Novel dopamine neurotransmission modulators

FIELD: chemistry.

SUBSTANCE: invention relates to novel 3-substituted 4-(phenyl-N-alkyl)piperazine compounds of formula (1) , where R1 represents OSO2CF3, OSO2CH3, SO2R3, COCF3 and COCH2CH3, R2 represents C1-C4 alkyl or allyl, R3 represents C1-C3 alkyl or CF3, as well as to their pharmaceutically acceptable salts. The disclosed compounds are capable of modulating dopamine neurotransmission.

EFFECT: invention discloses pharmaceutical compositions of compounds which are used for treating disorders of the central nervous system.

4 cl, 24 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 ek is trapezoidally side effects and remote dyskinesia when using dopaminergic antagonists as antipsychotic agents and dyskinesia and psychosis when using dopaminergic antagonists as agents aimed at treating Parkinson's disease. Therapeutic action is unsatisfactory in many respects. The search continues for improving efficiency and reducing the side effects of dopaminergic ligands pharmaceuticals, new ligands of dopamine receptors with selectivity towards specific subtypes of dopamine receptors or regional selectivity. In this context, to achieve an optimal level of stimulation of dopamine receptors have also been developed to partial antagonists of dopamine receptors, i.e., the ligands of dopamine receptors with some, but not full intrinsic activity relative to dopamine receptors, thus avoiding the blockade of dopamine receptor or excessive stimulation.

Previously the message and the compounds belonging to the class of substituted 4-(phenyl-N-alkyl)piperazine and substituted 4-(phenyl-N-alkyl)piperidino. Among these compounds, some are inactive in the CNS, some show serotonergically or mixed serotonergically/dopaminergic pharmacological profile, while some are partial or full agonists or antagonists of dopamine p is Ceptor 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. 61:10691c, 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. in international the patent applications WO 93/00313 and WO 91/09594 discloses various amines, and among them substituted piperazines as ligands of Sigma receptors. Clinical work that explores the properties of the ligands of Sigma receptors in patients with schizophrenia, not make it obvious that antipsychotic activity or activity in relation to any other Central nervous system diseases. With both of the most studied selective antagonists of the Sigma receptors, BW234U (rimcazole) and BMY14802, clinical studies on patients with schizophrenia (Borison et al., 1991, Psychopharmacol Bull 27(2): 103-106; Gewirtz et al., 1994, Neuropsychopharmacology. 10:37-40).

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 to the forest dualistic 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 the 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 CONR3where 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 and is Arushanyan development 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 tremor is hypoxia 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 is less effects 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, i.e. d-Amfetamine 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-dihydroxyphenyl the scurry 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 WO 91/09594, the compounds of example 6, 4-(3-methanesulfonyl)-1-propylpiperidine, there is no affinity to the Sigma receptor, <50% suppression of [3H]-DTG binding (in the accordance with the method of measurement of Sigma binding described Shirayama Y. et al., 1993, Eur. J. Pharmacol. 237, p.117) 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 in rats not exposed to pre-treatment, 3661±494 cm/60 min, controls, before 2553±471 cm/60 min; p>0,05, n=4, 33 μmol/kg and the absence of the 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 WO 91/09594 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 the 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/60 min (control) to 67±34 cm/60 min at 50 µmol/kg subcutaneously, p<0,05, n=4.

Comparative example 5:Very important properties of substituents in the meta position. 1-propyl-4-(3-triptoreline)piperazine increases the content of 3,4-dihydro who difeniluksousna 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 at 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°C (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 represents the 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:Physico-chemical properties provided by the Deputy on the main nitrogen is also important for obtaining same aemula profile. You cannot use any Deputy, for example, 1-phenethyl-4-(3-triptoreline)piperazine described as ligand-Sigma receptor in WO 91/09594 and WO 93/00313, which has some impact on 3,4-dihydroxyphenylalanine acid in the striatum; 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)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 (behavioral syndrome and the effectiveness, due to 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: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 mediated by dopamine. They may, for example, be used to reduce the symptoms of disorders of mood, obesity, as anorectics agent and other eating disorders, for improving cognitive functions and related emotional disorders, to improve cognitive and motor d is funktsii, 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, and so on

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

- disturbing the disorder, 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, kleptomania, pathological gambling, Pyromania and triacetone;

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

- caused m is documentosmi means of 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 compounds), sedative agents, hypnotic agents, and/or tranquilizers;

disorders, for the first time diagnostirovanie in infancy, childhood or adolescence, such as mental retardation, learning disorder, a disorder of motor skills, for example, disorder development coordination; communication disorders, for example, the Sam is eusto expressiveness of the 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, the disorder feeding babies 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 stereotypically the 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 the RNA 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, 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 is m 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 reductive amination of the amine f is rmula 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 acids are conventional bases, such as carbonates, bicarbonates and hydroxides of alkaline or alkaline earth metals, and organic bases, such as trialkylamine and trialkanolamines. The reaction is carried out in a suitable solvent, such as n-butanol, heated at about 50-150°C.

