Thia(dia)zoles as quick-dissociating antagonists of dopamine 2 receptor

FIELD: biotechnologies.

SUBSTANCE: invention relates to derivatives of [1-(benzyl)piperydine-4-yl]-([1,3,4]thiadiazole- 2-yl)amine and [1-(benzyl)piperydine-4-yl]-(thiazole-2-yl)amine of the formula (I) or their pharmaceutically acceptable salts, or their pharmaceutically acceptable salts, where R means hydrogen; R1 means phenyl, substituted with 1, 2 or 3 substitutes, each of them is independently selected from a group containing halogen, cyano, C1-4alkyl, perfluoroC1-4alkyl and perfluoroC1-4alkoxy; R2 means hydrogen or C1-4alkyl; R3 means hydrogen, trifluoromethyl or cyano; X means N or CR4, where R4 is trifluoromethyl. Also the invention relates to a pharmaceutical composition containing compounds of the formula as an active ingredient. The following derivatives are presented: derivatives of [1-(benzyl)piperydine-4-yl]-([1,3,4]thiadiazole-2-yl)amine and [1-(benzyl)piperydine-4-yl]-(thiazole-2-yl)amine of the formula (I) representing quick-dissociating antagonists of dopamine 2 receptors and used as medicinal agents for treatment or prevention of central nervous system.

EFFECT: improved properties of compounds.

7 cl, 22 ex

 

The technical field to which the invention relates.

The invention relates to derivatives [1-(benzyl)piperidine-4-yl]-([1,3,4]thiadiazole-2-yl)amine and [1-(benzyl)piperidine-4-yl]-(thiazol-2-yl)amine of the formula (I), which represent a rapidly dissociating antagonists of dopamine receptors 2, to methods of producing such compounds and to pharmaceutical compositions containing such compounds as active ingredient. These compounds can be used as medicines for the treatment or prevention of diseases of the Central nervous system such as schizophrenia, as they have an antipsychotic effect without motor side effects.

Description of the invention

Schizophrenia is a severe chronic mental illness that affects approximately 1% of the population. Clinical symptoms appear at a relatively early age, usually teenagers or young adults. The symptoms of schizophrenia are commonly subdivided into so-called positive, which include hallucinations, delusions and disorganized thinking, and the so-called negative, which include social isolation, impoverishment of emotions, lack of speech and the inability to experience pleasure. In addition, patients with schizophrenia suffer from a cognitive impairment, such as a disorder of attention to the project and memory. The etiology of this disease is still unknown, but there is an assumption that the symptoms of schizophrenia may be associated with disruption of the functioning of neurotransmitters. Dopaminergic hypothesis, which is one of the most common, is that positive symptoms observed in schizophrenic patients, due to increased activity of dopamine transmission. This hypothesis is based on the fact that drugs that enhance the action of dopamine, such as amphetamine or cocaine, can induce psychosis, as well as on the correlation of clinical doses of antipsychotics with their ability to block dopamine receptors D2. therapeutic effect of all those present on the market for antipsychotic drugs against the positive symptoms of schizophrenia mediated by blocking dopamine D2 receptor. In addition to the clinical effect of the main side effects of antipsychotics, for example, extrapyramidal symptoms (EPS) and late dyskinesia, also associated with antagonism against dopamine. Such debilitating patients side effects are most often seen when using typical antipsychotics, or antipsychotics first generation (e.g., haloperidol). They are expressed to a lesser extent when using atypical antipsycho the practical means, or antipsychotics second generation (e.g., risperidone, olanzapine), and even virtually absent during treatment with clozapine, which is considered the prototype atypical antipsychotic drugs. Among the different theories proposed to explain the low incidence of EPS in the treatment of atypical antipsychotic means, in the last fifteen years much attention is paid multireceptor hypothesis. It is based on the results of studies on receptor binding, demonstrating that many atypical antipsychotics in addition to dopamine receptors D2 interact with other receptors of neurotransmitters, especially serotonin receptors 5-HT2, whereas the typical antipsychotics, such as haloperidol, more selectively bind to receptors D2. In recent years, this theory is questioned, since all major atypical antipsychotics in clinically acceptable doses completely occupy the receptors serotonin 5-HT2, but still differ from each other in induction motor side effects. Alternatively multireceptor hypothesis Kapur and Seeman ("Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics?: A new hypothesis, Am. J. Psychiatry 2001, 158:3 p.360-369) suggest that atypical antipsychotic with whom estva can be distinguished from typical antipsychotic drugs for speed, they are detached from the dopamine receptors D2. Rapid dissociation of complexes with D2 receptor makes antipsychotics more suited for physiological dopamine transmission, that is, allows for antipsychotic effect without motor side effects. This hypothesis seems particularly compelling in the case of clozapine and quetiapine. These drugs are characterized by the highest rate of dissociation of complexes with dopamine receptors D2 and the low risk of inducing EPS in humans. Conversely, typical antipsychotics, characterized by high frequency of EPS, are the most slowly dissociating antagonists of the dopamine D2 receptor. Therefore, identification of new drugs on the basis of the rate of dissociation of their complex with the receptor D2 is an effective strategy for creating new atypical antipsychotic drugs. An additional challenge is the combination of the ability to rapid dissociation selectivity in receptor D2. It is believed that mnohorozmerny profile modern atypical antipsychotic drugs cause other side effects such as weight gain and the development of diabetes. This approach, as the search for selective D2 antagonists, some time ignored what I however, the inventors believe that the use in the clinic more selective compounds can reduce the incidence of metabolic disorders associated with currently used atypical antipsychotic drugs.

The aim of the present invention is the provision of new connections, which represents a rapidly dissociating antagonists of dopamine receptor D2, which are characterized by favorable pharmacological profile, as described above, in particular, reduction of motor side effects and moderate or negligible interactions with other receptors, which leads to a low risk of developing metabolic disorders.

This goal is achieved by the new compounds of the present invention, which correspond to the formula (I):

their pharmaceutically acceptable salt, hydrate and solvate, as well as stereoisomeric forms, where

R denotes hydrogen or C1-6alkyl;

R1denotes phenyl; phenyl substituted with 1, 2 or 3 substituents, each of which is independently selected from the group comprising halogen, cyano, C1-4alkyl, C1-4alkoxy, perfors1-4alkyl and perfers1-4alkoxy; thienyl; thienyl, substituted by 1 or 2 substituents selected from the group comprising galore and

With1-4alkyl; C1-4alkyl or C1-4alkyl substituted by hydroxyl,

With3-8cycloalkyl or C5-7cycloalkenyl;

R2denotes hydrogen or C1-6alkyl;

R3denotes hydrogen, trifluoromethyl or cyano; and

X represents N or CR4where R4denotes hydrogen, trifluoromethyl or cyano.

Compounds of the present invention represent a rapidly dissociating receptor antagonists D2. This property makes the compounds of the present invention is particularly suitable for use as a drug for treatment or prevention of schizophrenia, schizophrenia-like psychosis disorder, schizoaffective disorder, crazy disorder, brief psychotic disorder-induced psychotic disorder, psychotic disorder due to General health, psychotic disorder induced substance, undifferentiated psychotic disorder, psychosis associated with dementia, major depressive disorder, estimatesare disorder, premenstrual dysphoric disorder, undifferentiated depressive disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, undifferentiated bipolares the disorder, mood disorders due to General health, mood disorders induced by substances, undifferentiated mood disorders, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, acute stress disorder, posttraumatic stress disorder, mental retardation, General mental development, attention deficit disorder, attention deficit disorder and hyperactivity syndrome of aggressive behavior, paranoid personality disorder, schizoid personality disorders, systemically personality disorders, teak disorders, Tourette's syndrome, substance abuse, substance abuse, withdrawal of substances, trichotillomania.

An experienced specialist can choose the connection on the basis of experimental data, shown below in the experimental part. All selected compounds included in the scope of the present invention.

The first group includes the compounds of formula (I) and stereoisomeric forms in which

R denotes hydrogen;

R1denotes phenyl; phenyl substituted with 1, 2 or 3 substituents, each of which is independently selected from the group comprising hydrogen, halogen, cyano, C1-4alkyl, C1-4alkyloxy, perfors1-4alkyl and trip is ormaetxe; thienyl; thienyl, substituted by 1 or 2 substituents selected from the group comprising halogen and C1-4alkyl, C1-4alkyl, C1-4alkyl substituted by hydroxyl,

C3-8cycloalkyl or C5-7cycloalkenyl;

R2denotes hydrogen or methyl;

X denotes nitrogen and

R3represents trifluoromethyl.

The second group includes the compounds of formula (I) and stereoisomeric forms in which

R denotes hydrogen;

R1denotes phenyl; phenyl substituted with 1, 2 or 3 substituents, each of which is independently selected from the group comprising hydrogen, halogen, cyano, C1-4alkyl, C1-4alkyloxy, perfors1-4alkyl, triptoreline; thienyl; thienyl, substituted by 1 or 2 substituents selected from the group comprising halogen and C1-4alkyl, C1-4alkyl or C1-4alkyl substituted by hydroxyl,

C3-8cycloalkyl or C5-7cycloalkenyl;

R2denotes hydrogen or methyl;

X denotes nitrogen and

R3denotes cyano.

The third group includes the compounds of formula (I) and stereoisomeric forms in which

R denotes hydrogen;

R1denotes phenyl; phenyl substituted with 1, 2 or 3 substituents, each of which is independently selected from the group comprising hydrogen, halogen, cyano, C1-4alkyl, C1-4alkyloxy, PERFLUORO 1-4alkyl, triptoreline; thienyl; thienyl, substituted by 1 or 2 substituents selected from the group comprising halogen and C1-4alkyl, C1-4alkyl or C1-4alkyl substituted by hydroxyl,

C3-8cycloalkyl or C5-7cycloalkenyl;

R2denotes hydrogen or methyl;

R3denotes hydrogen; and

X represents CR4where R4represents trifluoromethyl.

Among the compounds of formula (I) and stereoisomeric forms of greatest interest, for example:

[1-(4-Terbisil)piperidine-4-yl]-methyl-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine (E1),

[1-(3-Terbisil)piperidine-4-yl]-methyl-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine (E2),

[1-(4-Terbisil)piperidine-4-yl]-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine (E4),

[1-(3,4-Diferensial)piperidine-4-yl]-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine (E5),

[1-(3-Fluoro-4-methylbenzyl)piperidine-4-yl]-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine (E9),

[1-(3-Fluoro-4-trifloromethyl)piperidine-4-yl]-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine (E10),

[1-(3-Cryptomaterial)piperidine-4-yl]-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine (E13),

5-[1-(3-Trifloromethyl)piperidine-4-ylamino]-[1,3,4]thiadiazole-2-carbonitrile (E17),

5-[1-(3-Fluoro-5-trifloromethyl)piperidine-4-ylamino]-[1,3,4]thiadiazole-2-carbonitrile (E18),

5-[1-(3,4-Diferensial)piperidine-4-ylamino]-[1,3,4]thiadiazole-2-carbonita the Il (E19),

5-[1-(3,4,5-Triptorelin)piperidine-4-ylamino]-[1,3,4]thiadiazole-2-carbonitrile (E21),

[1-(3,4-Diferensial)piperidine-4-yl]-(4-cryptomaterial-2-yl)amine (E22)

(1-Benzylpiperidine-4-yl)-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine (D3) and

(1-Benzylpiperidine-4-yl)-(4-cryptomaterial-2-yl)amine (D8).

