RU2730550C1 - 2-selenoxo-tetrahydro-4n-imidazol-4-one derivative, method for production and use thereof - Google Patents

Abstract

FIELD: chemistry.SUBSTANCE: invention relates to such fields of material science as bioorganic chemistry and molecular biology, namely to a compound which is 2-selenoxo-tetrahydro-4n-imidazol-4-one derivative of general formula 1 or its pharmaceutically acceptable salt, or optical isomer,where Ris phenyl, optionally substituted with 1–2 substitutes selected from a halogen atom, a lower alkoxy group, methyl, Ris phenyl optionally substituted with 1–2 substitutes selected from a halogen atom, a lower alkoxy group, cyano group, Rdenotes phenyl optionally substituted with 1 substituent selected from a halogen atom, a lower alkoxy group or methyl. Invention also discloses a method for synthesis of a compound of formula 1, an active component which is a compound of formula 1, use of the compound, a pharmaceutical composition, a medicinal agent and a method for preventing and treating oncological diseases.EFFECT: disclosed compounds have anti-tumour activity and can be used as active components for pharmaceutical compositions and medicinal agents for therapy of oncological diseases.20 cl, 1 tbl, 38 ex

Description

Technology area

This invention relates to the field of bioorganic chemistry, molecular biology and pharmaceuticals, and relates to the synthesis of a new family of biologically active substances - selenium-containing hydantoins, which can be used as active components for pharmaceutical compositions and drugs for the treatment of cancer.

State of the art

J; Pachl P;

L; Majer P; et al. Rational design of urea-based glutamate carboxypeptidase II (GCPII) inhibitors as versatile tools for specific drug targeting and delivery. Bioorganic Med Chem, 2014,22,4099-108]. Работы Хаггинса и Ходжеса впервые показали зависимость развития рака предстательной железы от экспрессии андрогенового рецептора [Figg WD; Chau CH; Small EJ. Drug Management of Prostate Cancer. New York, NY: Springer New York; 2010]. В настоящее время, терапия антиандрогеновыми препаратами является одной из основных разновидностей терапии онкологических патологий предстательной железы, наряду с гормональной терапией, хирургическим вмешательством, лучевой терапией и химиотерапией.Today, oncological diseases of the prostate gland are one of the most common causes of death among older men [Tykvart J; Schimer J;

J; Pachl P;

L; Majer P; et al. Rational design of urea-based glutamate carboxypeptidase II (GCPII) inhibitors as versatile tools for specific drug targeting and delivery. Bioorganic Med Chem, 2014, 22,4099-108]. The work of Huggins and Hodges first showed the dependence of the development of prostate cancer on the expression of the androgen receptor [Figg WD; Chau CH; Small EJ. Drug Management of Prostate Cancer. New York, NY: Springer New York; 2010]. At present, therapy with antiandrogen drugs is one of the main types of therapy for oncological pathologies of the prostate gland, along with hormonal therapy, surgery, radiation therapy and chemotherapy.

L;

L;

M;

E;

L;

Z; et al. Synthesis of and a comparative study on the inhibition of muscle and liver glycogen phosphorylases by epimeric pairs of D-gluco- and D-xylopyranosylidene-spiro-(thio)hydantoins and N-(D-glucopyranosyl) amides. J Med Chem, 2001,44,2843-8] и антиконвульсантной [Thenmozhiyal JC; Wong PTH; Chui WK. Anticonvulsant Activity of Phenylmethylenehydantoins: A Structure-Activity Relationship Study. J Med Chem, 2004,47,1527-35] активностью. Одним из самых успешных примеров, является энзалутамид («Xtandi») (I), который применяется в клинической практике с 2012 года и является антиандрогеновым препаратом [Zhou AN; Li B; Ruan L; Wang Y; Duan G; Li J. An improved and practical route for the synthesis of enzalutamide and potential impurities study. Chinese Chem Lett, 2017,28,426-30].Hydantoin and its derivatives are preferred biologically active moieties. It is known that many of them are characterized by anti-cancer [Mudit M; Khanfar M; Muralidharan A; Thomas S; Shah G V .; van Soest RWM; et al. Discovery, design, and synthesis of anti-metastatic lead phenylmethylene hydantoins inspired by marine natural products. Bioorganic Med Chem, 2009,17,1731-8, Basappa; Ananda Kumar CS; Nanjunda Swamy S; Sugahara K; Rangappa KS. Anti-tumor and anti-angiogenic activity of novel hydantoin derivatives: Inhibition of VEGF secretion in liver metastatic osteosarcoma cells. Bioorganic Med Chem, 2009,17,4928-34], antidiabetic [

L;

L;

M;

E;

L;

Z; et al. Synthesis of and a comparative study on the inhibition of muscle and liver glycogen phosphorylases by epimeric pairs of D-gluco- and D-xylopyranosylidene-spiro- (thio) hydantoins and N- (D-glucopyranosyl) amides. J Med Chem, 2001,44,2843-8] and anticonvulsant [Thenmozhiyal JC; Wong PTH; Chui WK. Anticonvulsant Activity of Phenylmethylenehydantoins: A Structure-Activity Relationship Study. J Med Chem, 2004,47,1527-35] activity. One of the most successful examples is enzalutamide (“Xtandi”) (I), which has been used in clinical practice since 2012 and is an antiandrogen drug [Zhou AN; Li B; Ruan L; Wang Y; Duan G; Li J. An improved and practical route for the synthesis of enzalutamide and potential impurities study. Chinese Chem Lett, 2017,28,426-30].