The compounds of formula 1 where X=N also receive the interaction of compounds of formula 6:

with aryl, substituted leaving group of formula 7:

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

The catalyst, preferably Pd, has the ability to form 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 alkaline earth metals, and some organic bases, such as trialkylamine and trialkanolamines. The reaction medium for such reactions may be any conventional organic solvent, inert under alkaline conditions; suitable solvents are acetonitrile, toluene, dioxane, NRM (N-methyl-2-pyrrolidone), DMA (dimethoxyethane), DMF (N,N-dimethylformamide), DMSO (dimethyl shall sulfoxide) and THF (tetrahydrofuran). Usually the reaction is carried out at an elevated temperature of the reaction mixture, for example, from ambient temperature to the boiling temperature under reflux, especially from 50°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 (for example, Bt2B(OH)2(the dotted line can represent 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)room.The Y may be a zinc - or mineralogico group (e.g., ZnCl2, ZnBr2, ZnI2, MgBr2, MgI2in accordance with known methods (Tetrhedron 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 or without proton KIS is the notes, 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 about 60°C. Formed in a similar manner the intermediate lithium anions or anions magnesium can then continue to interact with a suitable electrophile of formula 12:

where 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:

was the Dalen thus, so 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 an inert solvent such as ether or tetrahydrofuran.

Another alternative method of removing the hydroxyl group is first in the dehydrogenation of the alcohol to olefin such reagents as salt Burgess (J. Org. Chem., vol.38, 1973, 26) with subsequent catalytic hydrogenation of the double bond under standard conditions with the same catalyst as palladium on carbon. the Peart can also be digidrirovanny to olefin by treatment with an acid, such as a pair of 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 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 conversion of methoxy groups to the corresponding the total 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 term1-C4alkyl refers to alkyl containing 1-4 carbon atoms in any isomeric form. Various carbon fragments are defined as follows: alkyl refers to an aliphatic hydrocarbon radical and includes the forms of branched and non-branched chain such as methyl, ethyl, n-propyl, ISO-propyl, n-butyl, ISO-butyl, sec-butyl, tert-butyl. The term cycloalkyl refers to the radical of saturated cyclic hydrocarbons, such as cyclopropyl, cyclobutyl, cyclopentyl, Ziklag the KSIL.

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.

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

In clinical practice the compounds used in the fit is 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, mannitol, starch, such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatin or polyvinylpyrrolidine, and a lubricating agent such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin and the like, and then compressed into tablets. If you require coated tablets, content, obtained as described above, may be covered to centerowner 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 amylopectin), cellulose derivatives or gelatin. Liquid or semi-liquid dosage forms can fill hard gelatin capsules.

Dosage units for rectal injection can be solutions or suspensions, or may be obtained in the form of suppositories containing the active substance in a mixture with a neutral fat base, or gelatin rectal capsules that contain the active substance in a mixture with vegetable oil or PA is avinoam 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. The use and introduction to the patient in need of treatment in the clinic 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 of Voditsa 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 (H 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. 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 MeOH: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 Hcl salt and recrystallized from et is Nola/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°C. (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-triptoreline)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-4-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 80oC 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. Oil is NISTO balance chromatographic on a column of silica with Meon:CH 2CL2(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 122oC; 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, and the solvent is evaporated, obtaining 1-sec-butyl-(3-methanesulfonyl)piperidine in the form of an oily residue. Product chromatografic on a column of silica with HF2CL2:Meon (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-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 0oC. 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 25oC. 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 Meon: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°C (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)phenyl]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 been certified with qi net3(356 μl), butylvinyl ether (823 μl) of 1,3-bis(diphenylphosphino)propane (50 mg) and Pd(SLA)2(19 mg). The resulting mixture was then heated to 80°C, and across the 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 (Meon: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 allowed to warm to 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 evaporating the solvent getcity 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 are described in example 1. MS m/z (relative intensity, 70 eV) 323 (M+, 1), 252 (bp), 129 (9), 115 (6), 70 (17). Rf=0,3 (Meon, 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-matilal niversal (5.0 g, 24.6 mmol) dissolved in dry THF (40 ml) and cooled to -78°C 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-thrift methylphenyl)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-benzyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine allocate the same manner as 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 header soy is inane way 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 0oC. 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 0oC. In portions on billaut 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, created with 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), 115 (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% been certified with qi net 3)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 120oC in argon atmosphere for 3 hours. Excess HBr then evaporated, add the 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)pheno is × HBr

