obsessive-compulsive disease.

26. 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 claims 1 to 4.

27. 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 claims 1 to 4.

28. The method according to item 22, suitable for the treatment of sleep disorders, comprising the administration to a patient pharmaceutically who effectivnogo number of compounds, or pharmaceutically acceptable salt according to any one of claims 1 to 4.

29. 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 salt according to any one of claims 1 to 4.

30. The method according to any one of p-29, in which the substance is administered orally.

31. The method according to any one of p-29, in which the substance is administered by injection.



 

Same patents:

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 invention relates to new derivatives of 4-hydroxypiperidine General formula (I), where X denotes-O-, -NH-, -CH2-, -CH= , -CO2-, -SOP(lower alkyl) -, or-CONH-, R1- R4independently from each other, is hydrogen, hydroxy, nitro-group, a lower alkylsulfonyl, 1 - or 2-imidazolyl, 1-(1,2,4-triazolyl), R5and R6independently from each other, is hydrogen, lower alkyl, hydroxy - or oxoprop, R7- R10independently from each other, is hydrogen, lower alkyl, halogen, trifluoromethyl or lower alkoxygroup, n = 0 or 1, or their pharmaceutically acceptable acid additive salts

,diarylethene and method of production thereof" target="_blank">

The invention relates to a series of new derivatives,-diarylamino, which are antagonists of the serotonin receptor-2 and are useful, therefore, for the treatment and prevention of circulatory (cardiovascular disease) diseases associated with the circulatory disorders, and psychosis

The invention relates to certain derivatives of piperidine, the method of production thereof, compositions containing these compounds, and their use as fungicides

The invention relates to new chemical compounds, namely hydrochloridum derivatives of 1-benzyl-4-indane)-methylpiperidine formula IHClwhere R1- H or methoxy;

R2is methylene;

n is an integer 1 or 2, which have a high and strictly selective antiacetylcholinesterase activity and can find application in medicine

FIELD: chemico-pharmaceutical industry.

SUBSTANCE: the present innovation deals with applying the compound of formula I

for treating neuropathic pains. This compound I (retigabin) is of high efficiency in treating allodynia, hyperalgesia-conditioned pains, neuropathic pain in case of diabetic neuropathy, neuropathic pain at migraine. The compound suggested is low toxic being of high bioavailability.

EFFECT: higher efficiency of therapy.

6 cl, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted 2-aryl-3-(heteroaryl)imidazo[1,2-a]-pyrimidines of the formula (I):

or to their pharmaceutically acceptable salts wherein: (a) R1 is taken among the group consisting of -NH2, C1-5-alkylamino-, di-C1-5-alkylamino-, phenylmethylamino-group; (b) Y is taken among the group consisting of hydrogen atom (H), halogen atom, piperidine, OR4, SR4, -SO2CH3, NHR4 and NR4R5 wherein R4 and R5 are taken independently among hydrogen atom (H), α-alkylphenyl-C1-5-alkyl, linear or branched alkyl substituted optionally with C3-5-carbocycle, phenyl or substituted phenyl wherein indicated phenyl can be substituted with one or some substituted taken among C1-5-alkoxy-group; (c) R2 represents from one to five members taken independently among the group including hydrogen atom (H), halogen atom, trifluoromethyl; (d) R3 represents hydrogen atom (H), or radicals R3 taken in common form aromatic ring; (e) X represents nitrogen atom (N) or -CH. Also, invention relates to methods for preparing indicated compounds and to a method for treatment based on these compounds. Invention provides preparing novel compounds that can be used in relief states by reducing the level of inflammatory cytokines, for example, the indicated state represents proliferative (rheumatic) arthritis.

EFFECT: valuable medicinal properties of compounds and compositions.

