WO2019240615A1

WO2019240615A1 - Partial agonist of dopamine d2/d3 receptors - methylamide 4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}-piperidine-1-carbonic acid

Info

Publication number: WO2019240615A1
Application number: PCT/RU2019/000014
Authority: WO
Inventors: Александр Васильевич ИВАЩЕНКО; Александр Владимирович НИКИТИН; Рубен Навасардович КАРАПЕТЯН; Анастасия Александровна КУЗНЕЦОВА
Original assignee: Общество С Ограниченной Ответственностью Научно-Исследовательский Институт Химрар (Химрар Рди, Ллс)
Priority date: 2018-06-15
Filing date: 2019-01-15
Publication date: 2019-12-19
Also published as: RU2677268C9; RU2677268C1

Abstract

The invention relates to the field of pharmaceutics. A compound methylamide 4-{2-[4-(2,3-dichloropohenyl)-piperazin-1-yl]-ethyl}-piperidine-1-carbonic acid of formula 1, which can be used as a partial agonist of dopamine D2/D3 receptors. Furthermore, the claimed invention relates to a method for obtaining the compound of formula 1, and a pharmaceutical composition and a method for treating bipolar disorder and other neurodegenerative disorders, as well as to the use of the compound of formula 1 to treat bipolar disorder and a number of neurodegenerative disorders.

Description

PARTIAL DOPAMINE D2 / D3 AGONIST RECEPTOR - METHYLAMIDE 4- {2- [4- (2,3-DICHLES ORPHENYL) -PIPERAZIN-1 - IL] -ETHYL} -PIPERIDINE-1-CARBOXYLIC ACID

Technical field

The invention relates to the field of pharmaceuticals, namely to new physiologically active substances, new partial agonists of dopamine D2 / D3 receptors, active components for pharmaceutical compositions, to pharmaceutical compositions and medicines containing methylamide 4- {2- [4- (2,3 -dichlorophenyl) piperazine-1-yl] ethyl} piperidine-1-carboxylic acid as a partial agonist of dopamine D2 / D3 receptors, which can be used in the treatment of bipolar affective disorder.

State of the art

Bipolar disorder is a mental illness characterized by frequent mood swings, energy swings that can lead to serious consequences. This chronic disease affects in adults on the quality of work, in children - on the deterioration of school, in extreme cases, entails suicidal tendencies. Bipolar affective disorder is inherent in almost 1.5% of the population.

This disease has two opposite poles of impaired emotional behavior, and pathological mood swings reach the extremes of a depressed or manic state, sometimes lasting for years. Mental instability, abrupt mood swings are serious signs of bipolar disorder. The patient has a frequent change of behavior: from the symptoms of mania, manifested in overheating, euphoria, to severe depression with clear signs of lethargy. Between these conditions, the patient is calm and healthy, behaves like a person with a balanced psyche. Mania can be expressed in a person’s excessive excitement, an overabundance of energy, in which he is in a euphoric state, thoughtlessly spending money, solving “global problems”. The patient's sleep is disturbed, distraction is noticed, speech becomes abrupt, accelerated, it is almost impossible to interrupt him. There is no strict sequence for the manifestation of these phases of the incidence. At the heart of this pathology, as in a wide range of other neurological and mental disorders, there is a change in dopaminergic function, and the dopamine receptors themselves are targets for many drugs. Therefore, the main problem in the search for drugs for the treatment of bipolar disorder is not the activity of the potential drug, but its specificity.

Dopamine receptors are a class of transmembrane metabotropic G-protein-linked cell receptors that play an important role in the functioning of the central nervous system of vertebrates. The main endogenous ligand agonist of these receptors is dopamine. Dopamine receptors are involved in the processes of motivation, training, fine motor coordination, modulation of neuroendocrine signals. This class includes five types of receptors: Dl, D2, D3, D4, and D5. According to the structural, biochemical and pharmacological characteristics, all of these receptors are divided into D 1 -like (Dl, D5) and 02-like (D2, D3, D4).

02-like receptors include the D2, D3 and D4 receptors. These receptors bind to Gai / o family G-proteins and therefore inhibit adenylate cyclase. Unlike D1-like, D2 and D3 receptors are present not only on the postsynaptic membranes of dopamine-sensitive cells, but also on the presynaptic membranes of dopaminergic neurons, therefore it is D2-like receptors that are currently the “target of choice” for the treatment of bipolar disorders.

An important property that is extremely desirable for therapeutic agents of bipolar disorders is their PARTIAL binding to receptors - the ability to stabilize the dopamine system. The concept of a “partial agonist” emphasizes that the effect of the drug depends on the initial state of the functional activity of the dopamine network - such a drug enhances the activity of dopamine in those areas of the brain where it is reduced (mesocortical structures), and reduces the activity of dopamine in those brain structures where it is, on the contrary , strengthened (mesolimbic structures). In the first case, the clinical effect is manifested by a reduction in negative, in the second - by the relief of positive symptoms.

Among the agonists / partial agonists of dopamine D2 / D3 receptors, various classes of compounds are known. Including drugs from the benzothiophenediazepine series (Otsuka Pharmaceutical Co., Ltd. (JP)), 1,8-naphthyridinones developed by Pfizer (US), as well as arylpiperazines, Brexpiprazole and Aripiprazole (both Otsuka Pharmaceutical Co., Ltd. (JP)) and Cariprazine (Gedeon Richter (HU)).

It is the latter drug that can be considered as the closest prior art (prototype) of the presented invention.

It was unexpectedly discovered that 4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] ethyl} -piperidin-1-carboxylic acid methylamide is a compound of formula 1

1

-is an effective partial agonist of dopamine D2 / D3 receptors and can be used to develop drugs for the treatment of bipolar disorder.

Disclosure of invention

For the claimed compound of formula 1, its binding to the D2S and D3 receptors involved in the mechanism of development of bipolar disorder was unexpectedly observed, while for Kariprazin, which can be considered as the closest analogue to the claimed compound, the binding to D2S and D3 receptors differs by two orders. This suggests a higher activity of the compounds of formula 1 compared with cariprazine.

Moreover, the preparation of a compound of formula 1 is simpler for a specialist than the preparation of a comparable compound of Kariprazine, the formula of which contains two centers of asymmetry at once. The specialist is obvious simplicity and accessibility, as well as the cheapness of the compounds of formula 1 in comparison with its analogue - Kariprazin, while the biological activity of the compounds of formula 1 is not only not inferior to the known analogue, but also surpasses it. The following are definitions of terms that are used in the description of this invention.

“Agonists” means compounds that, by binding to receptors of a particular type, actively contribute to the transmission by these receptors of their specific signal and thereby elicit a biological response from the cell.

"Active component" (drug substance, drug substance, drug-substance) means a physiologically active substance of synthetic or other (biotechnological, plant, animal, microbial and other) origin, having pharmacological activity and is the active principle of the pharmaceutical composition used for the manufacture and manufacture medicinal product (means).

"Active substance" (drug substance, drug substance, drug-substance) means a physiologically active substance of synthetic or other (biotechnological, plant, animal, microbial and other) origin, having pharmacological activity and is the active principle of the pharmaceutical composition used for the manufacture and manufacture medicinal product.

“Combined medicinal product (preparation)” - a combination of several medicinal substances for simultaneous use in the form of tablets, capsules, injections, ointments, rectal suspensions and gels and other finished forms, designed to restore, correct or change physiological functions in humans and animals, as well as for the treatment and prevention of diseases, diagnosis, anesthesia, contraception, cosmetology and other things. Medicinal substances in one set can be presented in the form of various ready-made forms intended for administration into an animal or human body in various ways, for example, orally and rectally.

"Neurodegenerative disease" means a specific condition and disease characterized by damage and primary death of populations of nerve cells in certain areas of the central nervous system. Neurodegenerative diseases include, but are not limited to, Alzheimer's and Parkinson's disease; Huntington's disease (chorea); multiple sclerosis; cerebellar degeneration; amyotrophic lateral sclerosis; dementia with Levy bodies; spinal muscular atrophy; peripheral neuropathy; spongiform encephalitis ("mad cow disease", Creutzfeld-Jakob Disease); AIDS-related dementia; multi-infarct dementia; frontotemporal dementia; leukoencephalopathy (a disease of endangered white matter); chronic neurodegenerative diseases; stroke; ischemic, reperfusion, and hypoxic brain damage; epilepsy; cerebral ischemia; glaucoma; traumatic brain injury; Down syndrome; encephalomyelitis; meningitis; encephalitis; neuroblastoma; schizophrenia; bipolar disorder; depression. In addition, neurodegenerative diseases include pathological conditions and disorders that develop with hypoxia, abuse of addictive substances when exposed to neurotoxins, infectious and oncological diseases of the brain, as well as neuronal damage associated with autoimmune and endocrine diseases; and other neurodegenerative processes.

“Receptors” (from Latin recipere — to receive, to recognize) are biological macromolecules located on the cytoplasmic membrane of a cell or intracellular, capable of specifically interacting with a limited set of physiologically active substances (ligands) and transforming the signal of this interaction into a specific cellular response.