Based on 3-piperidine-4-yl-phenol × HBr (300 mg) and n-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°C (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 [Pd2(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 of the example is t 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 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 obyedinenny the organic phase is dried (MgSO 4) and evaporated. The remainder chromatographic on a column of silica, using Meon:CH2CL2(1:9 (vol./about.)) as eluent. The fractions containing pure named the title compound is 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 100oWith 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 Meon:CH2CL2(1:3 (vol/about.)) as eluent. The fractions containing pure named the title compound is collected, and the solvent is removed in vacuum, receiving 400 mg specified in the connection header. So 182o(Oxalate). MS m/z (relative intensity, 70 eV) 246 (M+, 4), 217 (bp), 131 (19), 100 (22), 70 (63).

The prep is exploring the 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 were placed in individual boxes measure the mobility of 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). Data behavioral activity of each carton dimension of mobility that represents the position (center of gravity) of the animal at each time point, were recorded with the selected frequency of 25 Hz and collected using specially made written LABView™ applicator. The data is of each cycle was analyzed from the point of view of distance and small-scale movements, for example, a stop in the center of the field of 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 from rats pre-treated with the medication. Pre-treated d-amphetamine rats received a dose of 1.5 mg/kg subcutaneously for 5 minutes to cycle registration measurement of mobility. 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 the test compounds according to the invention. On the first day, rats were implanted one catheter in the jugular vein, and the second catheter in the carotid artery under ketamine anesthesia. On the third day was administered to test the connection, or orally, or through a catheter in the jugular ve is at. 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 in a continuous way. The temperature of the GC was supported on the 90oC for 1 min after injection and then increased on the 30oC/min to a final temperature of 290oC. Each sample was duplicated. In General, it is found that the lowest ODA who shared the concentration of the tested compounds was 1 pmol/ml

1. Connection 3-substituted 4-(phenyl-N-alkyl)piperazine of the formula 1:

where R1selected from the group consisting of OSO2CF3, OSO2CH3, SO2R3, COCF3and the PINES2CH3,
where R3as defined below;
R2selected from the group consisting of C1-C4Akilov and alllow;
R3selected from the group consisting of C1-C3Akilov and CF3;
or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where R1selected from the group consisting of OSO2CF3, OSO2CH3, SO2CH3, SO2CF3.

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

4. Pharmaceutical composition having dopaminereleasing the property containing the compound according to any one of claims 1 to 3 and one or more pharmaceutically acceptable carriers or diluents.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing and aminophenol compound of formula (1) , where each of R1 and R2, which can be identical or different, are a hydrogen atom, C1-C6 alkyl group, which can be substituted with phenyl, or phenyl; R1 and R2 together with the neighbouring nitrogen atom can form a 5- or 6-member heterocyclic group, selected from piperidinyl and piperazinyl; the heterocyclic group can be substituted with one substitute selected from hydroxyl group, C1-C6 alkyl group and phenoxy group, which can have a C1-C6 alkoxy group, substituted with 1-3 halogen atoms. The method involves reacting a cyclohexanedione compound of formula (2) with a amine compound of formula (3) , where R1 and R2 assume values given above, in neutral or basic conditions.

EFFECT: wider range of use of the compound.

8 cl, 4 dwg, 13 ex

FIELD: chemistry.

SUBSTANCE: in derivatives of 1,2-di(cyclo)substituted benzole of general formula I, their salts and hydrates , R10 is 5-10 member cycloalkyl, optionally substituted, or 5-10 member cycloalkenyl, optionally substituted, n=0, 1 or 2; XI is CH or nitrogen.

EFFECT: inhibiting activity with respect to cell adhesion or cell infiltration and application as therapeutic or preventive agent for inflammatory and autoimmune diseases, connected with adhesion and infiltration of leucocytes.

22 cl, 3 tbl, 118 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to quaternary ammonium salts, with formula (I) where R1 represents alkyl with a straight or branched chain, with between 1 and 4 carbon atoms, R2 represents methyl or ethyl and X represents a fluorine containing anion. The invention also relates to electrolytes, electrolytic solutions and electrochemical devices.