The area of application of selenium-containing drugs, today, remains not fully understood due to extremely few examples of the use of this type of drugs in medical practice. The most studied pharmaceutical product today is Ebselen. Also in recent years, a number of its derivatives have been developed, which are also at various stages of clinical and preclinical trials [Engman L; Cotgreave I; Angulo M; Taylor CW; Paine-Murrieta GD; Powis G. Diaryl chalcogenides as selective inhibitors of thioredoxin reductase and potential antitumor agents. Anticancer Res 1997,17,4599-605]. However, to date, the main disadvantage of this class of compounds is the complexity of the synthesis (multistage synthesis), as well as the high general toxicity. All of the above factors hinder the use of these compounds in practice.

M; Meydan S; Nacar E;

M;

KT; et al. Effects of ebselen on ischemia/reperfusion injury in rat brain. Int J Neurosci, 2014,124,771-6] (антиоксидантные и противовоспалительные свойства) и Se-метилселеноцистеин (антиоксидантная и противораковая активность). Ряд других перспективных биологически активных селенсодержащих соединений на сегодняшний день находятся на различных стадиях клинических исследований [Cao S; Durrani FA;

K; Rustum YM. Se-methylselenocysteine offers selective protection against toxicity and potentiates the antitumour activity of anticancer drugs in preclinical animal models. Br J Cancer, 2014,110,1733-43]. Наиболее примечательные примеры селенсодержащих биологически активных препаратов приведены на схеме 1 [Ivanenkov YA; Veselov MS; Rezekin IG; Skvortsov DA; Sandulenko YB; Polyakova M V.; et al. Synthesis, isomerization and biological activity of novel 2-selenohydantoin derivatives. Bioorganic Med Chem, 2016,24,802-11].Until recently, selenium-containing organic compounds have not been the subject of intense research due to the widespread belief in their toxicity. However, after the discovery of selenium-containing enzymes, such as: glycine reductase [Sliwkowski MX; Stadtman TC. Selenium-dependent glycine reductase: differences in physicochemical properties and biological activities of selenoprotein A components isolated from Clostridium sticklandii and Clostridium purinolyticum. Biofactors, 1988,1,293-6], glutathione peroxidase [Wirth T. Small Organoselenium Compounds: More than just Glutathione Peroxidase Mimics. Angew Chemie Int Ed, 2015,54,10074-6], thioredoxin reductase [Tabassum A; Bristow RG; Venkateswaran V. Ingestion of selenium and other antioxidants during prostate cancer radiotherapy: A good thing? Cancer Treat Rev, 2010,36,230-4], etc., the chemistry of organoselenium compounds has been the subject of intense research. Of the entire spectrum of currently known selenium-containing biologically active drugs, at least two are already used in clinical practice: ebselen [Aras M;

M; Meydan S; Nacar E;

M;

KT; et al. Effects of ebselen on ischemia / reperfusion injury in rat brain. Int J Neurosci, 2014,124,771-6] (antioxidant and anti-inflammatory properties) and Se-methylselenocysteine (antioxidant and anti-cancer activity). A number of other promising biologically active selenium-containing compounds are currently at various stages of clinical trials [Cao S; Durrani FA;

K; Rustum YM. Se-methylselenocysteine offers selective protection against toxicity and potentiates the antitumour activity of anticancer drugs in preclinical animal models. Br J Cancer, 2014,110,1733-43]. The most notable examples of selenium-containing biologically active drugs are shown in scheme 1 [Ivanenkov YA; Veselov MS; Rezekin IG; Skvortsov DA; Sandulenko YB; Polyakova M V .; et al. Synthesis, isomerization and biological activity of novel 2-selenohydantoin derivatives. Bioorganic Med Chem, 2016,24,802-11].

The technical problem solved by the present invention is the absence of compounds with selective toxicity.

Disclosure of invention

The technical result is the synthesis of new derivatives of 2-selenohydantoin, the characterization of the obtained compounds by physicochemical methods, exhibiting selective toxicity in relation to cancer cells of various types, as well as a simple method for the synthesis of these compounds. The proposed invention makes it possible to significantly expand the range of derivatives obtained with an increase in the probability of finding more selective compounds and compounds with greater biological activity.

The stated technical result is achieved by new derivatives of 2-selenoxo-tetrahydro-4n-imidazol-4-one of general formula 1, or its pharmaceutically acceptable salts, or optical isomers, where:

R ₁ is phenyl, possibly substituted by 1-2 substituents selected from a halogen atom, a lower alkoxy group, methyl;

R ₂ is phenyl, possibly substituted by 1-2 substituents selected from a halogen atom, a lower alkoxy group, a cyano group;

R ₃ is phenyl optionally substituted with 1 substituent selected from a halogen atom, a lower alkoxy group, or methyl.