“Signal cascade” (signal system, signal transmission cascade) means a set of interconnected sequential and parallel molecular processes of regulation of cellular metabolism by external (primary) signals that carry information into the cell, which fundamentally distinguishes them from other chemical compounds entering the cell that serve as its source matter and energy. The molecular mechanisms of transmission (transduction) of external signals into the cell imply not only the transmission of signals as such, but also the whole complex of events associated with it, including amplification, attenuation and suppression (or switching off) of signals.

"Pharmaceutical composition" means a composition comprising a compound of general formula 1 and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible additives, which are selected from the group consisting of excipients, solvents, diluents, carriers auxiliary, distributing and perceiving means, means of delivery, such as preservatives, stabilizers, fillers, grinders, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterial agents, fungicides, lubricants, prolonged delivery regulators, choice and ratio which depends on the nature and method of administration and dosage. Examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, as well as mixtures of these substances. Protection against the action of microorganisms can be achieved using a variety of antibacterial and antifungal agents, for example, parabens, chlorobutanol, sorbic acid and the like. The composition may also include isotonic agents, for example, sugars, sodium chloride and the like. The prolonged action of the composition can be achieved using agents that slow down the absorption of the active principle, for example, aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, and also mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of excipients are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of grinders and distributors are starch, alginic acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol. The pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form, in the form of a mixture with traditional pharmaceutical carriers. Suitable unit dosage forms include oral forms such as tablets, gelatine capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms. Pharmaceutical compositions are generally prepared using standard procedures involving the mixing of the active compound with a liquid or finely divided solid carrier. For the manufacture of suppositories, in addition to the active components, cocoa butter, its alloys with paraffin and hydrogenated fats, vegetable and animal hydrogenated fats, solid fat, lanol, alloys of hydrogenated fats with wax, hard paraffin and other bases approved for medical use are also used. “Pharmaceutically acceptable salt” means the relatively non-toxic organic and inorganic salts of the acids and bases of the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of the compounds or prepared specially. In particular, base salts can be prepared on the basis of the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like. (A detailed description of the properties of such salts is given in Berge SM, et al., “Pharmaceutical Salts” J. Pharm. Sci. 1977, 66: 1-19). Salts of the claimed acids can also be specially prepared by reacting the purified acid with a suitable base, and metal and amine salts can be synthesized. Metal salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts. Suitable inorganic bases from which metal salts can be obtained are hydroxide, carbonate, sodium bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases from which salts of the claimed acids can be obtained, amines and amino acids are selected that are sufficiently basic to form a stable salt and are suitable for medical use (in particular, they should have low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris (hydroxymethyl) aminomethane and the like. In addition, tetraalkylammonium hydroxides, for example, such as choline, tetramethylammonium, tetraethylammonium and the like, can be used for salt formation. As amino acids, the main amino acids can be used - lysine, ornithine and arginine.

"Pharmaceutically acceptable additives" by pharmaceutically acceptable additives refers to pharmaceutical diluents, excipients and / or carriers. “Partial agonist” means a substance that is capable of activating a receptor, but with a lesser maximum possible effect than a natural receptor agonist. Although they are agonists, their pharmacological profile, in fact, corresponds to such competitive antagonists in the presence of a complete agonist. In pharmacology, they are used to activate some desired process, but with a warning its course is too active. The use of partial agonists in clinical practice can prevent the development of adaptive regulatory mechanisms ("addiction") in its chronic use.

The purpose of the present invention is to create new partial agonists of dopamine D2 / D3 receptors as potential drugs for the treatment of bipolar disorder.

This goal is achieved by 4- {2- [4- (2,3-dichlorophenyl) piperazine-Pyl] -ethyl} -piperidine-1-carboxylic acid methylamide of the formula 1.

An object of the present invention is a 4- {2- [4- (2,3-dichlorophenyl) piperazine-Pyl] ethyl} piperidine-1-carboxylic acid methylamide of the formula 1

1.

The compound of formula 1 exhibits the properties of a partial dopamine D2 / D3 receptor agonist.

The subject of this invention is also a process for the preparation of 4- {2- [4- (2,3-dichlorophenyl) piperazin-1-yl] ethyl} piperidin-1-carboxylic acid methylamide of the formula 1 starting from tert-butyl-4- (2-hydroxyethyl) piperidine-1-carboxylate 2 and 1- (2,3-dichlorophenyl) piperazine hydrochloride 3 (Scheme 1). Primary alcohol 2 is activated by converting sulfonic acid 4 into ether, the obtained alkylating agent 4, when boiling in acetonitrile, reacts with mono-aryl-substituted piperazine 3. C the resulting ester 5 formed by dropping, the protective group is removed under acidic conditions to form substituted piperidine 6, and when the latter is cooled to 0 ° C in acetonitrile under the influence of N-methylcarbamoyl chloride in the presence of triethylamine, structure 1 is formed.

Scheme 1

More specifically, the claimed method for producing the compounds of formula 1 includes the following steps:

A) reacting tert-butyl 4- (2-hydroxyethyl) piperidine-1-carboxylate of formula 2 with methanesulfonyl chloride to form tert-butyl-4 - [{(2-methylsulfonyl) oxy} ethyl] piperidine-1-carboxylate of formula 4;

B) the interaction of the sulfonic acid ester of formula 4 obtained in step (A) with 1 - (2,3-dichlorophenyl) piperazine hydrochloride to produce tert-butyl-4- {2- [4- (2,3-dichlorophenyl) piperazine-1 -yl] ethyl} piperidine-1-carboxylate of formula 5;

5

C) boiling the ester of formula 5 in a hydrochloric acid solution to obtain 1 - (2,3-dichlorophenyl) -4- (2-piperidin-4-yl-ethyl) piperazine of formula 6;

6

F) treating the substituted piperidine of formula 6 with N-methylcarbamoyl chloride to give a compound of formula 1.

A preferred embodiment of the production method comprises the following steps:

a) to the mixture of tert-butyl 4- (2-hydroxyethyl) piperidine-1-carboxylate and triethylamine in methylene chloride, methanesulfonyl chloride is added with cooling, the reaction mixture is washed with water and concentrated to form tert-butyl-4 - [{(2-methylsulfonium k) hydroxy} ethyl] piperidine-1-carboxylate;

b) tert-butyl 4- {2 - [(methylsulphonyl) oxy] ethyl} piperidine-1-carboxylate, 1- (2,3-dichlorophenyl) piperazine hydrochloride and potassium carbonate are boiled in acetonitrile, the precipitate formed at the end of the reaction is filtered off, washed and dried to form tert-butyl-4- {2- [4- (2,3-dichlorophenyl) piperazin-1-yl] ethyl} piperidin-1-carboxylate as beige crystals;

c) tert-butyl-4- {2- [4- (2,3-dichlorophenyl) piperazin-1-yl] ethyl} piperidine-1-carboxylate is dissolved in a water-methanol solution of hydrochloric acid at boiling, after completion of the reaction, methanol is distilled off and the residue is made alkaline with ice to pH = 10. After prolonged stirring, the precipitate of 1 - (2,3-dichlorophenyl) -4- (2-piperidin-4-yl-ethyl) piperazine is separated in the form of a beige powder;

d) 1- (2,3-dichlorophenyl) -4- (2-piperidin-4-yl-ethyl) piperazine is dissolved in acetonitrile and treated with N-th while cooling and stirring methylcarbamoyl chloride, and the precipitate formed is filtered off, washed, dried, dissolved in ethanol and passed through a layer of celite. The combined ethanol filtrates were slightly evaporated and crystallization of the product 4- {2- [4- (2,3-dichlorophenyl) piperazin-1-yl] ethyl} -A-methylpiperidin-1-carboxamide in the form of a white powder was observed, which was filtered and dried.

Specific modes / conditions for the implementation of the method of obtaining can be selected by a specialist experimentally.

The subject of the present invention is an active component having the property of a partial agonist of dopamine D2 / D3 receptors, which is 4- {2- [4- (2,3-dichlorophenyl) piperazine-1-yl] ethyl} -piperidine-1 - methylamide carboxylic acid of formula 1 in a therapeutically effective amount.

The subject of this invention is a pharmaceutical composition intended for the treatment of bipolar disorder, containing in an effective amount an active ingredient having the property of a partial agonist of dopamine D2 / D3 receptors.

The pharmaceutical composition may be in the form of tablets, capsules, and injections in a pharmaceutically acceptable package.

The pharmaceutical composition may include pharmaceutically acceptable additives. By pharmaceutically acceptable additives are meant diluents, excipients and / or carriers used in the pharmaceutical field. Pharmaceutically acceptable additives are preferably selected from potato starch and lactose monohydrate. Potato starch can be contained in an amount of 30.5 - 32 mg, and lactose monohydrate in an amount of about 67 mg.

Preferably, the pharmaceutical composition for treating bipolar disorder comprises:

- from 1 to 2.5 wt.% the compounds of formula 1,

- from 31 to 31.5 wt.% potato starch and

- from 66 to 68 wt.% lactose monohydrate.

The pharmaceutical composition along with the active component of the present invention may include other active ingredients, provided that they do not cause undesirable effects, for example, allergic reactions.

If it is necessary to use the pharmaceutical compositions of the present invention in clinical practice, they can be mixed for the manufacture of various forms, while they can include traditional pharmaceutical carriers; for example, oral forms (such as tablets, gelatine capsules, pills, solutions or suspensions); injection forms (such as injectable solutions or suspensions, or dry powder for injection, which only requires the addition of water for injection before use); local forms (such as ointments or solutions).