In this application, the term "C1-4alkyl", used alone or in combinations, such as "C1-4alkyloxy", "pervers1-4alkyl", "dis1-4alkylamino"includes, for example, methyl, ethyl, propyl, butyl, 1-methylpropyl, 1,1-dimethylethyl, the term "pervers1-4alkyl" includes, for example, trifluoromethyl, pentafluoroethyl, heptafluoropropyl and nonattributed; "C3-8cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; "C5-7cycloalkenyl includes cyclopentenyl, cyclohexenyl and cycloheptenyl. The term halogen includes fluorine, chlorine, bromine and iodine.

Pharmaceutically acceptable salt, by definition, include therapeutically active non-toxic acid additive salt form, which can form compounds of formula (I). These salts can be obtained by processing the basic forms of the compounds of formula (I) with appropriate acids such as inorganic acids, such as halogen acid, in particular hydrochloric acid, Hydrobromic acid,sulfuric acid, nitric acid and phosphoric acid and organic acids such as acetic acid, hydroxyestra acid, propionic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, mandelic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonate acid, econsultancy acid, benzolsulfonat acid, p-toluensulfonate acid, reklamowa acid, salicylic acid, p-aminosalicylic acid, pamula acid and mandelic acid. Conversely, these salt forms can be converted into the free form by treatment with a suitable base.

The term solvate refers to the hydrates and the alcoholate, which can form compounds of formula (I).

The term "stereochemical isomers" in this description refers to all possible isomeric forms of the compounds of formula (I). Unless expressly stated or not stated otherwise, the chemical name of the compounds comprises a mixture of all possible stereochemical isomers, and such mixtures include all diastereomers and enantiomers of basic molecular structure. In particular, stereogenic centers may have the R - or S-configuration; substituents of the divalent cyclic (partially) saturated radicals may the future of CIS - or TRANS-configuration. Compounds containing double bonds, can have the E - or Z-configuration on the specified double bonds. All stereochemical isomers of compounds of formula (I) are included in the scope of this invention.

The compounds of formula (I), obtained using the methods described below, can be synthesized as racemic mixtures of enantiomers which can be separated using known in the field of separation techniques. Racemic compounds of the formula (I) can be converted into the corresponding diastereomeric salt form by reacting with a suitable chiral acid. These diastereomeric salt form is divided, for example, by selective or fractionated crystallization, after which the enantiomers release by treatment with alkali. An alternative method of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. These pure stereochemical isomers can also be obtained from the corresponding pure stereochemical isomers of suitable starting compounds, provided that the reaction proceeds in a stereospecific. Preferably a specific stereoisomer is possible to synthesize by using stereospecific methods. These methods mainly use enantiomerically pure starting materials.

Headlight is Ecologia

To find antipsychotic compounds that are active against the positive symptoms of schizophrenia and which has an improved safety profile (low incidence of EPS and absence of metabolic disorders), the authors of this invention are subjected to screening compounds capable of selectively interacting with the receptor dopamine D2 and quickly detach from this receptor. First, compounds are screened for affinity to D2 using analysis of binding using [3N]spiperone and cell membranes containing human D2L receptor. To determine the dissociation rate, connection with IC50less than 1 micron, are tested using the adapted indirect analysis, developed on the basis of the method described Josee E. Leysen and Walter Gommeren, Journal of Receptor Research, 1984, 4(7), 817-845.

Then the connection is subjected to screening against more than 50 other G-protein-associated receptors (CEREP), getting a smooth profile with low affinity of the tested receptors.

Some connections are additionally tested for the models in vivo, e.g., "antagonism towards induced by apomorphine stimulation in rats, demonstrating the activity and bioavailability when administered orally.

The above pharmacological properties indicate that the compounds of formula (I) is zgodny for use as medicines in particular, antipsychotic. More specifically, these compounds can be used as medicines for the treatment or prevention of schizophrenia, schizophrenia-like psychosis disorder, schizoaffective disorder, crazy disorder, brief psychotic disorder-induced psychotic disorder, psychotic disorder due to General health, psychotic disorder induced substance, undifferentiated psychotic disorder, psychosis associated with dementia, major depressive disorder, estimatesare disorder, premenstrual dysphoric disorder, undifferentiated depressive disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, undifferentiated bipolar disorder, mood disorders due to General health, mood disorders induced by substance, undifferentiated mood disorders, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, acute stress disorder, posttraumatic stress disorder, mental retardation, General mental development, syndrome de is icita attention syndrome of attention deficit and hyperactivity syndrome of aggressive behavior, paranoid personality disorder, schizoid personality disorders, systemically personality disorders, teak disorders, Tourette's syndrome, substance abuse, substance abuse, withdrawal of substances, trichotillomania.

To optimize the treatment of patients suffering from referred to in the preceding paragraph disorders, the compounds of formula (I) can be entered together with other psychotropic compounds. So, in the case of schizophrenia treatment can be focused on the negative and cognitive symptoms.

The present invention also provides a method of treating warm-blooded animals suffering from such disorders, and the method includes systemic injection of a therapeutic amount of the compounds of formula (I), effective for the treatment of the above disorders.

The present invention also relates to the use of the above defined compounds of formula (I) for the medicinal product, in particular, antipsychotic drugs, more specifically, drugs for treatment or prevention of schizophrenia, schizophrenia-like psychosis disorder, schizoaffective disorder, crazy disorder, brief psychotic disorder induced psycho is practical disorder, psychotic disorder due to General health, psychotic disorder induced substance, undifferentiated psychotic disorder, psychosis associated with dementia, major depressive disorder, estimatesare disorder, premenstrual dysphoric disorder, undifferentiated depressive disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, undifferentiated bipolar disorder, mood disorders due to General health, mood disorders induced by substances, undifferentiated mood disorders, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, acute stress disorder, posttraumatic stress disorder, mental retardation, General mental development deficit disorder attention, attention deficit disorder and hyperactivity syndrome of aggressive behavior, paranoid personality disorder, schizoid personality disorders, systemically personality disorders, teak disorders, Tourette's syndrome, substance abuse, substance abuse, withdrawal of substances, trichotillomania.

The special is iality, with experience in the treatment of these disorders can define a daily therapeutically effective amount of such drug, based on the results of the following studies. Daily therapeutically effective amount is from about 0.01 to 10 mg/kg body weight, more preferably, from about 0.05 to 1 mg/kg body weight.

The invention also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of the compounds of formula (I).

For simplicity, the introduction of compounds that are the subject of the invention may be obtained in the form of pharmaceutical forms for different routes of administration. Compounds of the present invention, in particular, the compounds of formula (I), their pharmaceutically acceptable acidic or basic additive salt, stereochemical isomers, N-oxides, prodrugs or any sub-groups or combinations can be obtained in the form of pharmaceutical forms for different routes of administration. Suitable compositions may be mentioned composition, traditionally used for systemic administration of drugs. The pharmaceutical compositions of this invention are produced by homogeneous mixing an effective amount of concrete from the organisations, not necessarily in the form of a salt additive, used as an active ingredient, with a pharmaceutically acceptable carrier, and this carrier can vary widely depending on the form of preparation required for a way of introduction. Preferably, these pharmaceutical compositions are in unit dosage forms suitable in particular for oral, rectal, percutaneous, parenteral or inhalation administration. For example, upon receipt of the compositions in oral dosage forms can be used any conventional pharmaceutical environment, such as, for example, water, glycols, oils, alcohols and the like, in the case of liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions, or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, dezintegriruetsja tools and the like in the case of powders, pills, capsules and tablets. Due to the simplicity of the introduction of tablets and capsules represent the most preferred unit dosage forms for oral administration, for which, of course, are for solid pharmaceutical carriers. Carrier for parenteral compositions usually contain sterile water, component, at least a large part of it, although the may contain other ingredients, for example, increase the solubility. To obtain solutions for injection can be used, for example, media that contains saline solution, glucose solution or a mixture of saline and glucose solution. To obtain solutions for injection can be used, for example, media that contains saline solution, glucose solution or a mixture of saline and glucose solution. To provide a prolonged action, injectable solutions containing the compounds of formula (I)can be prepared in oil. Suitable oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic esters of glycerol and long chain fatty acids, and mixtures of these and other oils. To get a suspension for injection, use the appropriate liquid carriers, suspendresume tools, etc. In the scope of the invention also include solid preparations intended for conversion into liquid preparations immediately before use. To obtain the compositions suitable for percutaneous introduction, you can use the media that contains optional tool that enhances the permeability and/or a suitable moisturizer, optionally combined with suitable additives l the battle of nature, used in minor amounts which do not have a significant harmful impact on the skin. These supplements can facilitate the introduction of drugs through the skin and/or produce the desired compositions. Such compositions can be entered in different ways, for example, via a transdermal patch, a point of application or ointments. To obtain water compositions, it is preferable to use an acidic or basic additive salts of compounds of formula (I), because they are better soluble in water than the corresponding acidic or basic forms.

Especially, it is preferable to obtain the above pharmaceutical composition in unit dosage form, providing ease of administration and uniformity of dosage. The term unit dosage form in this description refers to physically discrete units suitable for the introduction of single doses, each unit contains a predetermined quantity of active ingredient calculated to obtain the desired therapeutic effect, in combination with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including corrugated or coated tablets), capsules, pills, sachet powders, pills, suppositories, solutions or suspensions for injection is similar, as well as their separate combinations.

Since the compounds of the present invention have activity when administered orally, especially preferred pharmaceutical compositions containing these compounds, which are intended for oral administration.

In order to improve the solubility and/or stability of the compounds of formula (I), pharmaceutical compositions preferably α-, β - or γ-cyclodextrins or their derivatives, especially hydroxyalkyl-substituted cyclodextrins, such as 2-hydroxypropyl-beta-cyclodextrin. In addition, the solubility and/or stability of the compounds of the present invention can be improved by adding in the pharmaceutical compositions of auxiliary solvents, such as alcohols.

Ways to get

The compounds of formula (I), where R, R1, R2and R3have the above meanings and X denotes nitrogen, can be obtained by reacting the compounds of formula (II)

where R2and R3have the above meanings and X denotes nitrogen, with a reagent of formula R1-CHY-R (III-a), where R and R1have the above meanings and Y represents a leaving group such as halogen, for example chlorine, bromine or iodine, or sulfanilamilny group, for example, methylsulfonylamino, tripterocalyx or methylphenylsulfonyl, in the presence of a base, such as diisopropylethylamine, or immobilized on the polymer 1,5,7-diazabicyclo[4.4.0]Dec-5-ene in a suitable solvent, such as acetonitrile, and in suitable reaction conditions, such as suitable temperature, which is provided either by conventional heating or by microwave irradiation, for a period of time to achieve completion of the reaction.

Alternative compounds of formula (I), where R, R1, R2and R3have the above meanings and X denotes nitrogen, can be obtained by reacting the compounds of formula (II), where R2and R3have the above meanings and X denotes nitrogen, with a reagent of formula R1-C(=O)-R (III-b), where R and R1have the above values, the method of reductive N-alkylation in the presence of a suitable reducing reagent, such as triacetoxyborohydride sodium or immobilized on the polymer triacetoxyborohydride, a suitable acid catalyst such as acetic acid, in a suitable reaction inert solvent such as dichloromethane, 1,2-dichloroethane or N,N-dimethylformamide.