The compound of general formula 1 is a compound selected from the group consisting of:

(Z) -3- (p-tolyl) -5- (4-ethoxybenzylidene) -2- (p-tolylselanyl) -imidazol-4-one (1.1)

(Z) -3- (4-methoxyphenyl) -5- (4-fluorobenzylidene) -2- (p-tolylselanyl) -imidazol-4-one (1.2)

(Z) -3- (4-methoxyphenyl) -5- (4-ethoxybenzylidene) -2 - ((3-fluorophenyl) selanyl) -imidazol-4-one (1.3)

(Z) -3- (4-methoxyphenyl) -5- (4-ethoxybenzylidene) -2- (p-tolylselanyl) imidazol-4-one (1.4)

(Z) -3- (4-methoxyphenyl) -5- (4-fluorobenzylidene) -2 - ((4-chlorophenyl) selanyl) -imidazol-4-one (1.5)

(Z) -3- (4-methoxyphenyl) -5- (4-ethoxybenzylidene) -2 - ((3-methoxyphenyl) selanyl) imidazol-4-one (1.6)

(Z) -3- (4-methoxyphenyl) -5- (4-ethoxybenzylidene) -2- (phenylselanyl) -imidazol-4-one (1.7)

(Z) -3- (4-methoxyphenyl) -5- (2-chlorobenzylidene) -2 - ((4-chlorophenyl) selanyl) -imidazol-4-one (1.8)

(Z) -3- (4-methoxyphenyl) -5- (2-chlorobenzylidene) -2- (p-tolylselanyl) -imidazol-4-one (1.9)

(Z) -3- (4-methoxyphenyl) -5- (4-chlorobenzylidene) -2 - ((4-chlorophenyl) selanyl) -imidazol-4-one (1.10)

(Z) -3- (4-methoxyphenyl) -5- (4-cyanobenzylidene) -2 - ((4-tolyl) selanyl) -imidazol-4-one (1.11)

(Z) -3- (4-methoxyphenyl) -5- (4-cyanobenzylidene) -2 - ((3-methoxyphenyl) selanyl) -imidazol-4-one (1.12)

(Z) -4- (4-ethoxybenzylidene) -1- (4-methoxyphenyl) -2 - ((2-tolyl) selanyl) -imidazol-4-one (1.13)

(Z) -4 - ((4- (4-ethoxybenzylidene) -1- (4-methoxyphenyl) -5-oxo-4,5-dihydro-imidazol-2-yl) selanyl) benzonitrile (1.14)

(Z) -4- (4-ethoxybenzylidene) -1- (4-methoxyphenyl) -2 - ((4-nitrophenyl) selanyl) -imidazol-5-one (1.15)

(Z) -4-benzylidene-1- (4-methoxyphenyl) -2- (p-tolylselanyl) -imidazol-5-one (1.16)

(Z) -1- (4-methoxyphenyl) -4- (4-methylbenzylidene) -2- (p-tolylselanyl) -imidazol-5-one (1.17)

(Z) -4- (4-chlorobenzylidene) -1- (4-methoxyphenyl) -2- (p-tolylselanyl) -imidazol-5-one (1.18)

(Z) -4- (3-chlorobenzylidene) -1- (4-methoxyphenyl) -2- (p-tolylselanyl) -1-imidazol-5-one (1.19)

(Z) -1- (4-methoxyphenyl) -2- (p-tolylselanyl) -4- (4-trifluoromethyl) benzylidene-imidazol-5-one (1.20)

(Z) -1- (4-methoxyphenyl) -4- (thiophen-2-ylmethylene) -2- (p-tolylselanyl) -imidazol-5-one (1.21)

(Z) -4-ethoxybenzylidene) -1- (3-methoxyphenyl) -2- (p-tolylselanyl) -imidazol-5-one (1.22)

(Z) -4- (ethoxybenzylidene) -1- (2-methoxyphenyl) -2- (p-tolylselanyl) -imidazol-5-one (1.23)

(Z) -4- (4-ethoxybenzylidene) -1-phenyl-2- (p-tolylselanyl) -imidazol-5-one (1.24)

(Z) -4- (4-ethoxybenzylidene) -1- (4-fluorophenyl) -2- (p-tolylselanyl) -imidazol-5-one (1.25)

(Z) -1- (4-chlorophenyl) -4- (4-ethoxybenzylidene) -2- (p-tolylselanyl) -imidazol-5-one (1.26)

(Z) -1- (4-bromophenyl) -4- (4-ethoxybenzylidene) -2- (p-tolylselanyl) -imidazol-5-one (1.27)

(Z) -1- (3-chloro-4-fluorophenyl) -4- (4-ethoxybenzylidene) -2- (p-tolylselanyl) -imidazol-5-one (1.28)

(Z) -4- (4-ethoxybenzylidene) -2- (p-tolylselanyl) -1- (4- (trifluoromethyl) phenyl) imidazol-5-one (1.29)

(Z) -4- (4- (4-ethoxybenzylidene) -5-oxo-2- (p-tolylselanyl) -4,5-dihydroimidazol-1-yl) benzonitrile (1.30)

(Z) -1-cyclopropyl-4- (4-ethoxybenzylidene) -2- (p-tolylselanyl) -imidazol-5-one (1.31)

(Z) -1-benzyl-4- (4-ethoxybenzylidene) -2- (p-tolylselanyl) imidazol-5-one (1.32).