40 cl, 1 tbl, 4 ex

FIELD: organic chemistry, chemical technology, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of propene carboxylic acid amidooximes of the formula (I):

wherein R means phenyl that is substituted optionally with 1-3 substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; R' means hydrogen atom (H); R4 and R5 mean independently of one another H, (C1-C5)-alkyl, phenyl that is substituted optionally with 1-3 substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; or R4 and R5 in common with adjacent nitrogen atom form 5- or 6-membered saturated or unsaturated heterocyclic group that can comprise additional nitrogen atom or oxygen atom as a heteroatom and it can be condensed with benzene ring, and heterocyclic group and/or benzene ring can comprise one or two substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; R1 and R2 mean H; R3 means H, OH; or R1 in common with R2 forms carbonyl group wherein carbon atom is joined with oxygen atom adjacent with R1 and with nitrogen atom adjacent with R2; R3 means H, OH; or R2 means H; and R1 in common with R3 form a valence bond between oxygen atom adjacent with R1 and carbon atom adjacent with R3; and its geometric isomers and/or optical isomers, and/or its pharmaceutically acceptable acid-additive salts. Compounds of the formula (I) inhibit activity of poly(adenisone diphosphate ribose) polymerase and can be used in pharmaceutical composition in treatment of states based on inhibition of this enzyme activity, and in treatment of states associated with oxygen insufficiency of heart and brain. Also, invention describes methods for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable medicinal properties of compounds and compositions.

9 cl, 1 tbl, 41 ex

FIELD: medicine, resuscitation.

SUBSTANCE: one should obtain the values on head's vertical position, pulmonary ventilation, efforts coming to organs of controlling and parameters of cabin's hermetic nature. A transport driver should get the information on irregular extreme situation, one should supply 100% oxygen. In case of acute respiratory insufficiency at the background of spontaneous respiration, in case of acute pain, high heart beating or gunshot wound it is necessary to perform additional electrostimulation of the muscles that actively participate in respiration act, with amplitude-frequency-modulated triangular series of impulses at impact duration being 1.5-2.0 sec at pause being about 3-4 sec. Moreover, electrostimulation should be combined with anesthesia performed due to automatic injection of medicinal preparation into biologically active point Tan'-Chzhun along with the intake of therapeutic dosage of an antiaggregant, a thrombolytic, a nitropreparation, beta-adrenoblocking agent and low-molecular heparin. Automatic pharmacoinjection should be conducted manually as a transport driver desired, and in critical situation - due to distance-controlled operation; moreover, injection should be fulfilled perpendicularly for the depth not exceeding 0.5-0.6 cm. The innovation increases the number of preparations applied in extreme situations to rescue a transport driver.

EFFECT: higher efficiency of rescue activity.

3 cl, 1 dwg

FIELD: neurological diseases.

SUBSTANCE: composition contains therapeutically effective amount of anticonvulsant agent dissolved or dispersed in aqueous carrier containing 10-80 vol % aliphatic alcohol, 10-80 vol % ethylene glycol, and 0.1-5 vol % bile acid salt or lecithin. Indicated carrier ensures increased access of anticonvulsant agent (such as benzodiazepin, in particular diazepam, clonazepam, phoenitoin, mephoenitoin, ethotoin, phenobarbital, carbamazepin, ethosuccinamide, valproic acid, gabapentine, trimethadion, lamotrigin) into blood and rapid pharmacological response when using nasal administration.

EFFECT: accelerated anticonvulsant effect.

11 cl, 9 dwg, 10 tbl, 13 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to new biarylcarboxamides of the general formula (I): wherein A means compound of the formula (II): ; D means oxygen atom (O) or sulfur atom (S); E means a simple bond, oxygen atom, sulfur atom or NH; Ar1 means 5-membered heteroaromatic ring comprising one nitrogen atom (N) and one sulfur atom (S) or one oxygen atom (O), or one S atom, or one N atom; or 6-membered aromatic ring, or heteroaromatic ring comprising one N atom; Ar2 means 5-membered heteroaromatic ring comprising one S atom or on O atom, or one N atom and one O atom, or one N atom; or 6-membered aromatic ring or heteroaromatic ring comprising one N atom; or 9-membered condensed heteroaromatic ring system comprising one O atom, or 10-membered condensed aromatic ring system, or heteroaromatic ring system comprising one N atom wherein aromatic ring Ar2 is possibly substituted with one or two substitutes taken among halogen atom, (C1-C4)-alkyl, cyano-group (-CN), nitro group (-NO2), NR1R2, OR3, trihalogen-(C1-C4)-alkyl, (C1-C4)-acylamino-, hydroxy-, morpholino-, amino-, methylamino-group, amino-(C1-C4)-alkyl and hydroxymethyl but if Ar1-phenyl and Ar2 represent quinolinyl group then Ar2 is substituted with one or two (C1-C4)-alkyls, -CN, -NO2, NR1R2, OR3 wherein R1, R2 and R3 mean (C1-C4)-alkyl and compound of the formula (III) doesn't represent .