The compounds of formula (II), where R2and R3have the above meanings and X denotes nitrogen, can be obtained after removal of the protective group of intermediate compounds of formula (IV)

where L represents a suitable leaving group, such as benzyloxycarbonyl, benzyl or tert-butoxycarbonyl, R2and R3have the above meanings and X denotes nitrogen, in suitable conditions, such as the presence of hydrochloric acid, if L denotes benzyloxycarbonyloxy group, the presence triperoxonane acid in dichloromethane, if L denotes tert-butoxycarbonyl group, or by reacting with 1-chloritisation, in the presence of a suitable base, such as diisopropylethylamine, in dichloromethane, if L denotes a benzyl group.

The compounds of formula (IV), where R2and R3have the above values, X represents nitrogen, and L represents a suitable leaving group, can be obtained by reacting the compounds of formula (V),

where R2has the values indicated above and L represents a suitable leaving group, such as benzyloxycarbonyl, benzyl or tert-butoxycarbonyl, 5-chloro-[1,3,4]thiadiazole of the formula (VI)

where R3has the above meanings and X denotes nitrogen, in the presence of a base, such as diisopropylethylamine, in a suitable solvent, such as acetonitrile, and in suitable reaction conditions, such as a suitable pace is of atur, which is provided either by conventional heating or by microwave irradiation, for a period of time to achieve completion of the reaction.

5-Chloro-[1,3,4]thiadiazole of the formula (VI), where R3denotes trifluoromethyl, and X denotes nitrogen, can be obtained using methods such as those described in DE 82/3218482.

5-Chloro-[1,3,4]thiadiazole of the formula (VI), where R is cyano and X denotes nitrogen, can be obtained using methods similar to those described in US 5736545.

The compounds of formula (I), where R, R1, R2and R3have the above meanings and X denotes nitrogen, can also be obtained by reacting 5-chloro-[1,3,4]thiadiazole of the formula (VI), where R3represents trifluoromethyl or cyano, and X denotes nitrogen, with a piperidine derivative of formula (VII)

where R, R1and R2have the above meanings, in the presence of a suitable base, such as diisopropylethylamine, in a suitable solvent, such as acetonitrile, and in suitable reaction conditions, such as suitable temperature, which is provided either by conventional heating or by microwave irradiation, for a period of time to achieve completion of the reaction.

The compounds of formula (VII), where R and R1have the above significance, and R2=H, can be obtained by interaction of the of conduct tert-butyl ether piperidine-4-ylcarbamate acid (VIII)

with a reagent of formula R1-CHY-R (III-a), where R and R1have the above meanings and Y represents a leaving group such as halogen, for example chlorine, bromine or iodine, or sulfanilamilny group, for example, methylsulfonylamino, tripterocalyx, or methylphenylsulfonyl, in the presence of a base, such as diisopropylethylamine, in a suitable solvent, such as dichloromethane, followed by removal of the protective tert-butyloxycarbonyl group with intermediate compounds of formula (IX) by treatment with acid, such as triperoxonane acid, to obtain the compounds of formula (VII), where R2=H.

Alternatively, the compounds of formula (VII), where R and R1have the above values, can be obtained by reacting tert-butyl ether piperidine-4-ylcarbamate acid with a reagent of formula R1-C(=O)-R (III-b), where R and R1have the above values, the method of reductive N-alkylation in the presence of a suitable reducing reagent, such as triacetoxyborohydride sodium, a suitable acid catalyst such as acetic acid, in a suitable reaction inert solvent such as 1,2-dichloroethane, followed by removal of the protective tert-butyloxycarbonyl group with intermediate compounds of formula (IX) by which the processing acid, such as triperoxonane acid, to obtain the compounds of formula (VII), where R2=H.

The compounds of formula (VII)in which R2represents C1-4alkyl, can be obtained by reacting the compounds of formula (X)

where R and R1have the above values, with C1-4alkylamino formula R2-NH2(XI) in the presence of a suitable reducing reagent, such as hydrogen, a suitable catalyst, such as palladium on charcoal, in a suitable reaction inert solvent such as ethanol.

The compounds of formula (X), where R and R1have the above values, can be obtained by reacting 4,4-ethylenedioxythiophene (XII)

with a reagent of formula R1-C(=O)-R (III-b), where R and R1have the above meanings, in the presence of a suitable reducing reagent, such as triacetoxyborohydride sodium, a suitable acid catalyst such as acetic acid, in a suitable reaction inert solvent such as 1,2-dichloroethane, followed by removal of the protective group of intermediate compounds of formula (XIII)

where R and R1have the values indicated above, by treatment with acid, such the AK hydrochloric acid.

The compounds of formula (I), where R, R1, R2and R4have the above values, R3denotes hydrogen, X is carbon, and R4denotes trifluoromethyl, can be obtained by reacting the compounds of formula (II)

where R2and R4have the above values, R3denotes hydrogen, and X denotes carbon, with a reagent of formula R1-CHY-R (III-a), where R and R1have the above meanings and Y represents a leaving group such as halogen, for example chlorine, bromine or iodine, or sulfanilamilny group, for example, methylsulfonylamino, tripterocalyx, or methylphenylsulfonyl, in the presence of a base, such as diisopropylethylamine, in a suitable solvent, such as acetonitrile, and in suitable reaction conditions, such as suitable temperature, which is provided either by conventional heating or by microwave irradiation, for a period of time to achieve completion of the reaction.

Alternative compounds of formula (I), where R, R1, R2and R4have the above values, R3denotes hydrogen, and X denotes carbon, can be obtained by reacting the compounds of formula (II), where R2and R4have the above values, R3denotes hydrogen, and X appears the t carbon with a reagent of formula R1-C(=O)-R (III-b), where R and R1have the above values, the method of reductive N-alkylation in the presence of a suitable reducing reagent, such as triacetoxyborohydride sodium, a suitable acid catalyst such as acetic acid, in a suitable reaction inert solvent such as 1,2-dichloroethane.

The compounds of formula (II), where R2and R4have the above values, R3denotes hydrogen, and X denotes carbon, can be obtained after removal of the protective group of intermediate compounds of formula (IV)

where R2and R4have the above values, R3denotes hydrogen, X is carbon, and L represents a suitable leaving group, such as benzyl, in suitable conditions, such as interaction with 1-claritinclaritin in the presence of a suitable base, such as diisopropylethylamine, in dichloromethane.

The compounds of formula (IV), where R2and R4have the above values, R3denotes hydrogen, X is carbon, and L represents a suitable leaving group, can be obtained by reacting (piperidine-4-yl)-thiourea of the formula (XIV),

where R2has the values indicated above and L represents a suitable whodas the group, with the derived 3-bromoacetone formula Br-CH2-C(=O)-CH2-R4(XV) in a suitable solvent, such as ethanol, and in suitable reaction conditions, such as suitable temperature, which is provided either by conventional heating or by microwave irradiation, for a period of time to achieve completion of the reaction.

(Piperidine-4-yl)-thiourea of the formula (XIV)where R2has the values indicated above and L represents a suitable leaving group, can be obtained using methods similar to those described in WO 03/062215.

Alternative compounds of formula (I), where R, R1, R2and R4have the above values, R3denotes hydrogen, and X denotes carbon, produced by the interaction of the compounds of formula (XVI)

where R, R1and R2have the above values, derived from 3-bromoacetone formula Br-CH2-C(=O)-CH2-R4(XV) in a suitable solvent, such as ethanol, at a suitable temperature, which is provided either by conventional heating or by microwave irradiation, for a period of time to achieve completion of the reaction.

The compounds of formula (XVI), where R, R1and R2have the above values, can be obtained from piperidine of formula (VII) using methods similar to opeaning WO 03/062215.

Experimental part

Chemistry

Reactions using microwave irradiation is carried out in a single mode microwave reactor Emrys™ Optimizer (Personal Chemistry A.B., currently Biotage). The device description can be found on the website www.personalchemistry.com.

Spectra1H recorded on the following instruments : Bruker DPX 400 or Bruker AV-500. The values of chemical shifts are expressed in ppm relative to tetramethylsilane was.

The melting temperature is determined using an instrument Mettler FP62.

Gradient HPLC provide using the HP 1100 from Agilent Technologies, which includes a pump for four-component mixtures with degasser, autosampler, column thermostat for (set at 40°C with the exception of mode 4, which use 60°C), the detector diode array (DAD) and a column as specified below in the relevant ways. Part of the flow coming from the column is sent to the MS detector. MS detector equipped with a source of ionization elektrorazpredelenie. As the spray gas using nitrogen. The temperature of the source of support at 140°C. the Data register using the software MassLynx-Openlynx.

Method 1

In addition to the General procedure: HPLC on reversed phase carried out on a column of ACE-C18 (3.0 mm, and 4.6×30 mm), Advanced Chromatography Technologies, a flow rate of 1.5 ml/min at 40°C. the gradient Conditions: 80% a (acetate solution of shumilkin) is 0.5 g/l), 10% B (acetonitrile), 10% C (methanol) to 50% B and 50% C for 6.5 minutes, and then to 100% B for 7 minutes, after which the balance to the initial conditions for a period of 7.5-9.0 minutes. The volume of injected sample 5 ál. Mass spectrometry high resolution (time-of-flight analyzer TOF) is carried out only in the positive mode ionization scanning from 100 to 750 in 0.5 seconds and the residence time of 0.1 seconds. The voltage at the end of the capillary is 2.5 kV in the positive mode ionization, and the voltage on the cone is 20 Century as the standard for fixed calibration weight using leucine-enkephalin.

Method 2

In addition to the General procedure: HPLC on reversed phase carried out on a column of ACE-C18 (3.0 mm, and 4.6×30 mm), Advanced Chromatography Technologies, a flow rate of 1.5 ml/min at 40°C. the gradient Conditions: 80% A (solution of ammonium acetate, 0.5 g/l), 10% B (acetonitrile), 10% C (methanol) to 50% B and 50% C for 6.5 minutes, and then to 100% B for 7 minutes, then cancel before the initial conditions within 7.5 to 9.0 minutes. The volume of injected sample 5 ál. The mass spectrum of the low-resolution detector (ZQ; quadrupole analyzer) is obtained by scanning from 100 to 1000 at a period of 1.0 seconds with a time of 0.3 seconds. The voltage at the end of the capillary is 3 kV. The voltage on the cone is 20 V and 50 V in the positive mode ionization and 20 In which egime negative ionization.

Method 3

In addition to the General procedure: HPLC on reversed phase conducted on the cartridge XDB-C18 (1,8 μm, and 2.1×30 mm), Agilent, with a flow rate of 1 ml/min at 60°C. the gradient Conditions: 90% A (solution of ammonium acetate, 0.5 g/l), 5% B (acetonitrile), 5% C (methanol) to 50% B and 50% C for 6.5 minutes, and then to 100% B for 7 minutes, after which the balance to the initial conditions in a period of 7.5-9.0 minutes. The volume of injected sample 2 ál. Mass spectrometry high resolution (time-of-flight analyzer TOF) is carried out only in the positive mode ionization scanning from 100 to 750 in 0.5 seconds and the residence time of 0.1 seconds. The voltage at the end of the capillary is 2.5 kV, and the voltage on the cone is 20 Century as the standard for fixed calibration weight using leucine-enkephalin.