The technical result is also achieved by a method for the synthesis of a compound of general formula 1, which consists in the fact that the corresponding 2-selenohydantoin is dissolved in an organic solvent, then arylboronic acid, copper salt and ligand are added to dissolve the copper salt, after dissolving all components, the reaction mixture is stirred at room temperature from 2 to 3 hours, then placed in a microwave reactor and stirred for 30 ± 15 min at the boiling point of the solvent, after the end of the reaction, inorganic impurities are removed from the reaction mixture, and the remaining organic fraction is concentrated by removing the solvent, the target product is isolated by column chromatography , after which the resulting powder is dried in air to constant weight. In this case, for 250 ± 50 mg of the initial 2-selenohydantoin, from 5 to 10 ml of an organic solvent is taken, which is used as tetrahydrofuran, 1,2-dichloroethane, dimethylformamide, and the salts of copper and ligand are taken at the rate of 1.5 ± 0.4 molar equivalents per 1 molar the equivalent of 2-selenohydantoin.

Preferably, various aromatic and heteroaromatic boric acids with donor and acceptor substituents are used as arylboronic acid, and 1 to 5 molar equivalents of arylboronic acid are taken per 1 molar equivalent of 2-selenohydantoin.

It is preferable to use divalent copper salts as copper salts, and as a ligand - compounds capable of forming strong mononuclear complexes with the copper (II) ion. For carrying out the method, it is preferable to use 2,2'-bipyridyl, 1,10-phenanthroline or tetramethylethylene diamine as ligands.

To separate the inorganic components, the reaction mixture is preferably washed with a saturated EDTA solution and extracted with ethyl acetate or dichloromethane.

It is preferred to remove the solvent on a vacuum rotary evaporator.

The technical result is also achieved by an active ingredient having the property of an androgen receptor inhibitor, which is a compound of general formula 1.

The technical result is also achieved by using a compound of general formula 1 as an androgen receptor inhibitor.

Also, the technical result is achieved by a pharmaceutical composition for the prevention and treatment of oncological disease associated with the activity of the androgen receptor, containing the active component in a therapeutically effective amount, while the cancer is prostate cancer.

The technical result is also achieved by a drug for the prevention and treatment of proliferative diseases associated with the activity of the androgen receptor, made in the form of tablets, capsules or injections, placed in a pharmaceutically acceptable package containing an active component or a pharmaceutical composition in an effective amount.

Also, the technical result is achieved by the method of inhibition of the androgen receptor, which consists in the introduction into the cell of a compound of general formula 1.

Implementation of the invention

Below are definitions of terms that are used in the description of the present invention.

"IC ₅₀ " (PC ₅₀ ) - the concentration of the compound at which there is 50% inhibition of enzymatic activity

"Aryl" is an aromatic monocyclic or polycyclic system containing from 6 to 14 carbon atoms, mainly from 6 to 10 carbon atoms. Aryl may contain one or more "ring system substituents" which may be the same or different. Representatives of aryl groups are phenyl or naphthyl, substituted phenyl or substituted naphthyl. Aryl could be annelated with aromatic and nonaromatic cyclic system or heterocycle, including aryl, aroyl, aralkoxy, arilgidroksi, aryloxy, aryloxycarbonyl, aralkylthio, arylsulfonyl, arilgalogen, heteroaryl, heterocyclyl, heteroaralkyloxy, heteroarylthio, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl , annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl, alkoxycarbonyl, aralkoxycarbonyl, geteroaralkiloksikarbonil or R _k ^a R _{k + 1 ^{a N-, R k a R k}} + ₁ ^{a NC (= O) -,} R k a R k ₊₁ ^a NC (= S) -, R _k ^a R _{k + 1} ^a NSO ₂ -, where R _k ^a and R _{k + 1} ^a independently of each other represent "amino group substituents", the meaning of which is defined in this section ...

"Halogen" means fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine are preferred.

"Hydrate" means a solvate in which water is a solvent molecule or molecules.

“Substituent” means a chemical radical that is attached to a moiety, for example, “alkyl substituent”, “amino group substituent”, “carbamoyl substituent”, “cyclic system substituent”, the meanings of which are defined in this section.

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

"Drug (drug)" - a substance (or a mixture of substances in the form of a pharmaceutical composition), in the form of tablets, capsules of injections, ointments and other ready-made forms intended for the restoration, correction or change of physiological functions in humans and animals, as well as for the treatment and disease prevention, diagnostics, anesthesia, contraception, cosmetology and others.