EFFECT: invention provides for electrochemical devices, used under high voltages, with high discharge capacity and capable of discharging by large current; the invention provides for electrolytic solutions, with high stability under voltage and high electrolytic conductance.

151 cl, 77 ex, 47 tbl, 10 dwg

FIELD: medicine; pharmacology.

SUBSTANCE: composition is intended for treatment or prevention of insulin resistance of susceptible warm-blooded animals, including humans, and contains selective modulator of estrogen receptor EM-652-HC1, taken in amount determined by therapeutic efficiency.

EFFECT: effective treatment of prevention of insulin resistance development for warm-blooded mammals.

5 cl, 20 ex, 12 tbl, 8 dwg

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 5-amino-1-pentene-3-ol of the general formula (I)

as a free form or as their physiologically compatible salts possessing the analgesic effect. In general formula (I) each R1 and R2 means independently of one another (C1-C6)-alkyl that can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or multi-substituted; or R1 and R2 form in common -(CH2)2-9-mono- or bicyclic ring; each R3 and R4 means independently of one another (C1-C6)-alkyl, or R3 and R4 form in common a ring and mean the group -CH2CH2NR22CH2CH2 wherein R22 represents (C1-C10)-alkyl; R5 means (C1-C10)-alkyl that is saturated or unsaturated, branched or unbranched, mono- or multi-substituted or unsubstituted, (C3-C9)-cycloalkyl that is saturated or means phenyl, heteroaryl that can be condensed with benzene ring and chosen from 5-membered heteroaryl with sulfur or oxygen atom as a heteroatom bound through saturated (C1-C3)-alkyl, phenyl bound through saturated (C1-C3)-alkyl-(C3-C10)-cycloalkyl wherein each among all these alkyl, phenyl, heteroaryl and cycloalkyl residues and independently of others can be unsubstituted or mono- or multi-substituted residues chosen independently of one another from the group comprising atoms F, Cl, Br, J, groups -OR18, (C1-C3)-alkyl) that is saturated or branched or unbranched, mono- or multi-substituted halide, or unsubstituted and wherein R18 represents hydrogen atom (H), (C1-C10)-alkyl that is saturated, branched or unbranched; R6 means (C1-C10)-alkyl that is saturated or unsaturated, branched or unbranched and unsubstituted, phenyl or heteroaryl that is chosen from 5-membered heteroaryl with oxygen atom as a heteroatom wherein each of them is unsubstituted or mono- or multi-substituted as indicated above; R7 means H. Also, invention relates to a medicinal agent based on proposed compounds and to a method for their synthesis.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds.

10 cl, 493 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel [(heterylonio)-methylcarbonyloxypoly(alkyleneoxy)]-[(ammonio)methylcarbonyloxypoly(alkyleneoxy)]propane trichlorides of the general formula: wherein: at X+ = Y+ means X+ means -N+R1R2R3 wherein R1 = R2 means hydrogen atom (H); R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e (total degree of oxypropylation) = 49; b + d + f (total degree of oxyethylation) = 9; at X+ = Y+ means Z+ means -N+R1R2R3 wherein R1 = R2 means H; R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e = 55; b + d + f = 10; at X+ means Y+ = Z+ means -N+R1R2R wherein R1 = R2 means H; R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e = 49; b + d + f = 9; at X+ means Y+ = Z+ means -N+R1R2R3 wherein R1 = R2 means H; R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e = 55; b + d + f = 10; at X+ means Y+ = Z+ means -N+R1R2R3 wherein R1 = R2 means H; R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e = 49; b + d + f = 0; at X+ means Y+ = Z+ means -N+R1R2R3 wherein R1 = R2 means H; R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e = 55; b + d + f = 0; at X+ = Y+ means Z+ means -N+R1R2R3 wherein R1 = R2 means H; R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e = 49; b + d + f = 0; at X+ = Y+ means Z+ means -N+R1R2R3 wherein R1 = R2 means H; R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e = 55; b + d + f = 0, and to a method for their synthesis. Method involves interaction of 1,2,3-tris-[hydroxypoly(alkyleneoxy)]propane of the formula: wherein a + c + e = 55; b + d + f = 0-10 with monochloroacetic acid in the presence of acid catalysts, in organic solvent medium and with azeotropic removal of formed water and the following treatment at heating of the synthesized reaction productwith a mixture of morpholine and aliphatic amine in the molar ratio of reagents - hydroxyl derivative of propane: monochloroacetic acid : morpholine : aliphatic amine = 1:(3.0-3.2):(1.0-2.1):(1.0-2.1), respectively and wherein the total amount of morpholine and aliphatic amine is 3.0-3.2 mole. Novel compounds possess emulsifying properties for aqueous-bitumen and aqueous-mazut emulsions.