Method 4

Spend as method 1, using the introduction of the sample volume of 10 µl.

Description 1

4-[Methyl-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-amino]-piperidine-1-carboxylic acid benzyl ester (D1)

A mixture of 2-chloro-5-trifluoromethyl-[1,3,4]thiadiazole (0,70 g, 3.72 mmol) (obtained according to the method similar to that described in DE 82/3218482), hydrochloride benzyl ester 4-methylaminopropyl-1-carboxylic acid (1.06 g, 3.72 mmol) and diisopropylethylamine (1.60 ml of 9.30 mmol) in acetonitrile (10 ml) stirred the ri 120°C for 30 min under microwave irradiation. After cooling to room temperature the reaction mixture was diluted with dichloromethane and extracted with a 10% solution of ammonium chloride (25 ml). The organic layer is separated, dried (Na2SO4) and the solvent evaporated in vacuum. The crude product is purified by chromatography on a short open column (silica gel; 0-0,5% ammonia in methanol (7M)/dichloromethane). The target fractions are collected and evaporated in vacuum, obtainingD1(0,91 g, 62%) as a solid. C17H19F3N4O2S requires 400; found: 401 (MH+).

Description 2

Methylpiperidin-4-yl-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine (D2)

A solution of benzyl ester 4-[methyl-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amino]piperidine-1-carboxylic acid (D1) (0,91 g of 2.27 mmol) in 6N solution of hydrochloric acid (15 ml) was stirred at 150°C for 10 min under microwave irradiation. After cooling to room temperature the reaction mixture was diluted with water and extracted with dichloromethane (25 ml). The aqueous layer was alkalinized with a saturated solution of sodium carbonate and extracted with dichloromethane (3×25 ml). The combined organic extracts dried (Na2SO4) and the solvent evaporated in vacuum, obtainingD2(0.56 g, 93%) as a solid. C9H13F3N4S requires 266; detected is: 266 (MH +).

1H NMR (400 MHz, Chloroform-d) δ ppm 1,67 and 1.80 (m, 2H), 1,86 (s, 2H), 2,74 (TD, J=12,13, 2,28 Hz, 2H), is 3.08 (s, 3H), 3,16-3,26 (m, 2H), 4,01-to 4.15 (m, 1H).

Description 3

(1-Benzylpiperidine-4-yl)-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine (D3)

A mixture of 2-chloro-5-trifluoromethyl-[1,3,4]thiadiazole (0,42 g, 2,24 mmol) (obtained according to the method similar to that described in DE 82/3218482), 4-aminomethyl-1-benzylpiperidine (0.4 ml, of 1.95 mmol) and diisopropylethylamine (0.5 ml, 2,90 mmol) in acetonitrile (6 ml) was stirred at 120°C for 15 min under microwave irradiation. After cooling to room temperature the reaction mixture was diluted with dichloromethane and extracted with a 10% solution of ammonium chloride (25 ml). The organic layer is separated, dried (Na2SO4) and the solvent evaporated in vacuum. The crude product is purified by chromatography on a short open column (silica gel; 0-0,5% ammonia in methanol (7M)/dichloromethane). The target fractions are collected and evaporated in vacuum, obtainingD3(0,368 g, 48%) as a solid. C15H17F3N4S requires 342; found: 343 (MH+).

1H NMR (400 MHz, Chloroform-d) δ ppm 1,62-1,71 (m, 2H), 2.05 is amounts to 2.24 (m, 4H), 2,85 (s, 2H), 3,40-3,51 (m, 1H), 3,53 (s, 2H), of 5.83 (d, J=6,63 Hz, 1H), 7,22 and 7.36 (m, 5H).

Description 4

Piperidine-4-yl-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine (D4)

To mix the solution (1-benzylpiperidine-4-yl)-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine (D3) (0.50 g, of 1.46 mmol) and diisopropylethylamine (0,76 ml of 4.38 mmol) in dichloromethane (20 ml) at 0°C was added 1-chloroethylphosphonic (0,47 ml of 4.38 mmol). The reaction mixture was stirred at room temperature for 2 h, then the solvent evaporated in vacuum. The crude product is dissolved in methanol (30 ml) and the reaction mixture is stirred at the boil under reflux for 1.5 hours After evaporation of the solvent the crude product is dissolved in water and extracted with diethyl ether (2×25 ml) and dichloromethane (3×25 ml). The aqueous layer was separated and evaporated in vacuum. The crude product is purified by HPLC on reversed phase. The target fractions are collected and evaporated in vacuum, obtainingD4(0,29 g, 79%) as a solid. C8H11F3N4S requires 252; found: 253 (MH+).

1H NMR (400 MHz, DMSO-d6) δ ppm 1,59-of 1.73 (m, 2H), 2,04 with 2.14 (m, 2H), 2,54 (s, 1H), 2,88-of 2.97 (m, 2H), 3,17-of 3.25 (m, 2H), 3,88-of 3.96 (m, 1H), 8,91 (Shir. s, 1H).

Description 5

4-(5-Cyano-[1,3,4]thiadiazole-2-ylamino)piperidine-1-carboxylic acid tert-butyl ester (D5)

A mixture of 5-chloro-[1,3,4]thiadiazole-2-carbonitrile (0.5 g, 3,44 mmol) (obtained according to the method similar to that described in US 5736545), tert-butyl ester 4-aminopiperidin-1-carboxylic acid (0,69 g, 3,44 mmol) and diisopropylethylamine (0,72 ml of 4.13 mmol) in acetonitrile (10 ml) peremeci is up at 130°C for 30 min under microwave irradiation. The solvent is then evaporated in vacuum. The crude product is dissolved in dichloromethane and extracted with a saturated solution of ammonium chloride. The organic layer is separated, dried (Na2SO4) and the solvent evaporated in vacuum. The crude product is purified by chromatography on a short open column (silica gel; 3-5% ammonia in methanol (7M)/dichloromethane). The target fractions are collected and evaporated in vacuum, obtainingD5(0.97 g, 63%) as a white solid. C13H19N5O2S requires 309; found: 308 (MH-).

Description 6

5-(piperidine-4-ylamino)-[1,3,4]thiadiazole-2-carbonitrile (D6)

To a stirred solution of tert-butyl ester 4-(5-cyano-[1,3,4]thiadiazole-2-ylamino)piperidine-1-carboxylic acid (D5) (0,973 g of 3.12 mmol) in dichloromethane (55 ml) at 0°C add triperoxonane acid (3 ml). The reaction mixture was stirred at 0°C for 1 h and at room temperature for a further 18 hours and Then the reaction mixture was extracted with a saturated solution of sodium carbonate. The aqueous layer was extracted with ethyl acetate (2×25 ml). The organic layer is separated, dried (Na2SO4) and the solvent evaporated in vacuum, obtainingD6(0,60 g, 92%) as a solid. C8H11N3S requires 209; found: 210 (MH+).

Description 7

1-(3,4-Debtorrent the l)piperidine-4-ylamine (D7)

A mixture of tert-butyl methyl ether piperidine-4-ylcarbamate acid (5 g, 25,0 mmol), 3,4-diferenciada (4.7 g, 22.7 mmol) and diisopropylethylamine (5,9 ml, 34,0 mmol) in dichloromethane (50 ml) was stirred at room temperature for 2 hours Then add triperoxonane acid (31 ml) and the reaction mixture is stirred for further 2 hours, the Solvent is evaporated in vacuum and add a saturated solution of sodium carbonate. The mixture is extracted with dichloromethane, separated organic layers are dried (Na2SO4), filtered and the solvent evaporated in vacuum, obtainingD7(of 5.2 g, 93%) as a solid. C12H16F2N2requires 226; found: 227 (MH+).

Description 8

(1-Benzylpiperidine-4-yl)-(4-cryptomaterial-2-yl)amine (D8)

To mix the solution (1-benzylpiperidine-4-yl)-thiourea (0.5 g, 2.0 mmol) (obtained according to the method similar to that described in WO 03/062215) in ethanol (15 ml) is added 3-bromo-1,1,1-triptorelin (to 0.22 ml, 2.1 mmol) and the reaction mixture is heated at the boil under reflux for 1 h After evaporation of the solvent the crude product is crystallized from acetonitrile and getD8(0,61 g, 88%) as a white solid. C16H18F3N3S-HBr in the form of a free base requires 341 detected: 342 (MH +).

Melting point (acetonitrile): 247,9°C.

1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 to about 1.75 (m, 1,5H), 1,92 is 2.10 (m, 1H), 2,18 (d, J=12,85 Hz, 1,5H), 3,03-up 3.22 (m, 2H), 3,23-3,47 (m, 2H), 3,70-3,86 (m, 0,75H), 3,95 (Shir. C, 0,25H), the 4.29 (d, J=4,98 Hz, 1,5H), 4,34 (d, J=4,98 Hz, 0,5H), 7,35-EUR 7.57 (m, 5H), to 8.20 (d, J=7,26 Hz, 0,75H), compared to 8.26 (d, J=5,80 Hz, 0,25H), 9,43 (Shir. C, 0,75H), 9,51 (Shir. C, 0,25H).

Description 9

Piperidine-4-yl-(4-cryptomaterial-2-yl)amine (D9)

To mix the solution (1-benzylpiperidine-4-yl)-(4-cryptomaterial-2-yl)amine (D8) (0,57 g, by 1.68 mmol) and diisopropylethylamine (1,04 ml, 5,88 mmol) in dichloromethane (15 ml) at 0°C was added 1-chloroethylphosphonic (0.45 ml, 4.2 mmol). The reaction mixture was stirred at room temperature for 3 h, then diluted with dichloromethane and extracted with a saturated solution of sodium bicarbonate (5 ml). The organic layer is separated, dried (Na2SO4) and the solvent evaporated in vacuum. The crude product is dissolved in methanol (5 ml), after which the reaction mixture is stirred at the boil under reflux for 3 hours After evaporation of the solvent the crude product is purified column chromatography (silica gel; 5-8% ammonia in methanol (7M)/dichloromethane). The target fractions are collected and evaporated in vacuum. The crude product is crystallized from acetonitrile, gettingD9(0.34 g, 81%) as a white solid prophetic the STV. C9H12F3N3S requires 251; found: 252 (MH+).

Melting point (acetonitrile): 133,0°C.

1H NMR (400 MHz, Chloroform-d) δ ppm to 1.38 to 1.48 (m, 2H), 2,07 with 2.14 (m, 2H), 2,69 was 2.76 (m, 2H), 3,11 (dt, J=13,01, the 3.65 Hz, 2H), 3,42-3,51 (m, J=14,36, 6,27, 4,15, Android 4.04 Hz, 1H), 5,28 (d, J=7,26 Hz, 1H), 6,92 (s, 1H).

Example 1

[1-(4-Terbisil)piperidine-4-yl]-methyl-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine (E1)

A mixture of methylpiperidin-4-yl-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine (D2) (0,050 g 0,19 mmol), 4-formanilide (0,029 ml, 0.24 mmol) and diisopropylethylamine (0,050 ml, 0.28 mmol) in acetonitrile (3 ml) was stirred at 120°C for 30 min under microwave irradiation. After cooling to room temperature the reaction mixture was diluted with dichloromethane and extracted with a 10% solution of ammonium chloride (25 ml). The organic layer is separated, dried (Na2SO4) and the solvent evaporated in vacuum. The crude product is purified column flash chromatography (silica gel; 0-1,5% ammonia in methanol (7M)/dichloromethane) and getE1(0,061 g, 87%) as a solid. C16H18F4N4S requires 374; found: 375 (MH+).