"Pharmaceutical composition" means a composition comprising a compound of Formula 1 and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, auxiliary, dispensing and receiving agents, agents delivery agents such as preservatives, stabilizers, fillers, grinders, humectants, emulsifiers, suspending agents, thickeners, sweeteners, fragrances, flavorings, antibacterial agents, fungicides, lubricants, sustained delivery regulators, the choice and ratio of 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, and mixtures of these substances. Protection against the action of microorganisms can be provided by a variety of antibacterial and antifungal agents, such as parabens, chlorobutanol, sorbic acid, and the like. The composition may also include isotonic agents such as sugars, sodium chloride and the like. The prolonged action of the composition can be provided by 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, as well as mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of fillers are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate, and the like. Examples of grinders and spreading agents are starch, alginic acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol. A pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, topical or rectal administration of an active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form, as a mixture with traditional pharmaceutical carriers. Suitable unit forms of administration include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, topical, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.

"Pharmaceutically acceptable salt" means the relatively non-toxic organic and inorganic salts of acids and bases disclosed in the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of compounds, or they can be specially prepared. In particular, base salts can be specially prepared starting from the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of the salts obtained in this way 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 (For a detailed description of the properties of such salts, see 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 a purified acid with a suitable base, whereby metal and amine salts can be synthesized. Metallic 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 derived are sodium hydroxide, carbonate, 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 basic enough to form a stable salt and are suitable for medical use (in particular, they must 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 such as, for example, choline, tetramethylammonium, tetraethylammonium, and the like, can be used for salt formation. The basic amino acids, lysine, ornithine and arginine, can be used as amino acids.

All reagents used are commercially available, all procedures, unless otherwise stated, were carried out at room temperature or ambient temperature, that is, in the range from 18 to 25 ° C.

The firstly synthesized 2-selenoxo-tetrahydro-4n-imidazol-4-ones (3-aryl-5-arylidene-2- (arylselanyl) -imidazol-4-ones) of the general formula 1 declared in this invention:

or their pharmaceutically acceptable salts or optical isomers, where:

R ₁ is phenyl, possibly substituted by 1-2 substituents selected from a halogen atom, a lower alkoxy group, methyl;

R ₂ is phenyl, possibly substituted by 1-2 substituents selected from a halogen atom, a lower alkoxy group, a cyano group;

R ₃ is phenyl optionally substituted by 1 substituent selected from a halogen atom, a lower alkoxy group or methyl

The inventive compounds can be used as a biologically active component that is an androgen receptor antagonist.

The following compounds of formulas (1.1-1.12) illustrate but do not limit the present invention.

The method for the synthesis of new 3-aryl-5-arylidene-2- (arylselanyl) -imidazol-4-ones consists in dissolving the original 2-selenohydantoin, arylboronic acid and copper acetate in an organic solvent. For this, the corresponding 2-selenohydantoin is dissolved in an organic solvent at the rate of 5 to 10 ml of solvent per 250 ± 50 mg of the starting 2-selenohydantoin. Tetrahydrofuran, 1,2-dichloroethane, dimethylformamide can be used as the organic solvent. Various aromatic and heteroaromatic boric acids with donor and acceptor substituents are used as arylboronic acid. Then add arylboronic acid, taken from the calculation of 1 to 5 molar equivalents of arylboronic acid per 1 molar equivalent of the original 2-selenohydantoin. The best result is achieved when using 4 molar equivalents of arylboronic acid taken for 1 molar equivalent of the starting 2-selenohydantoin, however, the reaction will proceed at any content of arylboronic acid in the specified range. Then add 1,10-phenanthroline and copper (II) salts, taken at the rate of 1.5 ± 0.4 molar equivalents of copper salt and ligand per equivalent of the original 2-selenohydantoin. As copper salts, any divalent copper salts are used, for example, chlorides, sulfates, nitrates, bromides, fluorides and acetates. To dissolve copper salts, a ligand must be used. The ligand should form strong mononuclear complexes with the copper (II) ion. Nitrogen-containing ligands have the highest affinity for this ion. Also, to increase selectivity and catalytic activity, it is desirable to use aromatic substances as ligands, which, due to their flat structure and the presence of a conjugated electronic system, improves both the complexing properties of the ligand itself and the catalytic properties of its complex with the copper (II) ion. In this process, 2,2'-bipyridyl, 1,10-phenanthroline or tetramethylethylenediamine are suitable for this purpose. After dissolution of all components, the reaction mixture is stirred at room temperature for 2 to 3 hours, then placed in a microwave reactor and stirred for 30 ± 15 minutes at the boiling point of the organic solvent used (approximately 80 ° C). After the end of the reaction, determined by thin layer chromatography (EA: hexane 1: 1; Rf of the _source = 0.3 ± 0.1; Rf of the _product = 0.5 ± 0.1), inorganic impurities are removed from the reaction mixture by extraction into the aqueous phase, after which the remaining organic fraction is concentrated by removing the solvent on a rotary evaporator and the target product is isolated from it by column chromatography. The fractions containing the target product (determined by TLC EA: hexane 1: 1; Rf of the _product = 0.5 ± 0.1) are combined, the solvent is evaporated, and then dried in air to constant weight.