EFFECT: improved method of synthesis, valuable properties of compounds.

6 cl, 2 tbl, 8 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel 1,2,3-tris-[(ammonio)methylcarbonyloxypoly(alkyleneoxy)]-propane trichlorides of the general formula:

wherein at -X+ as -N+R1RR, R1 = R2 mean hydrogen atom (H), R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms, a + c + e (the general degree of oxypropylation) = 49,b + d + f (the general degree of oxyethylation) = 0; at -X+ as -N+R1R2R3, R1 = R2 mean H, R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms, a + c + e = 55, b + d + f = 0; at -X+ as -N+R1R2R3, R1 = R2 mean H, R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms, a + c + e = 80, b + d + f = 24; at -X+ as -N+R1R2R3, R1 = R2 mean H, R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms, a + c + e = 90, b + d + f = 27; at -X+ as -N+R1R2R3, R1 = R2 means H, R3 means phenyl, a + c + e = 80, b + d + f = 24; at -X+ as -N+R1R2R3, R1 = R2 mean H, R3 means phenyl, a + c + e = 90, b + d + f = 27; at -X+ as , a + c + e = 80, b + d + f = 24; at -X+ as , a + c + e = 90, b + d + f =27. Also, invention relates to a method for synthesis of these compounds. Method involves interaction of 1,2,3-tris-[hydroxypoly(alkyleneoxy)]-propane of the formula:

wherein a + c + e = 49-90, b + d + f = 0-27 with monochloroacetic acid in the presence of acidic catalyst, in boiling organic solvent medium with azeotropic removal of water formed and the following treatment of synthesized reaction product in polar solvent medium at heating with amino-compounds of the formula: NR1R2R3 wherein R1 = R2 mean H, R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms, phenyl, or morpholine of the formula:

in the following mole ratios of reagents - propane hydroxyl derivative : monochloroacetic acid : amino-compound or morpholine = 1:(3.0-3.2):(3.0-3.2), respectively. New compounds show the bactericidal and fungicide activity and properties of demulsifying agents for petroleum emulsions.

EFFECT: improved method of synthesis, valuable properties of compounds.

7 cl, 3 tbl, 8 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to novel retinoid compounds of the structural formula (I) or their pharmaceutically acceptable salts and pharmaceutical compositions possessing agonistic activity with respect to retinoid receptors and comprising indicated compounds wherein n = 1; d = 0 or 1; B means -CR7=CR8-, -CH2O- wherein R7 and R8 each means independently hydrogen atom; X means phenyl optionally substituted with halogen atom, or 5-membered heteroaryl comprising sulfur atom (S) as a heteroatom; R1 means -C(=O)-R9 wherein R9 means alkyl, hydroxyl, amino-, heteroaryloxy-group comprising oxygen atom (O) or 6-membered heterocyclyl comprising nitrogen atom (N) as a heteroatom; R2 means: (a) -(CR10R11)m-Yp-R12; m means a whole number from 1 to 10; p means 0 or 1; R10 and R11 mean hydrogen atom; Y means -O-, -S- or -NR13-; R13 means hydrogen atom; R12 means hydrogen atom, alkyl, cycloalkyl, phenyl, 5- or 6-membered heteroaryl comprising atoms N, S, O as a heteroatom, 5- or 6-membered heteroarylalkyl comprising atoms N, S, O as a heteroatom, heteroalkyl comprising atoms N, S, O as a heteroatom, 5- or 6-membered heterocyclyl comprising atoms N, S, O as a heteroatom, or 5- or 6-membered heterocyclylalkyl comprising atoms N, S, O as a heteroatom under condition that when p means 0 then R12 doesn't mean hydrogen atom or alkyl; (b) 5- or 6-membered heteroaryl comprising atoms N, S, O as a heteroatom; (c) -Z-L wherein Z means -CR14=CR15-, -C≡C-, -C(=O) or -S-; R14 and R15 mean hydrogen atom; L means 5- or 6-membered heteroaryl comprising atoms N, S, O as a heteroatom; (d) -CR14=CR15-L1 wherein L1 means -S(O)2R17 or -SO2NR18R19 wherein R17 means alkyl; R18 and R19 mean hydrogen atom; each R3 means independently hydrogen atom, hydroxyl or oxo-group; t means 1 or 2.

EFFECT: valuable medicinal properties of compounds and compositions.