Melting point: 85,8°C.

1H NMR (400 MHz, Chloroform-d6) δ ppm 1,75-of 1.93 (m, 4H), 2,11 (dt, J=I 1,45, 3,21 Hz, 2H), 2,98 (s, 2H), of 3.07 (s, 3H), 3,49 (s, 2H), 3,91-4,08 (m, 1H), 6,95-7,06 (m, 2H), 7,22-7,33 (m, 3H).

Example 2

[1-(3-what tormentil)piperidine-4-yl]-methyl-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine (E2)

A mixture of methylpiperidin-4-yl-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine (D2) (0,050 g 0,19 mmol), 3-ftorangidridy (being 0.030 ml, 0.24 mmol) and diisopropylethylamine (0,050 ml, 0.28 mmol) in acetonitrile (3 ml) was stirred at 100°C for 5 min under microwave irradiation. After cooling to room temperature the reaction mixture was diluted with dichloromethane and extracted with a 10% solution of ammonium chloride (25 ml). The organic layer is separated, dried (Na2SO4) and the solvent evaporated in vacuum. The crude product is purified column flash chromatography (silica gel; 0-1,5% ammonia in methanol (7M)/dichloromethane) and getE2(0,062 g, 88%) as a solid. C16H18F4N4S requires 374; found:375 (MH+).

Melting point: 80,5°C.

1H NMR (400 MHz, DMSO-d6) δ ppm at 1.73 (s, 2H), 1,86 (DCV, J=12,02, to 3.73 Hz, 2H), 2,09 (TD, J=11,71, 2,07 Hz, 2H), 2,84-2,96 (m, 2H), of 3.07 (s, 3H), 3,52 (s, 2H), 3,81-of 3.94 (m, 1H),? 7.04 baby mortality-7,11 (m, 1H), 7,11-to 7.18 (m, 2H), 7,32-7,42 (m, 1H).

Example 4

[1-(4-Terbisil)piperidine-4-yl]-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine (E4)

A mixture of piperidine-4-yl-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine (D4) (0,040 g, 0.16 mmol), 4-formanilide (0,023 ml to 0.19 mmol) and diisopropylethylamine (0,042 ml, 0.24 mmol) in acetonitrile (3 ml) was stirred at 120°C for 30 min under microwave exposed the Institute. After cooling to room temperature the reaction mixture was diluted with dichloromethane and extracted with a 10% solution of ammonium chloride (25 ml). The organic layer is separated, dried (Na2SO4) and the solvent evaporated in vacuum. The crude product is purified column flash chromatography (silica gel; 0-3% ammonia in methanol (7M)/dichloromethane) and getE4(0,042 g, 73%) as a solid. C15H16F4N4S requires 360; found:361 (MH+).

1H NMR (400 MHz, Chloroform-d) δ ppm 1.61 of-of 1.74 (m, 2H), 2.05 is with 2.14 (m, 2H), 2,19 (s, 2H), 2,80-2,89 (m, 2H), 3,38-of 3.48 (m, 1H), 3,50 (s, 2H), 6,39 (Shir. s, 1H), 6,97-7,05 (m, 2H), 7.24 to 7,31 (m, 2H).

Example 5

[1-(3,4-Diferensial)piperidine-4-yl]-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine (E5)

A mixture of piperidine-4-yl-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine (D4) (0,040 g, 0.16 mmol), 3,4-diferenciada (0,024 ml to 0.19 mmol) and diisopropylethylamine (0,042 ml, 0.24 mmol) in acetonitrile (3 ml) was stirred at 100°C for 5 min under microwave irradiation. After cooling to room temperature the reaction mixture was diluted with dichloromethane and extracted with a 10% solution of ammonium chloride (25 ml). The organic layer is separated, dried (Na2SO4) and the solvent evaporated in vacuum. The crude product is purified column flash chromatography (silica gel; 0-3% ammonia in methanol (7M)/dichloro the Academy of Sciences) and get E5(0,048 g, 80%) as a solid. C15H15F5N4S requires 378; found: 379 (MH+).

1H NMR (400 MHz, Chloroform-d) δ ppm 1.61 of to 1.76 (m, 2H), 2.06 to and 2.14 (m, 2H), 2,19 (t, J=11,09 Hz, 2H), 2,78-2,87 (m, 2H), 3,37-of 3.46 (m, 1H), 3,47 (s, 2H), 6,66 (d, J=5,18 Hz, 1H), 6,98? 7.04 baby mortality (m, 1H), 7,05-7,13 (m, 1H), 7,17 (DDD, J=11,20, 7,88, 2,07 Hz, 1H).

Example 9

[1-(3-Fluoro-4-methylbenzyl)piperidine-4-yl]-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine (E9)

A mixture of piperidine-4-yl-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine (D4) (0.025 g, 0.1 mmol), 3-fluoro-4-methylbenzylamine (a 0.012 ml, 0.11 mmol) and immobilized on the polymer 1,5,7-diazabicyclo[4.4.0]Dec-5-ene (2.9 mmol/g) (is 0.102 g, 0.30 mmol) in acetonitrile (3 ml) was stirred at 80°C for 30 minutes After cooling to room temperature the reaction mixture is filtered through a cartridge Isolute SCX-2. Then the cartridge was washed with methanol. The crude product elute 7M solution of ammonia in methanol. The solvent is evaporated in vacuum. The crude product is purified column flash chromatography (silica gel; 5% ammonia in methanol (7M)/dichloromethane) and getE9(0,017 g, 45%) as a solid. C16H18F4N4S requires 374; found: 375 (MH+).

1H NMR (400 MHz, Chloroform-d) δ ppm 1,59-of 1.74 (m, 2H), 2.05 is-2,22 (m, 4H), and 2.26 (d, J=1,45 Hz, 3H), 2,75-2,89 (m, 2H), 3,38-to 3.49 (m, 1H), 3,48 (s, 2H), 6,17 (d, J=ceiling of 5.60 Hz, 1H), 6,93-7,02 (m, 2H), 7,11 (t, J=to 7.77 Hz, 1H).

Use the 10

1-(3-Fluoro-4-trifloromethyl)piperidine-4-yl]-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine (E10)

A mixture of piperidine-4-yl-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine (D4) (0,040 g, 0.16 mmol), 3-fluoro-4-(trifluoromethyl)benzaldehyde (0,038 ml, 0.32 mmol), immobilized on the polymer triacetoxyborohydride (2,07 mmol/g) (0,197 g, 0.95 mmol) and acetic acid (0,050 ml) in dichloromethane (2 ml) is shaken at room temperature for 16 hours Then the reaction mixture is filtered through a cartridge Isolute SCX-2. The cartridge was washed with methanol. The crude product elute 7M solution of ammonia in methanol. The solvent is evaporated in vacuum. The crude product is purified column flash chromatography (silica gel; 5% ammonia in methanol (7M)/dichloromethane) and getE10(0,029 g, 43%) as a white solid. C16H15F7N4S requires 428; found: 429 (MH+).

Melting point: 130,2°C.

1H NMR (500 MHz, Chloroform-d) δ ppm 1,64 to 1.76 (m, 2H), 2,07-2,17 (m, 2H), 2,23 (t, J=10,55 Hz, 2H), 2,74-2,89 (m, 2H), 3,41-of 3.53 (m, 1H), of 3.56 (s, 2H), 6,40 (Shir. s, 1H), 7,16-7,25 (m, 2H), 7,54 (t, J=7,66 Hz, 1H).

Example 13

[1-(3-Cryptomaterial)piperidine-4-yl]-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine (E13)

A mixture of piperidine-4-yl-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine (D4) (0.025 g, 0.10 mmol), 3-triphtalocyaninine (0,034 ml,0.29 mmol) and immobilized on the polymer triacetoxyborohydride (2,07 mmol/g) (0,165 g, 0.29 mmol) in 1,2-dichloroethane (2 ml) is shaken at room temperature for 16 hours Then the reaction mixture is filtered through a cartridge Isolute SCX-2. The cartridge was washed with methanol. The crude product elute 7M solution of ammonia in methanol. The solvent is evaporated in vacuum. The crude product is purified column flash chromatography (silica gel; 5% ammonia in methanol (7M)/dichloromethane) and getE13(0,029 g, 68%) as a white solid. C16H16F6N4OS requires 426; found: 427 (MH+).

Melting point: 116,3°C.

1H NMR (500 MHz, Chloroform-d) δ ppm 1.61 of is 1.70 (m, 2H), 2,09-of 2.16 (m, 2H), of 2.21 (t, J=10,98 Hz, 2H), 2,81-2,87 (m, 2H), 3.46 in is 3.57 (m, 1H), 3,54 (s, 2H), of 5.75 (d, J=5,78 Hz, 1H), 7,11 (d, J=8,09 Hz, 1H), 7.23 percent (DD, 2H), 7,34 (t, J=7,80 Hz, 1H).

Example 17

5-[1-(3-Trifloromethyl)piperidine-4-ylamino]-[1,3,4]thiadiazole-2-carbonitrile (E17)

A mixture of 5-(piperidine-4-ylamino)-[1,3,4]thiadiazole-2-carbonitrile (D6) (0.16 g, from 0.76 mmol), 3-(trifluoromethyl)benzaldehyde (0,152 ml, to 1.14 mmol) and triacetoxyborohydride sodium (0.24 g, 0.95 mmol) in N,N-dimethylformamide (3 ml) was stirred at room temperature for 16 hours Then the reaction mixture was diluted with ethyl acetate and extracted with a saturated solution of sodium carbonate (25 ml). The organic layer is separated, dried (Na2SO4) and the solvent evaporated in vacuum. The crude about the SPS clear column flash chromatography (silica gel; 1-4% ammonia in methanol (7M)/dichloromethane) and getE17(0.025 g, 9%) as a white solid. C16H16F3N5S requires 367; found: 368 (MH+).

1H NMR (500 MHz, Chloroform-d) δ ppm 1,68 and 1.80 (m, 2H), 2.06 to to 2.15 (m, 2H), 2,22 (t, J=10,69 Hz, 2H), 2,82 of 2.92 (m, 2H), 3,32 is-3.45 (m, 1H), to 3.58 (s, 2H), 7,45 (t, J=7,66 Hz, 1H), 7,49-of 7.55 (m, 2H), to 7.59 (s, 1H), to 7.61-7.68 per (m, 1H).

Example 18

5-[1-(3-Fluoro-5-trifloromethyl)piperidine-4-ylamino]-[1,3,4]thiadiazole-2-carbonitrile (E18)

A mixture of 5-(piperidine-4-ylamino)-[1,3,4]thiadiazole-2-carbonitrile (D6) (0.16 g, from 0.76 mmol), 3-fluoro-5-(trifluoromethyl)benzylbromide (0,124 ml, from 0.76 mmol) and diisopropylethylamine (0,20 ml, to 1.14 mmol) in acetonitrile (2 ml) and N,N-dimethylformamide (0.5 ml) was stirred at room temperature for 48 hours Then the reaction mixture was diluted with dichloromethane and extracted with a saturated solution of ammonium chloride (25 ml). The organic layer is separated, dried (Na2SO4) and the solvent evaporated in vacuum. The crude product is purified column flash chromatography (silica gel; 2-3% ammonia in methanol (7M)/dichloromethane) and getE18is 0.019 g, 7%) as a solid. C16H15F4N5S requires 385; found: 386 (MH+).