The carriers used in the pharmaceutical compositions of the present invention are carriers that are used in the pharmaceutical field to obtain common forms, including: in oral forms, binders, lubricants, disintegrants, solvents, diluents, stabilizers, suspending agents, colorless are used agents, flavoring agents of taste; antiseptic agents, solubilizers, stabilizers are used in injection forms; in local forms, bases, diluents, lubricants, antiseptic agents are used.

A new pharmaceutical composition can be obtained by mixing with an inert excipient and / or solvent of the active component, which is, a compound of formula 1.

The subject of this invention is a medicament containing 4- {2- [4- (2,3-dichlorophenyl) piperazin-1-yl] ethyl} piperidine-1-carboxylic acid methylamide of the formula 1 as an active component.

Medicines may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, topically or rectally). The clinical dosage of the active component (s), pharmaceutical composition or combination drug comprising a pharmaceutically effective amount of the active component in patients can be adjusted depending on the therapeutic efficacy and bioavailability of the active ingredients in the body, their metabolic rate and excretion from the body, as well as on the age, gender and stage of the patient’s disease. The daily dose of the active component in adults is usually 1 to 30 mg, preferably 1 to 2.5 mg. Therefore, during the preparation of the pharmaceutical compositions of the present invention in the form of dosage units, the above effective dosage must be taken into account, with each dosage unit of the preparation containing 1 to 2.5 mg, preferably 1 mg of the active component. In accordance with the instructions of a doctor or pharmacist, these drugs can be taken several times in for certain periods of time (preferably from one to six times).

The subject of this invention is a method of treating bipolar disorder and related neurodegenerative diseases by administering in an effective amount of an active component, which is a compound of formula 1 or a pharmaceutical composition containing a compound of formula 1 as an active component.

The subject of this invention is the use of a compound of formula 1 for the manufacture of a medicament for the treatment of bipolar disorder or for the treatment of other neurodegenerative diseases.

The claimed invention also relates to a compound of formula 1 for use in a method for treating bipolar disorder and / or other neurodegenerative diseases.

The invention is illustrated by the following drawings:

Fig. 1. The hydrogen bond system in the compound of formula 1.

Fig. 2. General view of the molecule of the compound of formula 1 (thermal vibration ellipsoids are given with a probability of 50%). The following examples illustrate but do not limit the invention.

The best embodiment of the invention

The structures of the compounds obtained were confirmed by chemical, chromatographic, x-ray structural and spectral analysis.

Example 1. Obtaining tert-butylmethylsulfonyl) hydroxy) ethyl1 piperidine-

1-carboxylate (4).

To a mixture of tert-butyl 4- (2-hydroxyethyl) piperidine-1-carboxylate (0.50 g, 2.18 mmol) and triethylamine (0.23 g, 2.29 mmol) in methylene chloride (100 ml), cooled to -10 ° C was added dropwise methanesulfonyl chloride (0.26 g, 2.29 mmol), the rate of addition should be such that the temperature of the reaction mixture does not exceed - 10 ° C. Upon completion of the addition, the mixture was stirred at room temperature for 1 hour. The completion of the reaction is monitored by thin layer chromatography (silica gel, hexane / ethyl acetate 2/1). The reaction mixture was washed with water, the organic layer was dried over sodium sulfate (anhydrous). Solvent evaporated in vacuo, the residue is technical tert-butyl-4 - [{(2-methylsulfonyl) oxy} ethyl] piperidine-1-carboxylate. The yield is 92% (0.58 g).

1H NMR spectrum (400 MHz, DSMO-db, d, ppm, J / Hz): 4.24 (t, 2H, J = 6.5 Hz), 3.90 (d, 2 N, J = 12.0 Hz), 2.94 (s, 3H), 2.78-2.61 (m, 2H), 1.70-1.52 (m, 5H), 1.38 (s, 9H), 1.09-0.94 (m, 2H) )

HPLC-MS, [M + H] 288.2.

Example 2 Preparation of tert-butyl-4- {2-G4- (2.3-dichlorophenyl) piperazin-1-yl1 ethyl) piperidin-1-carboxylate (5).

A mixture of tert-butyl 4- {2 - [(methylsulfonyl) oxy] ethyl} piperidine-1-carboxylate (0.50 g, 1.74 mmol), 1- (2,3-dichlorophenyl) piperazine hydrochloride (0.46 g, 1.74 mmol) and carbonate potassium (0.50 g, 3.62 mmol) in acetonitrile (250 ml) was stirred at the boil (81.6 ° C) for 72 hours. The completeness of the reaction is monitored by HPLC. The reaction mixture is cooled, the precipitate formed is filtered off, washed successively with water, then with diethyl ether and dried for 6 hours at 100 ° C. 0.50 g of tert-butyl-4- {2- [4- (2,3-dichlorophenyl) piperazin-1-yl] ethyl} piperidin-1-carboxylate are obtained in the form of a beige crystalline solid, yield 65%.

1H NMR spectrum (400 MHz, DMSO-db, d, ppm, J / Hz): 7.34-7.26 (m, 2H), 7.14 (dd, 1H, L = 2.6 Hz, J2 = 6.7 Hz), 3.92 (d, 2H, JM2.5 Hz), 3.04-2.92 (m, 4H), 2.78-2.61 (m, 2H), 2.57-2.51 (m, 4H), 2.37 (t, 2H, J = 7.0 Hz), 1.64 (d, 2H, J = 12.1 Hz), 1.53-1.41 (m, 3H), 1.39 (s, 9H), 1.07 - 0.92 (m, 2H).

HPLC-MS, [M + H] 443.4.

Example 3. Obtaining 1- (2,3-dichlorophenyl) -4- (2-piperidin-4-yl) ethyl piperazine

(61

To a mixture of methanol (10 ml), water (10 ml) and concentrated hydrochloric acid (10 ml), tert-butyl-4- {2- [4- (2,3-dichlorophenyl) piperazin-1-yl] ethyl is added in small portions. } piperidine-1-carboxylate (0.50 g, 1.13 mmol). Then the reaction mixture is stirred at the boil for 0.5 hours. The extent of the reaction is monitored by HPLC. After completion of the reaction, methanol was distilled off under reduced pressure, 10 g of ice was added to the residue, then alkalized with 3M NaOH (16 ml) to pH = 10. The product precipitates as a light brown oil, which begins to crystallize after 15 minutes. Stirring is continued for 4 hours, the precipitate is filtered, dried on the filter for 12 hours. 0.38 g (95%) of 1- (2,3-dichlorophenyl) -4- (2-piperidin-4-yl-ethyl) piperazine are obtained in the form of a beige powder.

1H NMR spectrum (400 MHz, DMSO-db, d, ppm, J / Hz): 7.37-7.24 (m, 2 N), 7.21-7.08 (m, 1 N), 3.06-2.81 (m, 8H ), 2.45-2.28 (m, 6 N), 1.65-1.51 (m, 2 N), 1.44-1.27 (m, 3 N), 1.09-0.91 (m, 2 N).

HPLC-MS, [M + H] 343.3.

Example 4. Preparation of 4- ( ^' 2-G4 - (' 2.3-dichlorophenyl piperazin-1-yl ethyl) - methylpiperidin-1-carboxamide (1).

To a mixture of 1- (2,3-dichlorophenyl) -4- (2-piperidin-4-yl-ethyl) piperazine (0.38 g, 1.12 mmol) and triethylamine (0.12 g, 1.23 mmol) in acetonitrile (10 ml), cooled to 0 ° C, N-methylcarbamoyl chloride (0.12 g, 1.23 mmol) in acetonitrile (5 ml) was added dropwise with stirring, after which the reaction mixture was stirred at room temperature for 2 hours. The precipitate formed is filtered off, washed successively with water (20 ml), hexane (20 ml), dried on the filter for 1 hour. The resulting precipitate was dissolved in 10 ml of ethanol and passed through a layer of celite (1 cm), celite was washed with 5 ml of ethanol. The combined ethanol filtrates were evaporated under reduced pressure to a volume of 50 ml. After 5 minutes, the product begins to crystallize. Stirring is continued for another 1 h, the precipitate is filtered, dried at 70 ° C for 24 hours. Obtain 0.24 g (53%) of 4- {2- [4- (2,3-dichlorophenyl) piperazin-1-yl] ethyl} -L ^? - methylpiperidin-1-carboxamide in the form of a white powder.

1H NMR spectrum (400 MHz, DMSO-db, d, ppm, J / Hz): 7.33-7.27 (m, 2H), 7.14 (dd, 1H, L = 3.1 Hz, J2 = 6.7 Hz), 6.30 (dd, 1H, L = 4.5 Hz, J2 = 8.8 Hz), 3.89 (d, 2H, J = l3.0 Hz), 3.01-2.94 (m, 4H), 2.65-2.56 (m, 6H), 2.54 ( d, 3H, J = 4.3 Hz), 2.36 (t, 2H, J = 7.2 Hz), 1.62 (d, 2H, J = 11.9 Hz), 1.50-1.34 (m, 3H), 1.05-0.92 (m, 2H )

HPLC-MS, [M + H] 399.2 / 403.4.