To separate the inorganic components of the mixture, the reaction mixture is washed with a saturated solution of EDTA and extracted with ethyl acetate or dichloromethane to isolate the organic components. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate or dichloromethane, after which hexane or petroleum ether is added dropwise until the characteristic cloudiness. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered on a Schott filter of the 2nd class and dried in air to a constant mass of the precipitate.

For the prevention and treatment of oncological disease associated with the activity of the androgen receptor, a pharmaceutical composition (preparation) is prepared.

A pharmaceutical preparation for the therapy and prevention of oncological pathology associated with the function of the androgen receptor includes a compound of the general formula 1 or pharmacologically acceptable salts and / or hydrates thereof as an active component in a therapeutically effective amount.

Pharmaceutical compositions can include pharmaceutically acceptable excipients. By pharmaceutically acceptable excipients is meant diluents, auxiliary agents and / or carriers used in the pharmaceutical field. The pharmaceutical composition along with the compound of general formula 1, or its pharmaceutically acceptable salt and / or hydrate according to the present invention, may include other active substances, including those with antitumor activity, provided that they do not cause undesirable effects.

If necessary, the use of the pharmaceutical composition of the present invention in clinical practice, it can be mixed with conventional pharmaceutical carriers.

The carriers used in the pharmaceutical compositions of the present invention are those used in the pharmaceutical field to produce common forms, including: in oral forms, binders, lubricants, disintegrants, solvents, diluents, stabilizers, suspending agents, and flavoring agents are used taste; while in injection forms antiseptic agents, solubilizers, stabilizers are used; topical forms use bases, diluents, lubricants, and antiseptic agents.

A drug for the prevention and treatment of proliferative diseases associated with the activity of the androgen receptor, in the form of tablets, capsules or injections, placed in a pharmaceutically acceptable package, containing in an effective amount the active ingredient or pharmaceutical composition of the present invention.

In accordance with the present invention, a method for the prevention or treatment of proliferative diseases associated with androgen receptor activity in animals and humans consists in administering a new drug or new pharmaceutical composition to a patient.

Medicines can be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally, or topically). The clinical dosage of the agent containing the compound of the general formula 1 in patients can be adjusted depending on the therapeutic efficacy and bioavailability of the active ingredients in the body, the rate of their metabolism and excretion from the body, as well as depending on the age, sex and stage of the patient's disease, while the daily the adult dose is usually 10 ~ 500 mg, preferably 50 ~ 300 mg. Therefore, during the preparation of the drug according to the present invention from the pharmaceutical composition in the form of dosage units, it is necessary to take into account the above effective dosage, while each dosage unit of the drug should contain 10 ~ 500 mg of the agent of general formula 1, preferably 50 ~ 300 mg. As directed by your doctor or pharmacist, these drugs can be taken several times over specific periods of time (preferably one to six times).

The present invention is illustrated by specific examples of execution, which are not the only possible, but clearly demonstrates the possibility of achieving the required technical result.

Example 1. Obtaining (Z) -3- (p-tolyl) -5- (4-ethoxybenzylidene) -2- (p-tolylselanyl) -imidazol-4-one (1.1)

To a solution of 0.25 g (0.6 mmol) (Z) -3- (p-tolyl) -5- (4-ethoxybenzylidene) -2-selenoxoimidazol-4-one 5 ml of 1,2-dichloroethane add 0.35 g (2.6 mmol) of p-tolylboronic acid, 0.23 g (1.3 mmol) of 1,10-phenanthroline and 0.15 g (0.8 mmol) of copper (II) acetate. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 1.43 (t, J = 7.0 Hz, 3H, OEt), 2.43 (s, 3H, CH ₃ ), 2.45 (s, 3H, CH ₃ ), 4.07 (q, J = 6.9 Hz, 2H, OEt), 6.78 (d, J = 8.8 Hz, 2H, Ha _r ), 6.95 (s, 1H, CH), 7.24-7.27 (m, 4H, Ha _r + CDCl ₃ ), 7.31 (d, J = 8.2 Hz, 2H, Ha _r ), 7.63 (d, J = 8.0 Hz, 2H, Ha _r ), 7.91 (d, J = 8.7 Hz, 2H, Ha _r ). 13С NMR spectrum (101 MHz, CDCl ₃ ) δ 14.9, 21.5, 21.6, 63.7, 114.6 (2С), 121.1, 125.8, 127.1 (2С), 127.3, 130.2 (2С), 130.4 (2С), 130.7, 134.2 (2С ), 136.5 (2C), 136.8, 139.5, 139.8, 160.4, 160.7, 169.0. IR spectrum (ZnSe, cm ^-1 ): 565, 630, 653, 733, 753, 800, 827, 913, 946, 1013, 1046, 1066, 1111, 1157, 1180, 1201, 1237, 1256, 1309, 1360 , 1389, 1493, 1508, 1565, 1600, 1637, 1714, 2916, 2984. High resolution mass spectrum (FTMS + cESI): M + H, found 477.1080. C ₂₆ H ₂₄ N ₂ O ₂ Se calculated 476.1002. Yellow crystals. Yield: 93%. m.p. 162-163 ° C