1H NMR (500 MHz, Chloroform-d) δ ppm 1.57 in is 1.70 (m, 2H), 2,07-of 2.15 (m, 2H), 2,22 (t, J=11,13 Hz, 2H), 2,81-of 2.93 (m, 2H), 3,19 (Shir. s, 1H), to 3.58 (s, 2H), 3,64-to 3.73 (m, 1H), 7,24 (d, J=8,09 Hz, 1H), 7,28 (d,J=8,96 Hz, 1H), 7,40 (s, 1H).

Example 19

5-[1-(3,4-Diferensial)piperidine-4-ylamino]-[1,3,4]thiadiazole-2-carbonitrile (E19)

A mixture of 5-chloro-[1,3,4]thiadiazole-2-carbonitrile (0.3 g, of 2.06 mmol) (D6) (obtained in the manner similar to that described in US 5736545), 1-(3,4-diferensial)piperidine-4-ylamine (D7) (0,47 g of 2.06 mmol) and diisopropylethylamine (0.54 ml, to 3.09 mmol) in acetonitrile (5 ml) in sealed tube was stirred at 80°C for 1 h under microwave irradiation. Then the reaction mixture was diluted with dichloromethane and extracted with a saturated solution of sodium carbonate (25 ml). The organic layer is separated, dried (Na2SO4) and the solvent evaporated in vacuum. The crude product is purified by chromatography on a short open column (silica gel; 0-2,5% ammonia in methanol (7M)/dichloromethane). The target fractions are collected and evaporated in vacuum. The crude product is precipitated from acetonitrile, gettingE19(0.17 g, 25%) as a solid. C15H15F2N5S requires 335; found: 336 (MH+).

Melting point (acetonitrile): 199,4°C.

1H NMR (500 MHz, Chloroform-d) δ ppm 1,64 of-1.83 (m, 2H), 2,15 (d, J=11,85 Hz, 2H), 2,24 (t, J=10,11 Hz, 2H), 2,89 (d, J=10,98 Hz, 2H), 3.46 in-to 3.58 (m, 3H), 6,74 (Shir. s, 1H), 7,02-was 7.08 (m, 1H), 7,09-7,16 (m, 1H), 7,22 (t, J=a 9.25 Hz, 1H).

Example 21

5-[1-(3,4,5-Triptorelin)piperidine-4-ylamino]-[1,3,4]thiadiazole-2-carbonic is l (E21)

A mixture of 5-chloro-[1,3,4]thiadiazole-2-carbonitrile (0.3 g, of 2.06 mmol) (D6) (obtained in the manner similar to that described in US 5736545), 1-(3,4,5-triptorelin)piperidine-4-ylamine [obtained by the method described for (D1)] (0.50 g, of 2.06 mmol) and diisopropylethylamine (0.54 ml, to 3.09 mmol) in acetonitrile (5 ml) in sealed tube was stirred at 80°C for 1 h under microwave irradiation. Then the reaction mixture was diluted with dichloromethane and extracted with a saturated solution of sodium carbonate (25 ml). The organic layer is separated, dried (Na2SO4) and the solvent evaporated in vacuum. The crude product is purified by chromatography on a short open column (silica gel; 0-2,5% ammonia in methanol (7M)/dichloromethane). The target fractions are collected and evaporated in vacuum. The crude product is precipitated from a mixture of acetonitrile/diisopropyl ether and receiveE21(0.18 g, 24%) as a solid. C15H14F3N5S requires 353; found: 354 (MH+).

Melting point (acetonitrile/diisopropyl ether): 211,3°C.

1H NMR (500 MHz, DMSO-d6) δ ppm 1,47-to 1.59 (m, 2H), 1,98 (d, J=10,69 Hz, 2H), 2,15 (t, J=10,55 Hz, 2H), 2,73 (d, J=11,27 Hz, 2H), 3,48 (s, 2H), 3,64 of 3.75 (m, 1H), 7,21-to 7.32 (m, 2H), 8,81 (Shir. s, 1H).

Example 22

[1-(3,4-Diferensial)piperidine-4-yl]-(4-cryptomaterial-2-yl)amine (E22)

A mixture of piperidine-4-yl-(4-cryptomaterial-2-yl)amine (D9) (0,050 g, 0.2 mmol), 3,4-diferenciada (0,028 ml, 0.22 mmol) and diisopropylethylamine (0,053 ml, 0.32 mmol) in acetonitrile (1 ml) was stirred at 120°C for 5 min under microwave irradiation. The reaction mixture was diluted with dichloromethane and extracted with water. The organic layer is separated, dried (Na2SO4) and the solvent evaporated in vacuum. The crude product is purified column chromatography (silica gel; AcOEt). The target fractions are collected and evaporated in vacuum. The obtained product is dissolved in acetonitrile (0.5 ml) and treated with hydrochloric acid in diethyl ether (2M), getting the corresponding hydrochloric saltE22(0,071 g, 85%) as a white solid. C16H16F5N3S-HCl in the form of a free base requires 377; found: 378 (MH+).

Melting point (acetonitrile): 238°C.

1H NMR (400 MHz, DMSO-d6) δ ppm 1,78-of 1.93 (m, 1,5H), 1,95-to 2.06 (m, 0,5H), to 2.13 (m, 2H), 2,97-3,11 (m, 1,5H), 3,11-of 3.27 (m, 1H), 3,34 (m, 1,5H), 3,69-of 3.85 (m, 0,75H), 3,90-3,98 (m, 0,25H), 4,25 (d, J=5,18 Hz, 1,5H), 4,30 (d, J=5,39 Hz, 0,5H), was 7.36 (d, J=1,24 Hz, 0,75H), 7,41 (d, J=1,04 Hz, 0,25H), 7,43-of 7.60 (m, 2H), 7,82 (DDD, J=11,51, 7,88, 1.97 Hz, 1H), 8.30 to (Shir. C, 0,75H), 8,48 (d, J=ceiling of 5.60 Hz, 0,25H), 11,03 (Shir. C, 0,25H), 11,22 (Shir. C, 0,75H).

Connection example (E3) is obtained from (D2) and the appropriate alkylating reagent according to the method used for gaining the compound of example (E2). Connection examples (E6-E8) is obtained from (D4) and the appropriate alkylating reagent according to the method used to obtain the compound of example (E5). Connection examples (E11-E12) is obtained from (D4) and the corresponding aldehyde according to the method used to obtain the compound of example (E10). Connection examples (E14-E16) is obtained from (D4) and the corresponding aldehyde according to the method used to obtain the compound of example (E13).

Connection examples (E20-E21) is obtained from 5-chloro-[1,3,4]thiadiazole-2-carbonitrile (D6) and the corresponding derivatives of 1-(benzyl)piperidine-4-ylamine according to the method used to obtain the compound of example (E19). The corresponding derivatives of 1-(benzyl)piperidine-4-ylamine obtained from tert-butyl ether piperidine-4-ylcarbamate acid and the appropriate alkylating reagent according to the method used in the description (D7).

The following additional connection examples (E23-E25) is obtained from (D9) and the appropriate alkylating reagent according to the method used to obtain the compound of example (E22). Connection examples (E22-E25) was isolated as salts of hydrochloric is islote.

Pharmacology

Analysis of the affinity of binding of the human D2 receptorLin vitro

Frozen membranes of CHO cells, transfected with the human dopamine receptor D2L, thawed, homogenized within a short period of time by using a homogenizer (Ultra-Turrax T25 and diluted with buffer to analyze Tris-HCl, containing NaCl, CaCl2, MgCl2, KCl (50, 120, 2, 1 and 5 mm, respectively, brought to a pH of 7.7 with HCl)to obtain a suitable concentration of the protein that are optimized for specific and nonspecific binding. Radioactively labeled ligand [3H]spiperone (NEN, specific activity ~70 CI/mmol) diluted with buffer for analysis to a concentration of 2 nmol/L. Then the resulting solution was radioactively labelled ligand (50 μl) together with 50 μl of either 10% DMSO as control or butaclamol (final concentration of 10-6mol/l)or test compounds are incubated (30 min, 37°C) with 400 µl of the obtained membrane preparation. Membrane-associated activity is filtered using a Packard harvester Filtermate on GF/B Unifilterplates and washed with chilled on ice with buffer Tris-HCl (50 mm; pH 7,7; 6×0.5 ml). The filters are allowed to dry, then add scintillation fluid and believe in acquired scintillation counter Topcount. The percentage specification is as binding and competitive binding curves are estimated using the software S-Plus (Insightful). Connections matter pIC50>5,0.

Fast dissociation

To determine the dissociation rate, connection with IC50less than 10 microns, are tested by indirect analysis, developed on the basis of the method described Josee E. Leysen and Walter Gommeren, Journal of Receptor Research, 1984, 4(7), 817-845. Compounds in concentrations greater than their IC504 times, first incubated for one hour with cell membranes containing human receptor D2Lin a volume of 2 ml at 25°C, and then filtered through a glass fiber filter under vacuum using a 40-hole holder. Immediately after the vacuum is removed. On the filter, add 0.4 ml of pre-warmed buffer (25°C)containing 1 nm [3H]spiperone, and incubated for 5 minutes. The incubation is stopped by the vacuum and immediately washed with 2×5 ml chilled on ice buffer. Associated with the filter radioactivity measured using a liquid scintillation spectrometer. In the basis of the analysis is the assumption that the faster the connection is disconnected from the D2 receptor, the faster [3H]spiperone binds to the D2 receptor. For example, if the D2 receptors are incubated with clozapine concentration 1850 nm (4×IC50), binding of [3H]spiperone after 5 minutes incubation, the filter is 60-70% of the total binding capacity (measured in the lack of what their medicines). During incubation with other antipsychotic means binding of [3H]spiperone varies from 20 to 50%. The test compound is considered rapidly dissociating D2 antagonists, if they dissociate as fast as clozapine, or faster than clozapine, which is used in each filter. Connections have a dissociation rate that exceeds the rate of dissociation of clozapine, i.e., >50%.

1. The compound of formula (I)

or its pharmaceutically acceptable salts, where R denotes hydrogen;
R1denotes phenyl, substituted by 1, 2 or 3 substituents, each of which is independently selected from the group comprising halogen, cyano, C1-4alkyl, perfors1-4alkyl and perfers1-4alkoxy;
R2denotes hydrogen or C1-6alkyl;
R3denotes hydrogen, trifluoromethyl or cyano;
X represents N or CR4where R4represents trifluoromethyl.

2. The compound according to claim 1, where
R denotes hydrogen;
R1denotes phenyl, substituted by 1, 2 or 3 substituents, each of which is independently selected from the group comprising halogen, cyano, C1-4alkyl, perfors1-6alkyl, triptoreline;
R2denotes hydrogen or methyl;
X denotes nitrogen, and
R3represents trifluoromethyl.