Example 5. X-ray diffraction study of the compounds of formula 1

An X-ray diffraction study of compound 1 was carried out on a Bruker APEX II diffractometer (MoKα radiation, graphite monochromator, w-scan. Structures were decoded by the direct method and refined by least squares _analysis in the anisotropic full-matrix approximation in F ² _hki - Hydrogen atoms were calculated geometrically and refined with restrictions on bond lengths CH and their isotropic displacement parameters - Basic crystallographic data and refinement parameters are presented in table. 1. All calculations were performed using the SHELXL ¹ , SHELXT, and OLEX-2 programs. The general view of the molecule is shown in Fig. 1-2.

Table 1. Crystallographic data of the compounds of formula 1.

Gross formula Ci9H ₂₈ Cl ₂ N ₄ 0

Molecular Weight of 399.35

T, K 120

Triclinic crystal system

Space group P-1

Z 4

a, A 10.0869 (4)

b, A 11.9244 (5)

c, A 16.6199 (6)

a, ° 96.6570 (10)

b, ° 99.6200 (10)

Y> ° 94.9860 (10)

v, A ³ 1946.08 (13)

d _Bbi4 , G-cm ^'3 1.363

m, cm ^'1 3.5

F (000) 848

fifty

The number of measured reflections 31678

The number of independent reflections 10368

Number of reflections with 1> 2 (1) 8580

Number of specified parameters 479

R1 0.0331

wR2 0.0864

GOF 0.998

Residual electron density, eA

0.329 / -0.227

(dm in / dmax) Table 2. Atomic coordinates (x 10 ^) and equivalent isotropic displacement parameters

for the compound of formula 1. U (eq) is defined as one third of the orthoganalized UU tensor

X Y z U (eq)

C1 (1B) 5602 (1) 10022 (1) 7229 (1) 20 (1)

Cl (2B) 7237 (1) 9204 (1) 8777 (1) 26 (1)

O (lB) -3458 (1) 7456 (1) 576 (1) 20 (1)

N (1B) -1310 (1) 7388 (1) 365 (1) 17 (1)

N (2B) -1910 (1) 8985 (1) 1119 (1) 15 (1)

N (3B) 2008 (1) 8553 (1) 4638 (1) 15 (1)

N (4B) 3367 (1) 8341 (1) 6269 (1) 15 (1)

C (lB) -1614 (1) 6253 (1) -83 (1) 22 (1)

C (2B) -2278 (1) 7915 (1) 683 (1) 15 (1)

C (3B) -2697 (1) 9329 (1) 1756 (1) 18 (1)

C (4B) -2135 (1) 8906 (1) 2564 (1) 16 (1)

C (5B) -618 (1) 9292 (1) 2859 (1) 15 (1)

C (6B) 167 (1) 9036 (1) 2153 (1) 16 (1)

C (7B) -488 (1) 9459 (1) 1365 (1) 17 (1)

C (8B) -72 (1) 8725 (1) 3611 (1) 16 (1)

C (9B) 1342 (1) 9236 (1) 4044 (1) 18 (1)

C (10B) 1280 (1) 8453 (1) 5322 (1) 17 (1)

C (11B) 2000 (1) 7775 (1) 5949 (1) 18 (1) C (12V)

C (13B) 3390 (1) 9077 (1) 4963 (1) 16 (1)

C (14B) 4086 (1) 7959 (1) 6973 (1) 14 (1)

C (15B) 3728 (1) 6918 (1) 7229 (1) 19 (1)

C (16B) 4432 (1) 6593 (1) 7941 (1) 23 (1)

C (17B) 5527 (1) 7284 (1) 8413 (1) 21 (1)

C (18B) 5900 (1) 8322 (1) 8167 (1) 17 (1)

C (19B) 5184 (1) 8671 (1) 7466 (1) 15 (1)

Cl (lA) 10180 (1) 4562 (1) 6218 (1) 23 (1)

Cl (2A) 11677 (1) 4367 (1) 7996 (1) 24 (1)

0 (1 A) 1520 (1) 7870 (1) 371 (1) 19 (1)

N (1A) 3675 (1) 7853 (1) 158 (1) 19 (1)

N (2A) 2788 (1) 6567 (1) 939 (1) 16 (1) Table 2 (continued). Atomic coordinates (x 10 ^) and equivalent isotropic displacement parameters (A ^ x 10 ^) for the compound of formula 1. U (eq) is defined as one third of the orthoganalized Ш tensor

N (3A) 6260 (1) 6327 (1) 4709 (1) 15 (1)

N (4A) 8360 (1) 6385 (1) 6117 (1) 15 (1)

C (lA) 3507 (1) 8696 (1) -406 (1) 23 (1)

C (2A) 2620 (1) 7463 (1) 494 (1) 15 (1)

C (3A) 1908 (1) 6383 (1) 1539 (1) 16 (1)

C (4A) 2606 (1) 6904 (1) 2407 (1) 16 (1)

C (5A) 3962 (1) 6428 (1) 2643 (1) 15 (1)

C (6A) 4836 (1) 6608 (1) 1989 (1) 15 (1)

C (7A) 4079 (1) 6094 (1) 1 137 (1) 16 (1)

C (8A) 4694 (1) 6897 (1) 3514 (1) 16 (1)

C (9A) 5828 (1) 6187 (1) 3810 (1) 17 (1)

C (lOA) 7279 (1) 7307 (1) 4991 (1) 18 (1)

C (l lA) 7797 (1) 7428 (1) 5916 (1) 18 (1)

C (l2A) 7283 (1) 5429 (1) 5876 (1) 18 (1)

C (13A) 6805 (1) 5292 (1) 4957 (1) 17 (1)

C (l4A) 9139 (1) 6398 (1) 6905 (1) 15 (1)

C (l5A) 9136 (1) 7234 (1) 7567 (1) 20 (1)

C (l6A) 9919 (2) 7200 (1) 8333 (1) 22 (1)

C (l7A) 10701 (1) 6319 (1) 8469 (1) 21 (1)

C (l8A) 10720 (1) 5483 (1) 7821 (1) 17 (1)

C (l9A) 9988 (1) 5533 (1) 7038 (1) 15 (1)

Table 3. The bond lengths [A] and the angles between bonds [°] for the compounds of formula 1.

C1 (1V) -C (19V) 1.7359 (13)

C1 (2V) -C (18V) 1.7328 (13)

0 (1V) -C (2V) 1.2413 (15)

N (lB) -C (2B) 1.3531 (16)

N (lB) -C (lB) 1.4481 (17)

N (1B) -H (1B) 0.829 (18)

N (2B) -C (2B) 1.3805 (16)

N (2B) -C (3B) 1.4676 (16)

N (2B) -C (7B) 1.4678 (16)

N (3B) -C (l3B) 1.4637 (15)

N (3B) -C (l0B) 1.4646 (16)

N (3B) -C (9B) 1.4653 (16)

N (4B) -C (l4B) 1.4142 (15)

N (4B) -C (l 1B) 1.4660 (15)

N (4B) -C (l2B) 1.4757 (16)

C (lB) -H (lBA) 0.9800

C (1B) -H (1BB) 0.9800

C (lB) -H (lBC) 0.9800

C (3B) -C (4B) 1.5282 (17)

C (3B) -H (3BA) 0.9900

C (3B) -H (3BB) 0.9900

C (4B) -C (5B) 1.5384 (17)

C (4B) -H (4BA) 0.9900

C (4B) -H (4BB) 0.9900

C (5B) -C (8B) 1.5351 (17)

C (5B) -C (6B) 1.5376 (17)

C (5B) -H (5B) 1.0000

C (6B) -C (7B) 1.5259 (17)

C (6B) -H (6BA) 0.9900

C (6B) -H (6BB) 0.9900

C (7B) -H (7BA) 0.9900

C (7B) -H (7BB) 0.9900

C (8B) -C (9B) 1.5252 (17)

C (8B) -H (8BA) 0.9900

C (8B) -H (8BB) 0.9900

C (9B) -H (9BA) 0.9900 Table 3 (continued). The bond lengths [A] and the angles between the bonds [°] for the compounds of formula 1.

C (9B) -H (9BB) 0.9900

C (10V) -C (11V) 1.5195 (17)

C (10V) -H (10A) 0.9900

C (10V) -H (10V) 0.9900

C (11B) -H (11A) 0.9900

C (11V) -H (11V) 0.9900

C (12V) -C (13V) 1.5140 (17)

C (12V) -H (12A) 0.9900

C (12V) -H (12V) 0.9900

C (13B) -H (13A) 0.9900

C (13V) -H (13V) 0.9900

C (14V) -C (15V) 1.3957 (18)

C (14V) -C (19V) 1.4106 (17)

C (15V) -C (16V) 1.3899 (19)

C (15V) -H (15V) 0.9500

C (16V) -C (17V) 1.384 (2)

C (16V) -H (16V) 0.9500

C (17V) -C (18V) 1.3885 (19)

C (17V) -H (17V) 0.9500

C (18V) -C (19V) 1.3903 (17)

C1 (1A) -C (19A) 1.7318 (13)

C1 (2A) -C (18A) 1.7337 (13)

0 (1 A) -C (2A) 1.2442 (15)

N (lA) -C (2A) 1.3534 (16)

N (lA) -C (lA) 1.4530 (17)

N (1A) -H (1A) 0.848 (17)

N (2A) -C (2A) 1.3759 (17)

N (2A) -C (3A) 1.4632 (16)

N (2A) -C (7A) 1.4662 (15)

N (3A) -C (lOA) 1.4650 (16)

N (3A) -C (l3A) 1.4677 (16)

N (3A) -C (9A) 1.4714 (16)

N (4A) -C (l4A) 1.4076 (16)

N (4A) -C (11 A) 1.4616 (16)

N (4A) -C (l2A) 1.4742 (16)

C (lA) -H (lAA) 0.9800 Table 3 (continued). The bond lengths [A] and the angles between the bonds [°] for the compounds of formula 1.