59 cl, 10 tbl, 54 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for purifying racemic cis-6-phenyl-5-[4-(2-pyrrolidine-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol that involves the following stages: (a) suspending racemic cis-6-phenyl-5-[4-(2-pyrrolidine-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol in ethanol and tetrahydrofuran mixture to form suspension wherein indicated mixture of ethanol and tetrahydrofuran has the volume ratio from 4:1 to 1:1; (b) stirring and heating the indicated suspension; (c) cooling the indicated suspension from the stage (b), and (d) collection of solid purified racemic cis-6-phenyl-5-[4-(2-pyrrolidine-1-ylethocy)phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol. Method provides preparing the end product containing less 0.1% of impurities.

EFFECT: improved purifying method.

11 cl, 11 tbl, 11 ex

FIELD: organic chemistry, medicine, endocrinology, pharmacy.

SUBSTANCE: invention relates to new derivatives of acylphenylurea of the formula (I) and to their physiologically acceptable salts possessing property of glycogen phosphorylase inhibitors. In compound of the formula (I) A means phenyl and phenyl residue can be substituted three times with fluorine (F), chlorine (Cl), bromine (Br) atoms, -CF3, -NO2, -O-(C1-C6)-alkyl, -SO2-(C1-C6)-alkyl, (C1-C6)-alkyl, -COOH; R1 means hydrogen atom (H), (C1-C6)-alkyl; R2 means H, (C1-C6(-alkyl, -CO-(C1-C6)-alkyl; 3, R4, R5 and R6 mean independently of one another H, F, Cl, Br, -O(C1-C6)-alkyl, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, -COOH, -COO-(C1-C6)-alkyl; X means oxygen (O), sulfur (S) atom; R7 means (C1-C10)-alkylene-COOH, (C1-C10)-alkylene-COO-(C1-C6)-alkyl, (C1-C10)-alkylene-NH2, (C1-C10)-alkylene-NH-(C1-C6)-alkyl, (C1-C10)-alkylene-N-[(C1-C6)-alkyl]2, (C1-C10)-alkylene-B wherein B means piperidinyl or furyl. Also, invention relates to a pharmaceutical composition and a method for preparing the pharmaceutical composition. Proposed compounds can be used for preparing pharmaceutical composition useful for declining level of blood glucose and for treatment of diabetes mellitus type II.

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

7 cl, 2 sch, 2 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel nonsteroid synthetic derivatives with the following structures or their pharmaceutically acceptable salts:

, , ,

,

or

, which are capable of modulating the androgen receptor.

EFFECT: invention relates to pharmaceutical compositions containing said derivatives and use thereof to make nonsteroid medicinal agents for treating and/or preventing conditions or diseases such as prostate hyperplasia, prostate cancer, hirsutism, severe hormone-dependant alopecia or acne etc, resulting from antagonistic activity towards the androgen receptor.

6 cl, 5 dwg, 3 tbl,12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to aryl or heteroarylpiperazines with general formula II , where R2 is hydrogen or C1-4-alkyl (i) R1 is branched C4-6-alkyl, branched C4-6-alkenyl or branched C4-6-alkynyl, under the condition that R1 is not isobutyl, - C3-5-cycloalkyl, C3-7-cycloalkenyl, C3-6-cycloalkyl-C1-3-alkyl or C3-6-cycloalkenyl-C1-3-alkyl, -R1 and R2 together form a C3-6-alkylene bridge, and A is or or (ii) R1 - is ethyl, n-propyl or isopropyl, - R1 and R2 together form a C3-6-alkylene bridge, and A is or . Described also is a pharmaceutical composition based on formula II compounds, use of formula II compounds and method of treatment.

EFFECT: compounds exhibit high and selective bonding affinity to histamine H3 receptor and can be used for treating diseases and disorders, related to histamine H3 receptor.

49 cl, 149 ex

FIELD: organic chemistry, biochemistry, enzymes.

SUBSTANCE: invention relates to compounds represented by the formula: wherein values of substitutes are given in the invention description. Also, invention relates to pharmaceutically acceptable salts of the compound that can be used in treatment and/or prophylaxis of cathepsin-dependent states or diseases of mammals. Proposed compound are useful in treatment of diseases wherein bone resorption inhibition is desired, such as osteoporosis, increased mineral density of bone and reducing risk of fractures. Proposed claimed compounds are designated for preparing a drug possessing the inhibitory activity with respect to cathepsin.

EFFECT: valuable medicinal and biochemical properties of compounds.