3. The compound according to claim 1, where R denotes hydrogen;
R denotes phenyl, substituted by 1, 2 or 3 substituents, each of which is independently selected from the group comprising halogen, cyano, C1-4alkyl, perfors1-4alkyl, triptoreline;
R2denotes hydrogen or methyl;
X denotes nitrogen and R3denotes cyano.

4. The compound according to claim 1, where
R denotes hydrogen;
R1denotes phenyl, substituted by 1, 2 or 3 substituents, each of which is independently selected from the group comprising halogen, cyano, C1-4alkyl, perfors1-4alkyl, triptoreline;
R2denotes hydrogen or methyl;
R3denotes hydrogen; and
X represents CR4where R4represents trifluoromethyl.

5. The compound according to claim 1, where the compound is selected from the group including
[1-(4-terbisil)piperidine-4-yl]-methyl-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine,
[1-(3-terbisil)piperidine-4-yl]-methyl-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine,
[1-(4-terbisil)piperidine-4-yl]-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine,
[1-(3,4-diferensial)piperidine-4-yl]-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine,
[1-(3-fluoro-4-methylbenzyl)piperidine-4-yl]-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine,
1-(3-fluoro-4-trifloromethyl)piperidine-4-yl]-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine,
[1-(3-cryptomaterial)piperidine-4-yl]-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)amine,
5-[1-(3-trifloromethyl)piperidin the-4-ylamino]-[1,3,4]thiadiazole-2-carbonitrile,
5-[1-(3-fluoro-5-trifloromethyl)piperidine-4-ylamino]-[1,3,4]thiadiazole-2-carbonitrile,
5-[1-(3,4-diferensial)piperidine-4-ylamino]-[1,3,4]thiadiazole-2-carbonitrile,
5-[1-(3,4,5-triptorelin)piperidine-4-ylamino]-[1,3,4]thiadiazole-2-carbonitrile and
[1-(3,4-diferensial)piperidine-4-yl]-(4-cryptomaterial-2-yl)amine.

6. Pharmaceutical composition suitable as an antagonist of the dopamine receptor 2, containing a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.

7. The compound according to claim 1 for use as antipsychotics.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to bicyclosubstituted pyrazolon azo derivatives of formula

or pharmaceutically acceptable salts thereof, intermediate compounds of formula ,

as well as methods for production thereof, a pharmaceutical composition containing a compound of formula (II), and use thereof as a therapeutic agent, which is a thrombopoietin (TPO) mimetic, as well as use thereof as agonists of the thrombopoietin receptor. Values of substitutes in formulae (I) and (IA) are given in the claim.

EFFECT: obtaining bicyclosubstituted pyrazolon azo derivatives.

12 cl, 58 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel cyclic 5-nitropyridin-2-yl-thioalkenyl-4-dithiocarbamate derivatives of general formula (I) or pharmaceutically acceptable acid- or base addition salts thereof. The compounds have antifungal activity even in case of deep, subcutaneous and surface mycoses in humans, caused by strains (including those resistant to existing drugs) of mycosis causative agents. In general formula , R denotes nitro, cyano, halide-substituted C1-C6 alkyl group, n=1, 2 or 3. The invention also relates to use of compounds of formula (I), a method of producing said compounds, a pharmaceutical composition and a method for treatment using said compounds.

EFFECT: improved method.

12 cl, 2 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), stereoisomers, trans- and cis-isomers, racemates or pharmaceutically acceptable salts thereof, having modulating activity on histamine H3-receptors. In formula (I) m equals 0; one of R1 and R2 is selected from a group which includes hydrogen, C1-10alkoxycarbonyl, amido-, carboxy-, C3-8cycloalkyl, halogen, -NRARB, (NRARB)carbonyl, or a group of formula -L2-R6; the other of R1 and R2 is selected from a group which includes hydrogen, halogen; each of R3a and R3b is independently selected from a group which includes hydrogen; each of R4 and R5 is independently selected from a group which includes C1-10alkyl and C1-10hydroxyalkyl; or R4 and R5, taken together with a nitrogen atom to which each is bonded, form a heteroaromatic ring of the type (a) or (b), where Q1 is O or C; Q2 is -N(R20)-; R20 is selected from a group which includes hydrogen and C1-10alkoxycarbonyl; each of p1 and p2 is independently equal to 1, 2 or 3; each of q1, q2, q3, q4 and q5 are independently equal to 0, 1 or 2; and wherein each carbon atom in the ring is substituted with hydrogen or 0, 1 or 2 substitutes, independently selected from a group which includes hydrogen, hydroxy group, fluorine, C1-10alkyl, C1-10hydroxyalkyl and C1-10fluoroalkyl; R6 is a phenyl, heterocycle or heterocycloC1-4alkyl, wherein the heterocycle is a 4-6-member aromatic or non-aromatic ring which contains 1 or 2 heteroatoms independently selected from N, O and S, optionally condensed with a benzene ring, wherein the phenyl or heterocycle can be unsubstituted or optionally substituted with one or more substitutes independently selected from a group which includes C1-4alkoxy, C1-4alkyl, cyano, halogen and oxo-; L is a bond or C1-4alkylene; L2 is a bond, C1-4alkylene, -C(=O)-, -SO2N(R14a)-, -N(R14a)SO2-, -C(O)N(R14a)-, -N(Rl4a)C(O)- or -N(R15)-; R10 is selected from a group which includes hydrogen; R14a is selected from a group which includes hydrogen; R15 is selected from a group which includes hydrogen; and RA and RB are independently selected from a group which includes hydrogen, C1-10alkyl, C1-10acyl, C1-4halogenalkyl, C1-10alkoxycarbonyl, C3-8cycloalkyl and C3-8cycloalkylcarbonyl. The invention also relates to a pharmaceutical composition which contains compounds of formula (I), a method for selective modulation of effects of histamine H3-receptors, use of said compounds in producing a medicament for treating a condition or disorder modulated by histamine H3-receptors, as well as specific compounds of formula (I).

EFFECT: improved properties of compounds.

18 cl, 2 tbl, 154 ex

FIELD: chemistry.

SUBSTANCE: disclosed is a compound having chemical formula or a salt thereof, where: Ar is an optionally substituted heteroaryl; R1 in each case is independently selected from a group which includes halogen, lower alkyl, optionally substituted with one or more substitutes selected from fluorine, lower alkoxy, fluorine-substituted lower alkoxy, monoalkylamino, dialkylamino, -O-R5, -N(R5)-R6 and -N(R5)-C(X)-R7; m equals 0 or 1; n equals 0, 1 or 2; R2 is hydrogen or a halogen; L2 is -S(O)2-; R3 is a lower alkyl, optionally substituted with fluorine, C3-6 cycloalkyl, optionally substituted with a lower alkyl, a 5- or 6-member nitrogen-containing heterocycloalkyl, optionally substituted with one or more substitutes selected from fluorine, lower alkyl, fluorine-substituted lower alkyl, lower alkoxy, fluorine-substituted lower alkoxy, lower alkylthio or fluorine-substituted lower alkylthio, aryl, optionally substituted with a halogen, lower alkyl, optionally substituted with a halogen or lower alkoxy, optionally substituted with a halogen, or a heteroaryl, optionally substituted with a halogen or a lower alkyl; L1 is selected from a group which includes -O-, -C(R12R13)-X-, -X-C(R12R13)-, -C(R12R13)-N(R11)-, -(R11)-C(R12R13)-, -C(X)-N(R11)-, -N(R11)-C(X)-; X is O; R11 is hydrogen; R4 is hydrogen or a lower alkyl; R5 and R6 in each case are independently selected from a group which includes hydrogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, where each is optionally substituted with one or more substitutes selected from fluorine, lower alkoxy, fluorine-substituted lower alkoxy, lower alkylthio, fluorine-substituted lower alkylthio, monoalkylamino, dialkylamino; R7 in each case is independently selected from a group which includes lower alkyl; where the terms "lower alkyl", "lower alkoxy", "lower alkylthio", "monoalkylamino", "dialkylamino", "cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", are as described in the claim. The invention also discloses a pharmaceutical composition for treating Raf kinase mediated diseases which is based on a compound of formula I; use of the compound of formula I to produce a medicinal agent is also disclosed.

EFFECT: novel compound which can be useful in treating diseases and conditions associated with aberrant activity of protein kinases is obtained and described.

9 cl, 13 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: application describes prodrugs being 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)-4-[4-(2-hydroxyethoxy)-phenyl]pyridine-3,5-dicarbonitryl derivatives, and a method for preparing them.

EFFECT: invention can find application in treating and/or preventing cardiovascular diseases.

8 cl, 4 tbl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula III which possess the properties of JAK pathway inhibitors and JAK-kinase inhibitors. In formula III: X is specified in a group consisting of C1-C10alkyl, amino, halogen, carboxyl, carboxylic acid ester, C2alkynyl, substituted tri-C1-C6alkylsilyl; R represents hydrogen; the cycle A is specified in a group consisting of C6aryl, bicycloheptene, five-and sis-member mono- or 10-member bicyclic heteroaryl including 1 to 3 heteroatoms specified in a group of heteroatoms, including N, O or S, and five- or six-member mono- or 10-member bicyclic heterocycle, including 1 to 2 heteroatoms specified in a group of heteroatoms, including N or O; p means 0, 1, 2 or 3; each of R2 is independently specified in a group consisting of C1-C6alkyl, C1-C4alkyl substituted by 1 to 3 substitutes. The other substitute and radical values are specified in the patent claim.

EFFECT: compounds may be used in preparing a therapeutic agent for T-cell mediated autoimmune disease, for treating or preventing allograft rejection in a recipient, for treating or preventing a type IV hypersensitivity reactions, which includes administering the above agent containing the compound according to cl 1-11, in an amount effective to treat the autoimmune disease or the allograft rejection or the type IV hypersensitivity.

23 cl, 7 dwg, 12 tbl, 43 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely to new 1,2-dihydroquinoline derivatives of general formula , or to a pharmaceutically acceptable salt thereof, wherein R1 represents a lower alkyl group; R2 represents a hydrogen atom; each of R3 and R4 represents a lower alkyl group; R5 represents a lower alkyl group; R6 represents a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group; X represents -CO-, -C(O)NR8 - or -S(O)2-; each of R7 and/or R8 may be identical or different, and represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower cycloalkyl group, a phenyl or naphthyl group, a saturated or unsaturated monocyclic 5- or 6-member heterocyclyl with one or two heteroatoms specified in nitrogen, oxygen and sulphur atoms, and 3-5 carbon atoms in a cycle, a lower alkoxy group, a phenoxy group; provided R7 and/or R8 represent a lower alkyl group, a lower alkoxy group, the mentioned lower alkyl group and lower alkoxy group may contain one or three groups specified in a halogen atom, a phenyl group, an unsubstituted monocyclic 6-member heterocyclyl with one heteroatom specified in a nitrogen atom, and 5 carbon atoms in a cycle, a lower alkoxy group, and -NRaRb as a substitute (substitutes); provided R7 and/or R8 represent a phenyl group, a saturated or unsaturated monocyclic 5- or 6-member heterocyclyl with one or two heteroatoms specified in nitrogen, oxygen and sulphur atoms, and 3-5 carbon atoms in a cycle, a phenoxy group, the mentioned phenyl group, saturated or unsaturated monocyclic 5- or 6-member heterocyclyl with one or two heteroatoms specified in nitrogen, oxygen and sulphur atoms, and 3-5 carbon atoms in a cycle, phenoxy group may contain one or two groups specified in a halogen atom, a lower alkyl group, a halogen-substituted lower alkyl group, a phenyl group, a hydroxyl group, a lower alkoxy group, a halogen-substituted lower alkoxy group, a lower alkylthio group, a lower alkylcarbonyl group, a lower alkoxycarbonyl group, a lower alkylcarbonyloxy group, -NRaRb, a nitro group and a cyano group as a substitute (substitutes); Ra and Rb may be identical or different, and each of them represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group; Y represents a lower alkylene group; Z represents an oxygen atom; p is equal to 2, provided p is equal to 2, R6 may be identical or different. The invention also relates to a pharmaceutical composition and a glucocorticoid receptor modulator of the compound of formula (1).