C (l A) -H (l AB) 0.9800

C (1A) -H (1AC) 0.9800

C (3A) -C (4A) 1.5304 (17)

C (3A) -H (3AA) 0.9900

C (3A) -H (3AB) 0.9900

C (4A) -C (5A) 1.5343 (17)

C (4A) -H (4AA) 0.9900

C (4A) -H (4AB) 0.9900

C (5A) -C (8A) 1.5288 (17)

C (5A) -C (6A) 1.5318 (17)

C (5A) -H (5A) 1.0000

C (6A) -C (7A) 1.5238 (17)

C (6A) -H (6AA) 0.9900

C (6A) -H (6AB) 0.9900

C (7A) -H (7AA) 0.9900

C (7A) -H (7AB) 0.9900

C (8A) -C (9A) 1.5314 (17)

C (8A) -H (8AA) 0.9900

C (8A) -H (8AB) 0.9900

C (9A) -H (9AA) 0.9900

C (9A) -H (9AB) 0.9900

C (10A) -C (11A) 1.5248 (18)

C (10A) -H (10C) 0.9900

C (l0A) -H (l0D) 0.9900

C (l lA) -H (l lC) 0.9900

C (l lA) -H (l lD) 0.9900

C (12A) -C (13A) 1.5069 (18)

C (12A) -H (12C) 0.9900

C (l2A) -H (l2D) 0.9900

C (13A) -H (13C) 0.9900

C (l3A) -H (l3D) 0.9900

C (14A) -C (15A) 1.3974 (18)

C (14A) -C (19A) 1.4110 (17)

C (15A) -C (16A) 1.3892 (19)

C (15A) -H (15A) 0.9500

C (16A) -C (17A) 1.3844 (19) Table 3 (continued). The bond lengths [A] and the angles between the bonds [°] for the compounds of formula 1.

C (16A) -H (16A) 0.9500

C (17A) -C (18A) 1.3837 (19)

C (17A) -H (17A) 0.9500

C (18A) -C (19A) 1.3945 (18)

C (2B) -N (l V) -C (1 V) 120.66 (11)

C (2B) -N (l B) -H (lB) 121.9 (12)

C (1 B) -N (1 V) -H (1 V) 117.3 (12)

C (2B) -N (2B) -C (3B) 1 16.68 (10)

C (2B) -N (2B) -C (7B) 121.70 (10)

C (3B) -N (2B) -C (7B) 111.06 (10)

C (l3B) -N (3B) -C (l0B) 109.14 (10)

C (l3B) -N (3B) -C (9B) 109.41 (10)

C (l0B) -N (3B) -C (9B) 1 1 1.75 (10)

C (l4B) -N (4B) -C (l 1B) 116.69 (10)

C (l4B) -N (4B) -C (l2B) 1 14.72 (10)

C (l lB) -N (4B) -C (l2B) 109.10 (10)

N (1 B) -C (l B) -H (1 BA) 109.5

N (lB) -C (lB) -H (lBB) 109.5

H (1VA) -C (1B) -H (1BB) 109.5

N (1 B) -C (1 B) -H (1 BC) 109.5

H (1VA) -C (1B) -H (1BC) 109.5

H (1BB) -C (1B) -H (1BB) 109.5

0 (1 B) -C (2B) -N (1 B) 121.03 (12)

0 (1B) -C (2B) -N (2B) 121.32 (1 1)

N (lB) -C (2B) -N (2B) 1 17.64 (1 1)

N (2B) -C (3B) -C (4B) 1 10.56 (10)

N (2B) -C (3B) -H (3BA) 109.5

C (4B) -C (3B) -H (3BA) 109.5

N (2B) -C (3B) -H (3BB) 109.5

C (4B) -C (3B) -H (3BB) 109.5

H (3BA) -C (3B) -H (3BB) 108.1

C (3B) -C (4B) -C (5B) 1 12.59 (10)

C (3B) -C (4B) -H (4BA) 109.1

C (5B) -C (4B) -H (4BA) 109.1

C (3B) -C (4B) -H (4BB) 109.1 Table 3 (continued). The bond lengths [A] and the angles between the bonds [°] for the compounds of formula 1.

C (5B) -C (4B) -H (4BB) 109.1

H (4BA) -C (4B) -H (4BB) 107.8

C (8B) -C (5B) -C (6B) 111.54 (10)

C (8B) -C (5B) -C (4B) 110.26 (10)

C (6V) -C (5V) -C (4V) 110.34 (10)

C (8V) -C (5V) -H (5V) 108.2

C (6V) -C (5V) -H (5V) 108.2

C (4V) -C (5V) -H (5V) 108.2

C (7V) -C (6V) -C (5V) 111.82 (10)

C (7V) -C (6V) -H (6VA) 109.3

C (5V) -C (6V) -H (6VA) 109.3

С (7В) -С (6В) -Н (6ВВ) 109.3

С (5В) -С (6В) -Н (6ВВ) 109.3

N (6VA) -C (6V) -H (6VV) 107.9

N (2B) -C (7B) -C (6B) 111.17 (10)

N (2B) -C (7B) -H (7BA) 109.4

C (6V) -C (7V) -H (7VA) 109.4

N (2B) -C (7B) -H (7BB) 109.4

C (6B) -C (7B) -H (7BB) 109.4

H (7VA) -C (7V) -H (7VV) 108.0

C (9V) -C (8V) -C (5V) 113.46 (10)

C (9V) -C (8V) -H (8VA) 108.9

C (5V) -C (8V) -H (8VA) 108.9

С (9В) -С (8В) -Н (8ВВ) 108.9

С (5В) -С (8В) -Н (8ВВ) 108.9

N (8VA) -C (8V) -H (8VV) 107.7

N (3B) -C (9B) -C (8B) 114.31 (10)

N (3B) -C (9B) -H (9BA) 108.7

C (8V) -C (9V) -H (9VA) 108.7

N (3B) -C (9B) -H (9BB) 108.7

С (8В) -С (9В) -Н (9ВВ) 108.7

N (9VA) -C (9V) -H (9VV) 107.6

N (3B) -C (lOB) -C (l lB) 1 11.44 (10)

N (3 V) -C (10 V) -H (10 A) 109.3

C (1 1B) -C (10V) -H (10A) 109.3

N (3B) -C (10B) -H (10B) 109.3 Table 3 (continued). The bond lengths [A] and the angles between the bonds [°] for the compounds of formula 1.

C (11V) -C (10V) -H (10V) 109.3

H (10A) -C (10V) -H (10V) 108.0

N (4B) -C (l 1V) -C (10V) 109.11 (10)

N (4B) -C (l 1B) -H (11 A) 109.9

C (10V) -C (11B) -H (11A) 109.9

N (4B) -C (l 1B) -H (11B) 109.9

C (10V) -C (11V) -H (11V) 109.9

H (11A) -C (1 1B) -H (11B) 108.3

N (4B) -C (l2B) -C (l3B) 109.22 (10)

N (4B) -C (l2B) -H (l2A) 109.8

C (13V) -C (12V) -H (12A) 109.8

N (4B) -C (l2B) -H (l2B) 109.8

C (13V) -C (12V) -H (12V) 109.8

H (12A) -C (12V) -H (12V) 108.3

N (3B) -C (l3B) -C (l2B) 111.18 (10)

N (3B) -C (l3B) -H (l3A) 109.4

C (12V) -C (1B) -H (13A) 109.4

N (3B) -C (l3B) -H (l3B) 109.4

C (12V) -C (13V) -H (13V) 109.4

H (13A) -C (13B) -H (13B) 108.0

C (15V) -C (14V) -C (19V) 117.63 (11)

C (15V) -C (14B) -N (4B) 122.95 (11)

C (19B) -C (14B) -N (4B) 119.37 (11)

C (16V) -C (15V) -C (14V) 121.09 (12)

C (16V) -C (15V) -H (15V) 119.5

C (14V) -C (15V) -H (15V) 119.5

С (17В) -С (16В) -С (15В) 121.00 (13)

C (17V) -C (16V) -H (16V) 119.5

C (15V) -C (16V) -H (16V) 1 19.5

C (16V) -C (17V) -C (18V) 118.66 (12)

C (16V) -C (17V) -H (17V) 120.7

C (18V) -C (17V) -H (17V) 120.7

C (17V) -C (18V) -C (19V) 120.99 (12)

С (17В) -С (18В) -С1 (2В) 1 18.49 (10)

С (19В) -С (18В) -С1 (2В) 120.46 (10)

С (18В) -С (19В) -С (14В) 120.59 (12) Table 3 (continued). The bond lengths [A] and the angles between the bonds [°] for the compounds of formula 1.