24 cl, 13 sch, 4 tbl, 15 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel soluble pharmaceutical salts formed from salt-forming active compound of the general formula (I) or (II) and sugar substitute that can be used in preparing medicinal agents useful in pain and enuresis treatment. Salt-forming active substance represents a salt-forming compound among 1-phenyl-3-dimethylaminopropane compounds of the general formula (I) wherein X means -OH, F, Cl, H or group -OCOR6; R1 represents (C1-C4)-alkyl group; R2 represents H or (C1-C4)-alkyl group; R3 represents H or (C1-C4)-alkyl group with a direct chain, or R2 and R3 form in common (C4-C7)-cycloalkyl group and if R5 means H then R4 represents group O-Z in meta-position wherein Z means H,(C1-C3)-alkyl, -PO-(O-C1-C4-alkyl)2, -CO-(O-C1-C5-alkyl), -CONH-C6H4-(C1-C3-alkyl), -CO-C6H4-R7 wherein R7 represents -OCO-C1-C3-alkyl in ortho-position or group -CH2N(R8)2 in meta- or para-position and wherein R8 means (C1-C4)-alkyl or 4-morpholino-group, either R4 represents S-(C1-C3)-alkyl in meta-position, meta-Cl, meta-F, group -CR9R10R11 in meta-position wherein R9, R10 and R11 mean H or F, group -OH in ortho-position, O-(C2-C3)-alkyl in ortho-position, para-F or group -CR9R10R11 in para-position wherein R9, R10 and R11 mean H or F, or if R5 means Cl, F, group -OH or O-C1-C3-alkyl in para-position then R4 means Cl, F, group -OH or O-(C1-C3)-alkyl in meta-position, or R4 and R5 form in common group 3,4-OCH=CH- or OCH=CHO-; R6 means (C1-C3)-alkyl, or salt-forming active substance represents a salt-forming compound among 6-dimethylaminomethyl-1-phenylcyclohexane compounds of the general formula (II) wherein R1' represents H, -OH, Cl or F; R2' and R3' have similar or different values and represent H, (C1-C4)-alkyl, benzyl, -CF3, -OH, -OCH2-C6H5, O-(C1-C4)-alkyl, Cl or F under condition that at least one among radicals R2' either R3' means H; R4' represents H, -CH3, -PO-(O-C1-C4-alkyl)2, -CO-(O-C1-C5-alkyl, -CO-NH-C6H4-(C1-C3)-alkyl, -CO-C6H4-R5', CO-(C1-C5)-alkyl), -CO-CHR6'-NHR7' or unsubstituted either substituted pyridyl, thienyl, thiazolyl or phenyl group; R5' represents -OC(O)-(C1-C3)-alkyl in ortho-position or -CH2N(R8')2 in meta- or para-position and wherein R8' means (C1-C4)-alkyl, or both radicals R8' in common with nitrogen atom (N) form 4-morpholino-group, and R6' and R7' have similar or different values and represent H or (C1-C6)-alkyl under condition that if both radicals R2' and R3' represent H then R4' doesn't mean -CH3 when R1' represents additionally H, -OH or Cl, either R4' doesn't mean H when R1' represents additionally -OH. Also, invention relates to a medicinal agent based on indicated salts.

EFFECT: valuable medicinal properties of salts and drug.

14 cl, 1 tbl, 8 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of formula I , wherein G is carbon or nitrogen atom; A is i) phenyl substituted with any from -COOH, -CONH2, COOCH3, -CN, -NH2 or -COCH3; ii) naphthyl, benzophuranyl, and quinolinyl; and iii) formulae , , .

Compounds of present invention are useful in particular in pain treatment.

EFFECT: new agents for pain treatment.

58 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of adamantane of the general formula:

wherein m = 1 or 2; each R1 represents independently hydrogen atom; A represents C(O)NH or NHC(O); Ar represents the group:

or

wherein X represents a bond, oxygen atom or group CO, (CH2)1-6, CH=, O(CH2)1-6, O(CH2)2-6O, O(CH2)2-3O(CH2)1-3, CR'(OH), NR5, (CH2)1-6NR5, CONR5, S(O)n, S(O)nCH2, CH2S(O)n wherein n = 0, 1 or 2; R' represents hydrogen atom; one of R2 and R3 represents halogen atom, nitro-group, (C1-C6)-alkyl; and another is taken among R2 and R3 and represents hydrogen or halogen atom; either R4 represents 3-9-membered saturated or unsaturated aliphatic heterocyclic ring system comprising one or two nitrogen atoms and oxygen atom optionally being heterocyclic ring system is substituted optionally with one or more substitutes taken independently among hydroxyl atoms, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, -NR6R7, -(CH2)rNR6R7; or R4 represents 3-8-membered saturated carbocyclic ring system substituted with one or more substitutes taken independently among -NR6R7, -(CH2)NR6R7 wherein r = 1; R5 represents hydrogen atom; R6 and R7 each represents independently hydrogen atom or (C1-C6)-alkyl, or (C2-C6)-hydroxyalkyl group eliciting antagonistic effect with respect to R2X7-receptors. Also, invention describes a method for their preparing, pharmaceutical composition comprising thereof, a method for preparing the pharmaceutical composition and their applying in therapy for treatment of rheumatic arthritis and obstructive diseases of respiratory ways.