EFFECT: there are produced new 1,2-dihydroquinoline derivatives possessing glucocorticoid receptor binding activity.

7 cl, 1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyrrol derivatives of formula (1): or a pharmaceutically acceptable salt thereof wherein the values A, R1-R3, n are specified in clause 1 of the patent claim.

EFFECT: compounds (1) inhibit activity against the interleukin IL-6 production that allows using them both in pharmaceutical compositions, and in a prophylactic drug for ocular inflammatory disease.

23 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing substituted pyrimidin-5-yl carboxylic acids of formula I and can be used in organic chemistry. The method is realised by reacting N-substituted guanidines and hetarylamidines with ethoxymethylene derivatives of 1,3-ketoesters according to a scheme given below (where the substitutes are as defined in the claim).

EFFECT: improved method of producing substituted pyrimidin-5-yl carboxylic acids of formula I.

2 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to a method of producing M-(1,5,3-dithiazepan-3-yl)amides of general formula (1) where R = p-C5H4N (a), (CH3)3CO (b), o-CH3OC6H4 (c), which involves reaction of N1,N1,N6,N6-tetramethyl-2,5-dithiahexane-1,6-diamine with a hydrazide of general formula RC(O)NHNH2 [R is as described above] in the presence of a samarium nitrate crystalline hydrate Sm(NO3)3·6H2O catalyst with molar ratio N1,N1,N6,N6-tetramethyl-2,5-dithiahexane-1,6-diamine:RC(O)NHNH2:Sm(NO3)3·6H2O=10:10:(0.3-0.7) at temperature of 65-75°C and atmospheric pressure in the mixture of solvents - ethyl alcohol and chloroform for 20-28 hours.

EFFECT: method of producing N-(1,5,3-dithiazepan-3-yl)amides with high selectivity and output, which can be used as biologically active compounds, selective sorbents and extractants of noble and precious metals.

1 cl, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine. The use of eslicarbazepine or eslicarbazepine acetate for treating epilepsy in the patients previously treated with a drug which was a substrate for P- glycoprotein (P-gp) or multiple drug resistance (MRP) proteins, wherein epilepsy is refractory epilepsy and a refractory condition of epilepsy is an effect of P-gp and/or MRP overexpression. The pharmaceutical composition contains eslicarbazepine or eslicarbazepine acetate, and a pharmaceutically acceptable carrier for treating epilepsy in the patient previously treated with a drug which was a substrate for P- glycoprotein or multiple drug resistance (MRP) proteins.

EFFECT: invention provides higher clinical effectiveness.

12 cl, 2 tbl, 1 ex, 6 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or pharmaceutically acceptable salts thereof wherein A, R1, R2, R3 and m are specified in the patent claim. The present invention also refers to the number of specific compounds, and to a pharmaceutical composition containing the above compounds effective for inhibition of kinases, such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

EFFECT: preparing the specific compounds and pharmaceutical composition containing the above compounds effective for kinase inhibition.

18 cl, 393 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents microspheres for treating schizophrenia, having a nucleus/coating structure and a spherical shape wherein the nucleus contains ariliprazol in the solid state, and the coating covers the entire surface or most of the nucleus and contains a biodegradable polymer.

EFFECT: invention provides producing the microspheres of ariliprazol characterised by the high content and sustained release of the active substance, and preparing an injectable aqueous suspension of the above microspheres.

17 cl, 18 ex, 14 dwg

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to psychiatry, and concerns treating schizophrenia. That is ensured by administering a composite solution of cytokines which is prepared by arteriovenous perfusion of porcine spleen by physiological saline at a flow rate of 30-40 ml/min followed by sterilisation filtration and cryo-preservation. The cytokine solution is administered by inhalations in the form of a fine aerosol by a nebuliser in a dose of 10 ml/administration. Depending on the patient's initial state and the distinctions/severity of the disease for the first 3-5 days, the preparation is administered every 8 hours, then for 5-10 days - 1-2 times a day with a frequency of administration to be reduced to 1 time/3 days for 3 months with underlying total withdrawal of psychotropic agents.

EFFECT: administration of the cytokine solution which has a pronounced immunomodulatory effect in the developed regimen enhances the clinical effectiveness in the schizophrenic patients that manifests itself in the form of a pronounced reduction of the psychopathology by the scale PANSS and an induction of sustained remission lasting more than 6 months.

1 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to method of obtaining aripiprazole suspension. Method includes the following stages: (a) combining aripiprazole mass and carrier with formation of primary suspension; (b) first refining of primary suspension with obtaining secondary suspension using apparatus for refining with large shearing force, dispersant, in which shearing force is applied for material processing, or high-pressure homogeniser; and (c) second refining of secondary suspension with obtaining final sterile suspension by high-pressure homogeniser. Claimed composition also relates to methods of obtaining lyophilysed composition from aripiprazole suspension.

EFFECT: claimed invention provides possibility of obtaining aripiprazole suspension with the average size of particles from 1 to 10 mcm, without necessity to use special crystallisation technologies for obtaining initial aripiprazole mass and without application of vacuum mixing at the stage of combining aripiprazole mass and carrier.

33 cl, 13 tbl, 15 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) and salts thereof wherein R1 represents -A11-A12-; R2 represents tetrahydrofurylmethyl, tetrahydropyranylmethyl or tetrahydropyranyl; A11 represents a single bond, methylene or 3,2-ethylene; A12 represents C1-6 alkyl, C3-6 cycloalkyl or C3-6 cycloalkyl containing methyl; R3 represents methoxy, cyano, cyclobutyloxymethyl, methoxymethyl or ethoxymethyl; and R4 represents methoxy or chlorine. Also, the invention also refers to a pharmaceutical composition possessing corticotrophin-releasing factor (CRF) receptor antagonist activity, containing a compound of formula (I), to a therapeutic/preventive agent, and a method of treating the diseases specified in the patent claim.

EFFECT: there are presented the compounds of formula (I) as corticotropin-releasing factor (CRF) receptor antagonists.

20 cl, 2 dwg, 2 tbl, 51 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1), in which Ar is a group of formula (Ar-1) or (Ar-2), in which R1 is a halogen, R2 is hydrogen, R3 is hydrogen, R4 is hydrogen, alkyl or alkenyl, X is a nitrogen atom or CH, R5 and R6 are each hydrogen and h equals 1; 1 equals 1 or 2; m equals 1 or 2; n equals 0, 1 or 2; o equals an integer from 0 to 3, under the condition that n and o are equal to 0 at the same time. Values of group A are as given in claim 1 of the invention. Described also is a pharmaceutical composition having agonistic activity with respect to 7 serotonin (5-HT4-receptors), which contains a compound of formula (1) and an agent which stimulates enterokinesis or improves functioning of the alimentary canal, which contains a compound of formula (1) as an active ingredient.

EFFECT: novel compounds are obtained and described, which have strong affinity towards 4 serotonin receptors, which are useful as an agent which stimulates enterokinesis or an agent which improves functioning of the alimentary canal.

28 cl, 233 ex, 29 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are offered: a pharmaceutical combination comprising an a7 nicotinic receptor agonist, which represents (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofurane-2-carboxamide or a pharmaceutically acceptable salt or a solvate thereof, and at least one antipsychotic agent, wherein the mentioned combination provides a synergistic therapy of a mental disorder, the use thereof for preparing a therapeutic agent for treating or preventing the mental disorder, an appropriate method of treating, and a set comprising a package and the specified synergistic combination. What is shown is a synergistic effect of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofurane-2-carboxamide in a combination with clozapine on the state of fear, or in a combination with quetiapine by a value of a start pulse (startle response and PPI).

EFFECT: what is presented is a combination of alpha 7 nicotinic agonist receptors and antipsychotic agents.

23 cl, 14 dwg, 1 tbl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula

, wherein X represents a halogen atom or C1-6-alkyl; and has the value of 0, 1, 2 or 3; R1 represents H; R2 represents or ; R3 represents C1-6-alkyl, C3-10-cycloalkyl, phenyl, 6-member heterocycloalkyl representing tetrahydropyranyl, or 5-10-member heteroaryl specified in pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzo[1,3]dioxolyl and 2,3-dihydrobenzo[1,4]dioxynyl; which be substituted and contains one to five substitutes specified in the patent claim. The invention also refers to pharmaceutical compositions possessing high affinity to dopamine D3 receptor and serotonin 5-HT2A receptor containing said compounds, and the use thereof in preparing drugs.

EFFECT: preparing the compounds of formula (I) possessing high affinity to dopamine D3 receptor and serotonine 5-HT2A receptor.

15 cl, 4 dwg, 5 tbl, 78 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to novel compounds specified in [1-(3,4-difluorobenzyl)-piperidin-4-yl]-(5-trifluoromethylpyridin-2-yl)amine, 6-{methyl-[1-(3-trifluoromethylbenzyl)-piperidin-4-yl]amino}nicotinonitrile, 6-[1-(3-trifluoromethylbenzyl)-piperidin-4-ylamino]nicotinonitrile, 6-[1-(3-fluoro-5-trifluoromethylbenzyl)-piperidin-4-ylamino]nicotinonitrile, 6-[1-(3,5-difluorobenzyl)-piperidin-4-ylamino]nicotinonitrile, 6-[1-(3,4,5-trifluorobenzyl)-piperidin-4-ylamino]nicotinonitrile, 2-{methyl-[1-(3-trifluoromethylbenzyl)piperidin-4-yl]amino}isonicotinonitrile, 6-[1-(3-fluoro-5-trifluoromethylbenzyl)piperidin-4-ylamino]pyridin-2-carbonitrile, (1-benzyl-piperidin-4-yl)-(5-trifluoromethylpyridin-2-yl)amine, 6-[1-(3,5-difluorobenzyl)piperidin-4-ylamino]-pyridin-2-carbonitrile; 6-[1-(3,4,5-trifluorobenzyl)piperidin-4-ylamino]-pyridin-2-carbonitrile and 6-(1-benzyl-piperidin-4-ylamino)-pyridin-2-carbonitrile, to their pharmaceutically acceptable salts and stereoisomer forms used as antipsychotic agents, as well as to a based pharmaceutical composition.

EFFECT: preparing the compounds used as antipsychotic agents.

3 cl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or pharmaceutically acceptable salts thereof wherein A, R1, R2, R3 and m are specified in the patent claim. The present invention also refers to the number of specific compounds, and to a pharmaceutical composition containing the above compounds effective for inhibition of kinases, such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

EFFECT: preparing the specific compounds and pharmaceutical composition containing the above compounds effective for kinase inhibition.

18 cl, 393 ex

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