C (18V) -C (19V) -C1 (1 V) 119.30 (10)

С (14В) -С (19В) -С1 (1 В) 120.04 (10)

C (2 A) -N (1 A) -C (1 A) 120.24 (11)

C (2 A) -N (1 A) -H (1 A) 122.2 (12)

C (1 A) -N (1 A) -H (1 A) 117.2 (12)

C (2A) -N (2A) -C (3A) 118.68 (10)

C (2A) -N (2A) -C (7A) 123.58 (10)

C (3A) -N (2A) -C (7A) 112.41 (10)

C (l0A) -N (3A) -C (l3A) 109.95 (10)

C (l0A) -N (3A) -C (9A) 111.24 (10)

C (13 A) -N (3 A) -C (9A) 109.67 (10)

C (l4A) -N (4A) -C (l 1 A) 118.07 (10)

C (14A) -N (4 A) -C (12A) 114.26 (10)

C (l 1 A) -N (4A) -C (l2A) 108.67 (10)

N (lA) -C (lA) -H (lAA) 109.5

N (1A) -C (1A) -H (1AB) 109.5

H (1 A A) -C (1 A) -H (1 AB) 109.5

N (1A) -C (1 A) -H (1 AC) 109.5

H (1 A A) -C (1 A) -H (1 AC) 109.5

H (1 AB) -C (1 A) -H (1 AC) 109.5

0 (1 A) -C (2 A) -N (1 A) 121.00 (12)

0 (1 A) -C (2A) -N (2A) 121.33 (11)

N (1 A) -C (2 A) -N (2 A) 117.60 (11)

N (2A) -C (3A) -C (4A) 110.94 (10)

N (2A) -C (3A) -H (3AA) 109.5

C (4A) -C (3A) -H (3AA) 109.5

N (2A) -C (3A) -H (3AB) 109.5

C (4A) -C (3A) -H (3AB) 109.5

H (3AA) -C (3A) -H (3AB) 108.0

C (3A) -C (4A) -C (5A) 110.63 (10)

C (3 A) -C (4 A) -H (4 A A) 109.5

C (5A) -C (4A) -H (4AA) 109.5

C (3A) -C (4A) -H (4AB) 109.5

C (5A) -C (4A) -H (4AB) 109.5

H (4AA) -C (4A) -H (4AB) 108.1

C (8A) -C (5A) -C (6A) 112.66 (10) Table 3 (continued). The bond lengths [A] and the angles between the bonds [°] for the compounds of formula 1.

C (8A) -C (5A) -C (4A) 113.08 (10)

C (6A) -C (5A) -C (4A) 109.52 (10)

C (8A) -C (5A) -H (5A) 107.1

C (6A) -C (5A) -H (5A) 107.1

C (4A) -C (5A) -H (5A) 107.1

C (7A) -C (6A) -C (5A) 110.62 (10)

C (7A) -C (6A) -H (6AA) 109.5

C (5A) -C (6A) -H (6AA) 109.5

C (7A) -C (6A) -H (6AB) 109.5

C (5 A) -C (6 A) -H (6 AB) 109.5

H (6AA) -C (6A) -H (6AB) 108.1

N (2A) -C (7A) -C (6A) 111.02 (10)

N (2A) -C (7A) -H (7AA) 109.4

C (6A) -C (7A) -H (7AA) 109.4

N (2A) -C (7A) -H (7AB) 109.4

C (6A) -C (7A) -H (7AB) 109.4

H (7 A A) -C (7 A) -H (7 AB) 108.0

C (5A) -C (8A) -C (9A) 111.37 (10)

C (5A) -C (8A) -H (8AA) 109.4

C (9A) -C (8A) -H (8AA) 109.4

C (5A) -C (8A) -H (8AB) 109.4

C (9A) -C (8A) -H (8AB) 109.4

H (8AA) -C (8A) -H (8AB) 108.0

N (3A) -C (9A) -C (8A) 114.17 (10)

N (3A) -C (9A) -H (9AA) 108.7

C (8A) -C (9A) -H (9AA) 108.7

N (3A) -C (9A) -H (9AB) 108.7

C (8A) -C (9A) -H (9AB) 108.7

H (9AA) -C (9A) -H (9AB) 107.6

N (3A) -C (l0A) -C (l 1A) 111.99 (10)

N (3A) -C (l0A) -H (l0C) 109.2

C (11 A) -C (10 A) -H (1 OS) 109.2

N (3A) -C (l0A) -H (10D) 109.2

C (11 A) -C (10A) -H (10D) 109.2

H (10C) -C (10 A) -H (10D) 107.9

N (4A) -C (l lA) -C (10A) 108.89 (10) Table 3 (continued). The bond lengths [A] and the angles between the bonds [°] for the compounds of formula 1.

N (4 A) -C (11 A) -H (11 C) 109.9

C (10A) -C (11 A) -H (l 1C) 109.9

N (4A) -C (l 1 A) -H (l 1D) 109.9

C (10 A) -C (11 A) -H (11 D) 109.9

H (11C) -C (11A) -H (1 W) 108.3

N (4A) -C (l2A) -C (l3A) 109.47 (10)

N (4A) -C (l2A) -H (l2C) 109.8

C (13A) -C (12A) -H (12C) 109.8

N (4 A) -C (12 A) -H (12D) 109.8

C (13 A) -C (12 A) -H (12D) 109.8

H (12C) -C (12 A) -H (12D) 108.2

N (3 A) -C (13 A) -C (12A) 110.47 (10)

N (3A) -C (l3A) -H (l3C) 109.6

C (12A) -C (13A) -H (13C) 109.6

N (3A) -C (13A) -H (13D) 109.6

C (12A) -C (13 A) -H (13D) 109.6

H (13C) -C (13A) -H (13D) 108.1

C (15 A) -C (14A) -N (4A) 123.63 (11)

C (15 A) -C (14A) -C (19A) 117.56 (11)

N (4 A) -C (14 A) -C (19 A) 118.80 (11)

C (16 A) -C (15 A) -C (14 A) 121.14 (12)

C (16 A) -C (15 A) -H (15 A) 119.4

C (14A) -C (15A) -H (15 A) 119.4

C (17A) -C (16A) -C (15 A) 120.87 (12)

C (17 A) -C (16 A) -H (16A) 119.6

C (15 A) -C (16 A) -H (16 A) 119.6

C (18A) -C (17A) -C (16A) 118.88 (12)

C (18 A) -C (17A) -H (17A) 120.6

C (16A) -C (17A) -H (17A) 120.6

C (17A) -C (18 A) -C (19A) 120.94 (12)

C (17A) -C (18A) -C1 (2A) 118.84 (10)

C (19A) -C (18A) -C1 (2A) 120.22 (10)

C (18 A) -C (19A) -C (14A) 120.44 (11)

C (18 A) -C (19A) -C1 (1 A) 119.66 (10)

C (14 A) -C (19A) -C1 (1 A) 119.85 (9) To generate equivalent atoms, symmetry transformations were used.

Table 4. Anisotropic substitution Parameters (A ² x U ³⁾ for a compound of formula 1. Factor anisotropic exponential substitution taken from: -2D ² [h ² a * ² ljl 1 + 2 + ... hk a * b * Xjl2] and ^{1 1} and ²² and ³³ and ²³ and ¹³ and ¹²

C1 (1B) 21 (1) 17 (1) 23 (1) 3 (1) 2 (1) -3 (1)

C1 (2B) 19 (1) 34 (1) 19 (1) 0 (1) -3 (1) -4 (1)

0 (1B) 10 (1) 27 (1) 22 (1) 2 (1) S) -1 (1)

N (1B) 11 (1) 20 (1) 18 (1) -2 (1) 2 (1) 0 (1)

N (2B) 13 (1) 18 (1) 15 (1) 2 (1) 2 (1) 3 (1)

N (3B) 13 (1) 17 (1) 14 (1) 4 (1) 1 (1) 2 (1)

N (4B) 12 (1) 18 (1) 13 (1) 4 (1) 2 (1) 0 (1)

C (1B) 20 (1) 22 (1) 22 (1) -3 (1) 2 (1) 3 (1)

C (2B) 13 (1) 20 (1) 12 (1) 6 (1) 0 (1) 3 (1)

C (ST) 16 (1) 22 (1) 17 (1) 3 (1) 5 (1) 8 (1)

C (4B) 14 (1) 20 (1) 16 (1) 3 (1) 2 (1) 4 (1)

C (5B) 16 (1) 14 (1) 15 (1) 2 (1) 2 (1) 2 (1)

C (6B) 12 (1) 19 (1) 16 (1) 1 (1) 2 (1) 1 (1)

C (7B) 17 (1) 16 (1) 17 (1) 3 (1) 3 (1) -2 (1)

C (8B) 16 (1) 16 (1) 16 (1) 4 (1) 1 (1) 1 (1)

C (9B) 17 (1) 18 (1) 17 (1) 5 (1) 0 (1) 0 (1)

C (10V) 12 (1) 21 (1) 18 (1) 5 (1) 2 (1) 1 (1)

C (11B) 14 (1) 20 (1) 18 (1) 6 (1) 2 (1) -2 (1)

C (12V) 14 (1) 22 (1) 14 (1) 2 (1) 3 (1) 3 (1)

C (13B) 14 (1) 19 (1) 16 (1) 4 (1) 2 (1) 0 (1)

C (14B) 13 (1) 16 (1) 14 (1) 2 (1) 4 (1) 3 (1)

C (15V) 19 (1) 16 (1) 21 (1) 3 (1) 0 (1) -1 (1)

C (16B) 26 (1) 19 (1) 24 (1) 8 (1) 3 (1) 2 (1)

C (17B) 22 (1) 25 (1) 17 (1) 6 (1) 1 (1) 6 (1)

C (18B) 14 (1) 23 (1) 14 (1) -1 (1) 2 (1) 2 (1)

C (19B) 15 (1) 14 (1) 16 (1) 1 (1) 4 (1) 2 (1)

C1 (1A) 29 (1) 22 (1) 20 (1) 0 (1) 6 (1) 10 (1)

C1 (2A) 21 (1) 26 (1) 28 (1) 9 (1) 2 (1) 9 (1) Table 4 (continued). Parameters anisotropic substitution (A ² x U ²⁾ for compounds of formula 1. Factor anisotropic exponential substitution taken from: -2 □ ² [h ²

Table 5. Hydrogen coordinates (x 10 ^) and isotropic substitution parameters (A ² x 10 2) for the compound of formula 1.