Example 2. Obtaining (Z) -3- (4-methoxyphenyl) -5- (4-fluorobenzylidene) -2- (p-tolylselanyl) -imidazol-4-one (1.2)

To a solution of 0.25 g (0.7 mmol) (Z) -3- (4-methoxyphenyl) -5- (4-fluorobenzylidene) -2-selenoxoimidazol-4-one in 5 ml of 1,2-dichloroethane add 0, 36 g (2.7 mmol) of p-tolylboronic acid, 0.23 g (1.3 mmol) of 1,10-phenanthroline and 0.15 g (0.8 mmol) of copper (II) acetate. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 2.46 (s, 3H, CH ₃ ), 3.87 (s, 3H, OMe), 6.91 (s, 1H, CH), 6.94 (t, J = 8.8, 2H, Ha _r ), 7.02 (d, J = 8.8, 2H, Ha _r ), 7.26-7.31 (m, 4H, Ha _r ), 7.62 (d, J = 8.0, 2H, Ha _r ), 7.95 (dd, J = 8.6, 5.8, 2H, Ha _r ). 13С NMR spectrum (101 MHz, CDCl ₃ ) δ 21.6, 55.7,

115.0 (2C), 115.7 (115.60, 115.81, d, J = 21.6, 2C), 120.9, 123.92 (123.91, 123.93, d, J = 1.3), 125.6, 128.7 (2C), 130.2 (2C), 130.88 (130.87 , 130.9, d, J = 3.3), 134.24 (134.20, 134.29, d, J = 8.3, 2C), 136.5 (2C), 138.38 (138.36, 138.39, d, J = 2.6), 140.0, 160.4, 163.0, 163.6 (162.38, 164.89, d, J = 252.7), 169.1. IR spectrum (ZnSe, cm ^-1 ): 593, 653, 681, 702, 732, 787, 804, 827, 852, 890, 947, 1016, 1026, 1071, 1108, 1155, 1176, 1201, 1238, 1250 , 1305, 1351, 1416, 1492, 1513, 1597, 1643, 1726.2835, 2933. High resolution mass spectrum (FTMS + cESI): M + H, found 467.0661. C ₂₄ H ₁₉ FN ₂ O ₂ Se calculated 466.0596. Yellow crystals. Yield: 95%. m.p. 188-189 ° C.

Example 3. Preparation of (Z) -3- (4-methoxyphenyl) -5- (4-ethoxybenzylidene) -2 - ((3-fluorophenyl) selanyl) -imidazol-4-one (1.3)

To a solution of 0.25 g (0.6 mmol) (Z) -3- (4-methoxyphenyl) -5- (4-ethoxybenzylidene) -2-selenoxoimidazol-4-one in 5 ml of 1,2-dichloroethane add 0, 34 g (2.5 mmol) of (3-fluorophenyl) boric acid, 0.22 g (1.2 mmol) of 1,10-phenanthroline and 0.14 g (0.7 mmol) of copper (II) acetate. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

1H NMR spectrum (400 MHz, CDCl ₃ ) δ 1.43 (t, J = 7.0, 3H, OEt), 3.86 (s, 3H, ОМе), 4.07 (q, J = 7.0, 2Н, OEt), 6.82 (d, J = 8.8, 211, Ha _r ), 6.99 (s, 1H, CH), 7.02 (d, J = 8.8, 2H, Ha _r ), 7.19 (td, J = 8.3, 2.2, 1H, Ha _r ), 7.29 (d, J = 8.8, 2H, Ha _r ), 7.39 (td, J = 8.0, 6.0, 1H, Ha _r ), 7.50 (d, J = 7.7, 1H, Na), 7.61 (dt, J = 1.5, 8.5, 1H), 7.95 (d, J = 8.8, 2H). 13C NMR spectrum (101 MHz, CDCl ₃ ) δ 14.8, 55.7, 63.7, 114.7 (2C), 115.0 (2C), 116.6 (116.47, 116.68, d, J = 21.0), 123.3 (123.19, 123.42, d, J = 22.8), 125.6, 126.1 (126.04, 126.12, d, J = 7.7), 126.5, 127.1, 128.8 (2C), 130.4 (130.39, 130.47, d, J = 7.9), 131.6 (131.62, 131.66, d, J = 3.2), 134.2 (2C), 136.7, 159.3, 160.3, 160.9, 162.6 (161.34, 163.83, d, J = 250.1), 169.0. IR spectrum (ZnSe, cm ^-1 ): 563, 680, 734, 778, 826, 855, 912, 945, 1029, 1112, 1154, 1179, 1205, 1256, 1305, 1360, 1424, 1472, 1508, 1597 , 1636, 1712, 2977, 3223. High resolution mass spectrum (FTMS + cESI): M + H, found 497.0773. C ₂₅ H ₂₁ FN ₂ O ₃ Se calculated 496.070142. Yellow crystals. Yield: 58%. m.p. 185-186 ° C.