EFFECT: improved preparing and treatment methods.

33 cl, 69 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of dihydrobenzo[b][1,4]diazepine-2-one. Invention describes derivatives of dihydrobenzo[b][1,4]diazepine-2-one of the general formula (I): wherein X means a simple bond or ethynediyl group wherein if X means a simple bond then R1 means cyano-group, halogen atom, lower alkyl, (C1-C3)-cycloalkyl, (lower)-alkoxyl, fluoro-(lower)-alkyl or it means pyrrole-1-yl that may be free or substituted with 1-3 substitutes taken among the group consisting of fluorine, chlorine atom, cyano-group, -(CH2)1-4-hydroxyl group, fluoro-(lower)-alkyl, lower alkyl, -(CH2)n-(lower)-alkoxyl, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'', hydroxy-(lower)-alkoxyl and -(CH2)n-COR'R'', or it means free phenyl or phenyl substituted with one or two substitutes taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, fluoro-(lower)-alkoxyl and cyano-group; if X means ethynediyl group then R1 means free phenyl or phenyl substituted with 1-3 substituted taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (C3-C6)-cycloalkyl, (lower)-alkoxyl and fluoro-(lower)-alkoxyl; R2 means -NR'R'', fluoro-(lower)-alkoxyl or 3-oxopiperazin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl wherein their rings are substituted optionally with R''; R' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl or 2-(lower)-alkoxy-(lower)-alkyl; R'' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl, 2-(lower)-alkoxy-(lower)-alkyl, -(CH2)2-4-di-(lower)-alkylamino-group, -(CH2)2-4-morpholinyl, -(CH2)2-4-pyrrolidinyl, -(CH2)2-4-piperidinyl or 3-hydroxy-(lower)-alkyl; Y means -CH= or =N-; R3 means halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, cyano-group, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'' or it means optionally substituted 5-membered aromatic heterocycle that can be substituted with halogen atom, fluoro-(lower)-alkyl, fluoro-(lower)-alkoxyl, cyano-group, -(CH2)n-NR'R'', -(CH2)n-C(O)OR'', -(CH2)n-C(O)NR'R'', -(CH2)n-SO2NR'R'', -(CH2)n-C(NH2)=NR'', hydroxyl, (lower)-alkoxyl, (lower)-alkylthio-group or lower alkyl that is optionally substituted with fluorine atom, hydroxyl, (lower)-alkoxyl, cyano-group or carbamoyloxy-group; n means 0, 1, 2, 3 or 4, and their pharmaceutically acceptable additive salts. Also, invention describes a medicinal agent as antagonist of mGlu receptors of group II based on compounds of the formula (I). Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 496 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of dihydrobenzo[b][1,4]diazepine-2-one. Invention describes derivatives of dihydrobenzo[b][1,4]diazepine-2-one of the general formula (I): wherein X means a simple bond or ethynediyl group wherein if X means a simple bond then R1 means cyano-group, halogen atom, lower alkyl, (C1-C3)-cycloalkyl, (lower)-alkoxyl, fluoro-(lower)-alkyl or it means pyrrole-1-yl that may be free or substituted with 1-3 substitutes taken among the group consisting of fluorine, chlorine atom, cyano-group, -(CH2)1-4-hydroxyl group, fluoro-(lower)-alkyl, lower alkyl, -(CH2)n-(lower)-alkoxyl, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'', hydroxy-(lower)-alkoxyl and -(CH2)n-COR'R'', or it means free phenyl or phenyl substituted with one or two substitutes taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, fluoro-(lower)-alkoxyl and cyano-group; if X means ethynediyl group then R1 means free phenyl or phenyl substituted with 1-3 substituted taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (C3-C6)-cycloalkyl, (lower)-alkoxyl and fluoro-(lower)-alkoxyl; R2 means -NR'R'', fluoro-(lower)-alkoxyl or 3-oxopiperazin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl wherein their rings are substituted optionally with R''; R' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl or 2-(lower)-alkoxy-(lower)-alkyl; R'' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl, 2-(lower)-alkoxy-(lower)-alkyl, -(CH2)2-4-di-(lower)-alkylamino-group, -(CH2)2-4-morpholinyl, -(CH2)2-4-pyrrolidinyl, -(CH2)2-4-piperidinyl or 3-hydroxy-(lower)-alkyl; Y means -CH= or =N-; R3 means halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, cyano-group, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'' or it means optionally substituted 5-membered aromatic heterocycle that can be substituted with halogen atom, fluoro-(lower)-alkyl, fluoro-(lower)-alkoxyl, cyano-group, -(CH2)n-NR'R'', -(CH2)n-C(O)OR'', -(CH2)n-C(O)NR'R'', -(CH2)n-SO2NR'R'', -(CH2)n-C(NH2)=NR'', hydroxyl, (lower)-alkoxyl, (lower)-alkylthio-group or lower alkyl that is optionally substituted with fluorine atom, hydroxyl, (lower)-alkoxyl, cyano-group or carbamoyloxy-group; n means 0, 1, 2, 3 or 4, and their pharmaceutically acceptable additive salts. Also, invention describes a medicinal agent as antagonist of mGlu receptors of group II based on compounds of the formula (I). Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 496 ex