1B) -515 (18) 7680 (15) 440 (1 1) 29 (5)

N (1VA) -1958 6298 -664 33 Table 5 (continued). Hydrogen coordinates (x 10 ^) and isotropic substitution parameters (A ^ x 10 3) for the compound of formula 1.

N (1BB) -2300 5824 148 33

N (1BC) -790 5868 -35 33

N (SVA) -3654 9012 1571 21

N (ZVV) -2662 10167 1843 21

N (4VA) -2279 8066 2491 19

N (4BB) -2641 9191 2994 19

N (5V) -507 10133 3027 18

N (6VA) 1107 9405 2322 19

N (6BB) 204 8 207 2045 19

N (7VA) -432 10299 1454 20

N (7BB) 12 9237 918 20

N (8VA) -699 8794 4009 20

N (8BB) -52 7906 3433 20

N (9VA) 1913 9337 3623 21

N (9BB) 1279 9997 4335 21

N (10A) 355 8075 5106 20

N (10V) 1201 9221 5596 20

H (1 1A) 1491 7723 6405 21

H (11B) 2051 6996 5685 21

H (12A) 4173 7623 5315 20

N (12V) 5047 8767 5793 20

H (13A) 3363 9859 5229 20

H (13B) 3895 9123 4503 20

H (15V) 2990 6423 6910 23

H (16V) 4158 5886 8108 28

H (17B) 6013 7053 8895 26

H (1A) 4470 (18) 7683 (14) 307 (10) 28 (4)

H (1AA) 3017 8331 -944 34

H (1AB) 4398 9041 -464 34

H (1AC) 2994 9286 -188 34

N (ZAA) 1671 5558 1529 20

N (CAV) 1060 6731 1386 20

H (4AA) 2014 6734 2806 19

H (4AB) 2763 7740 2432 19

H (5A) 3759 5589 2629 18

H (6AA) 5081 7432 1995 18 zo Table 5 (continued). Hydrogen coordinates (x IO ^) and isotropic substitution parameters (A ^ x 10 3) for the compound of formula 1.

H (6AB) 5683 6251 2119 18

H (7AA) 4643 6249 721 19

H (7AB) 3908 5260 1118 19

H (8AA) 4037 6899 3895 20

H (8AB) 5081 7691 3522 20

H (9AA) 5518 5375 3614 21

H (9AB) 6619 6396 3555 21

H (lOC) 6881 8006 4853 21

H (lOD) 8049 7224 4697 21

H (l lC) 8502 8083 6082 21

H (l lD) 7046 7563 6217 21

H (l2C) 6518 5576 6162 22

H (l2D) 7633 4722 6037 22

H (l3C) 7569 5133 4673 21

H (l3D) 6095 4640 4793 21

H (l5A) 8589 7837 7492 23

H (l6A) 9917 7789 8770 27

Щ17А) 11217 6289 8998 25

Table 6. Torsion angles [°] for the compounds of formula 1.

C (1 B) -N (1 B) -C (2B) -0 (1 V) -2.52 (19)

C (1 B) -N (1 B) -C (2B) -N (2B) 178.54 (1 1)

C (3B) -N (2B) -C (2B) -0 (1 V) 28.32 (17)

C (7B) -N (2B) -C (2B) -0 (1 V) 169.86 (1 1)

C (3B) -N (2B) -C (2B) -N (lB) -152.74 (1 1)

C (7B) -N (2B) -C (2B) -N (1 V) -11.21 (17)

C (2B) -N (2B) -C (3B) -C (4B) 85.18 (13)

C (7B) -N (2B) -C (3B) -C (4B) -60.28 (13)

N (2B) -C (3B) -C (4B) -C (5B) 54.96 (14)

C (3B) -C (4B) -C (5B) -C (8B) -173.03 (10)

C (3B) -C (4B) -C (5B) -C (6B) -49.37 (14)

C (8B) -C (5B) -C (6B) -C (7B) 172.22 (10)

C (4B) -C (5B) -C (6B) -C (7B) 49.31 (14)

C (2B) -N (2B) -C (7B) -C (6B) -82.43 (14)

C (3B) -N (2B) -C (7B) -C (6B) 61.01 (13)

C (5B) -C (6B) -C (7B) -N (2B) -55.58 (14)

C (6B) -C (5B) -C (8B) -C (9B) 68.55 (14)

C (4B) -C (5B) -C (8B) -C (9B) -168.49 (10)

C (l3B) -N (3B) -C (9B) -C (8B) 175.46 (10)

C (lOB) -N (3B) -C (9B) -C (8B) -63.55 (14)

C (5B) -C (8B) -C (9B) -N (3B) -166.56 (10)

C (l3B) -N (3B) -C (l0B) -C (l 1B) -57.09 (13)

C (9B) -N (3B) -C (10B) -C (l 1B) -178.23 (10)

C (14B) -N (4B) -C (1 lB) -C (lOB) 167.81 (10)

C (l2B) -N (4B) -C (l lB) -C (lOB) -60.17 (13)

N (3B) -C (lOB) -C (l lB) -N (4B) 59.27 (14)

C (l4B) -N (4B) -C (l2B) -C (l3B) -166.39 (10)

C (1 1 B) -N (4B) -C (12B) -C (13B) 60.56 (13)

C (l OB) -N (3B) -C (l3B) -C (l2B) 57.26 (13)

C (9B) -N (3B) -C (13B) -C (12B) 179.82 (10)

N (4B) -C (l2B) -C (l 3B) -N (3B) -59.59 (13)

C (l 1 B) -N (4B) -C (14B) -C (15B) 17.60 (17)

C (l2B) -N (4B) -C (l4B) -C (l5B) -1 1 1.79 (13)

C (1 1 B) -N (4B) -C (14B) -C (19B) -159.65 (11)

C (12B) -N (4B) -C (14B) -C (19B) 70.96 (14)

C (19B) -C (14B) -C (15B) -C (16B) -0.28 (19) Table b (continued). Torsion angles [°] for the compound of formula 1.

N (4B) -C (l4B) -C (l 5B) -C (l6B) -177.57 (12)

C (14B) -C (15B) -C (16B) -C (17B) -1.1 (2)

C (15B) -C (16B) -C (17B) -C (18B) 1.0 (2)

С (16В) -С (17В) -С (18В) -С (19В) 0.6 (2)

C (16B) -C (17B) -C (18B) -Cl (2B) 177.97 (1 1)

С (17В) -С (18В) -С (19В) -С (14В) -2.09 (19)

C1 (2B) -C (18V) -C (19V) -C (14V) -179.36 (9)

C (17B) -C (18V) -C (19V) -C1 (1 V) 174.82 (10)

C1 (2V) -C (18V) -C (19V) -C1 (1 V) -2.45 (15)

С (15В) -С (14В) -С (19В) -С (18В) 1.87 (18)

N (4B) -C (l4B) -C (l 9B) -C (l 8B) 179.26 (1 1)

С (15В) -С (14В) -С (19В) -С1 (1 В) -175.02 (10)

N (4B) -C (14V) -C (19V) -C1 (1V) 2.38 (16)

C (1 A) -N (1 A) -C (2A) -0 (1 A) -4.81 (19)

C (1 A) -N (lA) -C (2A) -N (2A) 172.07 (1 1)

C (3 A) -N (2 A) -C (2 A) -0 (1 A) -24.56 (17)

C (7A) -N (2A) -C (2A) -0 (1 A) -176.77 (11)

C (3A) -N (2A) -C (2A) -N (lA) 158.57 (1 1)

C (7A) -N (2A) -C (2A) -N (1 A) 6.37 (18)

C (2A) -N (2A) -C (3A) -C (4A) -97.23 (13)

C (7A) -N (2A) -C (3A) -C (4A) 57.92 (14)

N (2A) -C (3A) -C (4A) -C (5A) -56.13 (14)

C (3A) -C (4A) -C (5A) -C (8A) -178.69 (10)

C (3A) -C (4A) -C (5A) -C (6A) 54.78 (13)

C (8A) -C (5A) -C (6A) -C (7A) 178.20 (10)

C (4A) -C (5A) -C (6A) -C (7A) -55.02 (13)

C (2A) -N (2A) -C (7A) -C (6A) 95.51 (14)

C (3 A) -N (2 A) -C (7 A) -C (6 A) -58.22 (14)

C (5A) -C (6A) -C (7A) -N (2A) 56.58 (14)

C (6A) -C (5A) -C (8A) -C (9A) -70.23 (14)

C (4A) -C (5A) -C (8A) -C (9A) 164.92 (1 1)

C (lOA) -N (3A) -C (9A) -C (8A) -85.40 (13)

C (l 3 A) -N (3 A) -C (9A) -C (8A) 152.75 (1 1)

C (5A) -C (8A) -C (9A) -N (3A) -160.1 1 (10)

C (l3A) -N (3A) -C (l0A) -C (l lA) -55.15 (13)

C (9 A) -N (3 A) -C (10A) -C (1 1A) -176.84 (10)

C (l4A) -N (4A) -C (l 1 A) -C (lOA) 167.25 (10) Table b (continued). Torsion angles [°] for the compound of formula 1.