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

13 cl, 88 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to N-(indolcarbonyl)piperazine derivatives of general formula I

, wherein R1 is optionally substituted phenyl or naphthyl; R2 and R3 are independently Hal or Het1, A, OA, CN; R4 is H, CN, acyl, Hal, CONH2, CONHA or CONA; R1 is H; or R4 and R5 together form C3-C5-group; Het1 is aromatic heterocyclic ring, optionally substituted with one or two halogen atoms and containing 1-3 similar or different heteroatoms such as nitrogen, sulfur and oxygen, A-(C1-C6)-alkyl; Hal is F, Cl,Br, and J; and indole ring may be substituted with isatin, except for (1H-indole-5-yl)-(4-phenethylpiperazine-1-yl)-methanone and 1-((5-methoxy-1H-indole-7-yl)-carbonyl)-4-(2-phenethyl)-piperazine. Claimed compounds are potent 5-HT2A antagonists and are useful in treatment of psychosis, schizophrenia, depression, neurological diseases, dismepodia, Parlinson's disease, Alzheimer's disease, Hungtington's disease, amyotrophic lateral sclerosis, bulimia or anorexia, premenstrual syndrome, and/or in alleviation of hypomania.

EFFECT: new pharmaceutical agents.

9 cl, 10 ex, 1 tbl

FIELD: organic synthesis.

SUBSTANCE: invention provides substituted methyl-N-amidooxamoyl-N-phenyl-D,L-alaninates having general formula I:

where R1 and R2 represent C1-C4-alkyl, R3 and R4 either represent H, C1-C6-alkyl or form together group -(CH3)2-X-(CH2)2- wherein X is O or CH2. Compounds exhibit fungicide activity and can be used to prevent and treat plant diseases.

EFFECT: increased choice of fungicides.

5 cl, 1 tbl, 11 ex

The invention relates to derivatives of piperazine or piperidine derivatives of General formula I, in which G represents a carbon atom or nitrogen; And selected from (i) phenyl substituted by a group-COOH, CONH2-SOON3, -CN, NH2or-PINES3; (ii) naphthyl, benzofuranyl and hineline; or a group of the formula (iii), R1selected from hydrogen; branched or straight C1-C6of alkyl, C1-C6alkenyl - (C1-C6alkyl); each of R9, R10, R13, R14, R17and R18independently has the meanings indicated above for R1; Represents a substituted or unsubstituted aromatic, optionally substituted C5-C10hydroaromatics balance

The invention relates to new derivatives of piperidine-ketocarboxylic acids of the formula (I), where R1- COR4or SO2R4, R4means of alkenyl, substituted phenyl or pyridine, naphthyl, honokalani, chinoline, benzothiophene, dihydroxyphenyl or pyridyl, substituted with allmineral, R2- C1-C6-alkyl which can be substituted by phenyl or pyridium, R3group-OR6or other6where R6means hydrogen, C1-C6-alkyl, which may be a phenyl, pyridine or morpholinium, their tautomeric and isomeric forms, and salts

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely neurology and can be used for treating infantile cerebral paralysis (ICP). The method is implemented as follows: when detecting a mixed infection, there is determining its sensitivity to antibacterial preparations. It is followed with myeloexfusion of bone marrow to recover mononuclear leukocytes; the recovered fraction of mononuclear leukocytes is irradiated with a helium-neon laser light of the power 2.0 mWt during 15 minutes. Further, an etiotropic antibacterial preparation is adsorbed on these mononuclear leukocytes in a daily dosage considering the patient's age and body weight and introduced intravenously. Therapeutic procedure is daily within 5-7 days; additionally hepatoprotectors, immunomodulators and dysbacteriosis preventive agents are administered.

EFFECT: application of the invention allows improving clinical effectiveness in relation to ICP due to the reparation of tissues exposed to infection by the directed antibiotics delivery through hematoencephalic barrier into the centre of neuroinfection.

1 ex

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