FIELD: medicine.

SUBSTANCE: the method for improving quality of sleep in mammalians deals with introducing them an efficient quantity of nonpathogenic lactobactera, moreover, cellular walls of the mentioned bacteria should be hydrolyzed with mutanolysine at obtaining a soluble muramylpeptides-containing fraction. The intake of muramylpeptides either directly or due to digesting nonpathogenic lactobacteria improves the quality of sleep in mammalians, in particular, due to increasing sleep phase with nonquick ocular movements. The innovation enables to improve restoration in case of fatigue, causes no pathological responses such as super-production of cytokins, and, also, provides no side effects in case of barbiturates intake and other soporific preparations.

EFFECT: higher efficiency.

16 cl, 4 dwg

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

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

FIELD: medicine, narcology.

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

EFFECT: enhanced effectiveness of treatment.

3 ex

FIELD: chemistry of heterocyclic compounds, chemical technology, pharmacy.

SUBSTANCE: invention relates to a method for preparing 1,2,5-trimethyl-4-phenyl-4-propionyloxypiperidine hydrochloride (promedol) used extensively as an analgetic medicinal agent. Method involves reaction of 1,2,5-trimethylpiperidone-4 with aromatic compound of alkaline or earth-alkaline metal that is carried out at temperature from -10°C to -100°C and wherein 1-1.15 mol of aromatic compound of alkaline or earth-alkaline metal, in particular, phenyllithium or phenylmagnesium bromide is used per 1 mol of 1,2,5-trimethylpiperidone-4 followed by two-fold treatment with propionyl chloride. Invention provides enhancing yield of promedol.

EFFECT: improved preparing method.

5 cl, 8 ex

FIELD: medicine.

SUBSTANCE: method involves administering typical neuroleptics according to titration scheme and tricyclic antidepressants. Neuroleptics are applied according to titration scheme in the morning and tricyclic antidepressants are introduced as intravenous drop-by-drop infusion in the evening in combination with per os application of atypic neuroleptic risperidon. After having given 12-14 intravenous infusions, strategic supporting risperidon psychopharmacotherapy in combination with tricyclic antidepressants during 4-6 months.

EFFECT: enhanced effectiveness in overcoming pharmacological resistance; accelerated schizo-affective syndrome relief.

The invention relates to the field of creation of a combined preparation on the basis of metamizol sodium and Campidano with analgesic, antipyretic and antispasmodic activity
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