C (l2A) -N (4A) -C (l 1 A) -C (JA) -60.55 (13)

N (3A) -C (l 0 A) -C (1 1 A) -N (4A) 57.85 (14)

C (14 A) -N (4 A) -C (12 A) -C (13 A) -163.06 (10)

C (l 1 A) -N (4 A) -C (12 A) -C (1 WA) 62.74 (13)

C (10 A) -N (3 A) -C (13 A) -C (12 A) 56.07 (13)

C (9A) -N (3A) -C (l 3A) -C (l2A) 178.69 (10)

N (4 A) -C (12 A) -C (13 A) -N (3 A) -60.43 (13)

C (l 1 A) -N (4A) -C (l4A) -C (l 5A) 16.29 (18)

C (12 A) -N (4 A) -C (14A) -C (15 A) - 1 13.37 (14)

C (1 1 A) -N (4A) -C (14 A) -C (19 A) - 162.76 (1 1)

C (12 A) -N (4 A) -C (14A) -C (19A) 67.57 (15)

N (4A) -C (14 A) -C (15 A) -C (16A) 179.56 (12)

C (19A) -C (14A) -C (15A) -C (16A) -1.37 (19)

C (14A) -C (15 A) -C (16 A) -C (17 A) -1.6 (2)

C (15A) -C (16A) -C (17A) -C (18A) 1.6 (2)

C (16 A) -C (17 A) -C (18 A) -C (19 A) 1.3 (2)

C (16 A) -C (17 A) -C (18 A) -Cl (2 A) - 178.87 (10)

C (17 A) -C (18 A) -C (19 A) -C (14 A) -4.35 (19)

Cl (2 A) -C (18 A) -C (19 A) -C (14 A) 175.85 (10)

C (17A) -C (18A) -C (19A) -C1 (1A) 172.89 (10)

Cl (2A) -C (18 A) -C (19 A) -Cl (1 A) -6.91 (15)

C (15 A) -C (14A) -C (19A) -C (18 A) 4.28 (18)

N (4A) -C (14 A) -C (19 A) -C (18 A) - 176.61 (1 1)

C (15A) -C (14A) -C (19A) -C1 (1A) -172.95 (10)

N (4 A) -C (14 A) -C (19 A) -Cl (1 A) 6.16 (16)

To generate equivalent atoms, symmetry transformations were used.

Table 7. Hydrogen bonds in the compound of formula 1. [A and °].

D-H ... A d (D-H) d (H ... A) d (D ... A) <(DHA)

N (1A) -H (1A) ... 0 (1B) 0.848 (18) 2.1 1 1 (18) 2.9523 (15) 171.3 (16) Example 6. The study of in vitro activity.

The compound of formula 1 was tested for binding to the D2S (h) receptor and D3

(h) a receptor in the presence of ligands - [ ³ H] 7-OH-DPAT (1 nM, Kd 0.68 nM) and [3N] - methylspiperone (0.3 nM, Kd 0.085 nM), respectively, and a nonspecific binding inhibitor - butaclamol (10 μM) in the concentration range from OD nM to 1 μM in comparison with Kariprazin. The IC50 values for the compound of formula 1 were 6.2 and 7.2 nM with respect to the D2S and D3 receptors, respectively, and for Kariprazin, 110 and 3 nM, respectively. Thus, the same binding of the compound of formula 1 was observed with both types of receptors involved in the mechanism of development of bipolar disorder, which coincided in order with the lowest inhibitory concentration for Kariprazin, while for Kariprazin, the IC50s for two types of receptors were two orders of magnitude, which allows suggest a higher activity of the compounds of formula 1 compared with cariprazine.

Example 7. In vivo study of the antipsychotic activity of a compound of formula 1

The study was conducted on the models 1) apomorphine-induced stereotype (male Sprague Dawley rats), 2) apomorphine-induced hyperlocomotion (male C57B1 / 6 mice), 3) pre-stimulus inhibition (ICT) of the acoustic start-reflex (male C57B1 / 6 mice), 4) the conditioned reflex of passive avoidance (male Sprague Dawley rats) and 5) the cataleptogenic properties (male Sprague Dawley rats) in comparison with the typical Haloperidol and atypical Olanzapine antipsychotic drugs.

On the model of apomorphine-induced stereotypy in rats, it was shown that compound 1 at doses of 0.3 and 3 mg / kg reduced the severity of stereotypy 10 and 60 min after administration of apomorphine. At a dose of 10 mg / kg, the compound of formula 1 caused a decrease in the severity and throughout the observation period, lengthening the period of development and shortening the duration of stereotype. Moreover, the effect of the compound of formula 1 at a dose of 10 mg / kg on apomorphine-induced stereotype was comparable to the effect of the drug olanzapine at a dose of 10 mg / kg.

In a model of apomorphine-induced hyperactivity and hyperlocomotion, it was found that the compound of formula 1 in all doses studied (0.3, 1, 3 and 10 mg / kg), as well as olnazapine at a dose of 10 mg / kg and haloperidol at a dose of 1 mg / kg, caused a decrease in hyperlocomotion and hyperactivity.

In the rat horizontal rod test, the cataleptogenic properties of the compound of formula 1 at doses of 5, 20 and 40 mg / kg were revealed.

In the conditioned reflex of passive avoidance (passive avoidance reaction), learning and memory disorders after administration to rats of a compound of formula 1 at doses of 0.3, 1, 3, 10 mg / kg were not detected. Comparison preparations olanzapine at a dose of 10 mg / kg and haloperidol at a dose of 5 mg / kg caused memory impairment in rats, as evidenced by a decrease in the latent period of entry into the dark compartment when testing 22 hours after training.

Thus, the study showed the antipsychotic activity of the compound of formula 1 in in vivo models mimicking positive symptoms (aopomrfin-induced hyperactivity in mice and stereotyping in rats. Also, cataleptogenic properties were revealed, indicating extrapyramidal effects characteristic of typical antipsychotics. this compound of formula 1 in the studied doses did not have a worsening effect on conditioned reflex memory in rats.

Industrial applicability

The invention can be used in medicine and veterinary medicine.

Claims

Claim

1. Methylamide 4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl] ethyl} -piperidin-1-carboxylic acid of the formula 1

1

2. 4- {2- [4- (2,3-Dichlorophenyl) piperazin-1-yl] ethyl} -piperidin-1-carboxylic acid methylamide of formula 1 according to claim 1, having the properties of a partial dopamine D2 / D3 receptor agonist .

3. Methylamide of 4- {2- [4- (2, 3-Dichlorophenyl) piperazin-1-yl] ethyl} -piperidin-1-carboxylic acid of the formula 1 according to and. 1 or 2, as an active ingredient in an effective amount for the manufacture of a medicament for the treatment of a psychotic disorder.

4. A pharmaceutical composition for treating a psychotic disorder having the properties of a partial agonist of dopamine D2 / D3 receptors containing in a therapeutically effective amount a compound of formula 1 according to claim 1 and pharmaceutically acceptable additives.

5. The pharmaceutical composition according to claim 4, in which the compound of formula 1 is contained in an amount of from 1 to 30 mg. preferably from 1 to 2.5 mg.

6. The pharmaceutical composition according to claim 4, wherein the pharmaceutically acceptable additives are selected from the diluents of auxiliary agents and carriers used in the pharmaceutical field.

7. The pharmaceutical composition of claim 6, wherein the pharmaceutically acceptable additives are selected from potato starch, lactose monohydrate.

8. The pharmaceutical composition according to claim 7, characterized in gem. which contains potato starch in an amount of 30.5 - 32 mg, lactose monohydrate in an amount of 67 mg.

37

FIXED SHEET (RULE 91)

9. The pharmaceutical composition according to claim 4 for the treatment of a psychotic disorder, comprising:

- from 1 to 2.5 wt.% the compounds of formula 1,

- from 31 to 31, 5 wt.% potato starch,

- the rest of lactose monohydrate.

10. A method of treating a psychotic disorder by administering in a therapeutically effective amount of a compound of formula 1 according to claim 1 or a pharmaceutical composition according to any one of paragraphs 4 to 9 to a recipient in need thereof.