Example 4. Preparation of (Z) -3- (4-methoxyphenyl) -5- (4-ethoxybenzylidene) -2- (p-tolylselanyl) -imidazol-4-one (1.4)

To a solution of 0.25 g (0.7 mmol) (2) -3- (4-methoxyphenyl) -5- (4-ethoxybenzylidene) -2-selenoxoimidazol-4-one in 5 ml of 1,2-dichloroethane add 0, 34 g (2.7 mmol) of p-tolylboronic acid, 0.23 g (1.3 mmol) of 1,10-phenanthroline and 0.15 g (0.8 mmol) of copper (II) acetate. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.43 (t, J-6.9, 3H, OEt), 2.45 (s, 3H, CH ₃ ), 3.86 (s, 3H, ОМе), 4.06 (q, J = 6.8 , 2H, OEt), 6.77 (d, J = 8.6, 2H, Ha _r ), 6.94 (s, 1H, CH), 7.01 (d, J = 8.7, 2H, Ha _r ), 7.24-7.30 (m, 4H , Ha _r ), 7.63 (d, J = 7.8, 2H, Ha _r ), 7.91 (d, J = 8.5, 2H, Ha _r ). 13С NMR spectrum (101 MHz, CDCl ₃ ) δ 14.9, 21.6, 55.7, 63.6, 114.6 (2С), 115.0 (2С), 121.2, 125.7, 125.9, 127.4, 128.8 (2С), 130.2 (2С), 134.2 (2С ), 136.5 (2C), 137.0 (2C), 139.7, 160.2, 160.7, 169.3. IR spectrum (ZnSe, cm ^-1 ): 635, 658, 684, 705, 738, 754, 796, 808, 894, 941, 1014, 1025, 1046, 1067, 1112, 1175, 1209, 1235, 1254, 1312 , 1347, 1362, 1393, 1424, 1443, 1455, 1470, 1496, 1563, 1598, 1626, 1713, 2843, 2975, 3083. High resolution mass spectrum (FTMS + cESI): M + H, found 493.1026. C ₂₆ H ₂₄ N ₂ O ₃ Se calculated 492.0952. Yellow crystals. Yield: 59%. m.p. 189-190 ° C.

Example 5. Obtaining (Z) -3- (4-methoxyphenyl) -5- (4-fluorobenzylidene) -2 - ((4-chlorophenyl) selanyl) imidazol-4-one (1.5)

To a solution of 0.25 g (0.7 mmol) (g) -3- (4-methoxyphenyl) -5- (4-fluorobenzylidene) -2-selenoxoimidazol-4-one in 5 ml of 1,2-dichloroethane add 0, 42 g (2.7 mmol) of (4-chlorophenyl) boric acid, 0.23 g (1.3 mmol) of 1,10-phenanthroline and 0.15 g (0.8 mmol) of copper (II) acetate. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction

the mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

1H NMR spectrum (400 MHz, CDCl ₃ ) δ 3.87 (s, 3H, ОМе), 6.93 (s, 1H, СН), 6.96-7.04 (m, 4Н, Ha _r ), 7.29 (d, J = 8.8, 2Н , Ha _r ), 7.44 (d, J = 8.4, 2H, Ha _r ), 7.68 (d, J = 8.4, 2H, Ha _r ), 7.92 (dd, J-8.6, 5.8, 2H, Ha _r ). 13С NMR spectrum (101 MHz, CDCl ₃ ) δ 55.7, 115.1 (2С), 115.9 (115.75, 115.97, d, J = 21.6, 2С), 122.6, 124.5 (124.47, 124.48, d, J = 1.0), 125.4, 128.7 (2C), 129.7 (2C), 130.7 (130.65, 130.69, d, J = 3.4), 134.2 (134.19, 134.27, d, J = 8.4, 2C), 136.3, 138.0 (2C), 138.1 (138.11 , 138.14, d, J = 2.8), 160.5, 162.2, 163.8 (162.53, 165.05, d, J = 253.0), 168.9. IR spectrum (ZnSe, cm ^-1 ): 592, 630, 653, 681, 702, 732, 754, 787, 812, 829, 853, 899, 947, 1011, 1026, 1087, 1154, 1178, 1203, 1242 , 1255, 1303, 1363, 1390, 1415, 1437, 1478, 1495, 1510, 1519, 1599, 1642, 1718, 2840, 2975, 3032, 3087. High resolution mass spectrum (FTMS + cESI): M + H, found 487.0112. C ₂₃ H ₁₆ ClFN ₂ O ₂ Se calculated 486.0049. Yellow crystals. Yield: 75%. m.p. 204-205 ° C.

Example 6. Preparation of (Z) -3- (4-methoxyphenyl) -5- (4-ethoxybenzylidene) -2 - ((3-methoxyphenyl) selanyl) imidazol-4-one (1.6)

To a solution of 0.25 g (0.7 mmol) (Z) -3- (4-methoxyphenyl) -5- (4-ethoxybenzylidene) -2-selenoxoimidazol-4-one in 5 ml of 1,2-dichloroethane add 0, 40 g (2.7 mmol) of (3-methoxyphenyl) boric acid, 0.23 g (1.3 mmol) of 1,10-phenanthroline and 0.15 g (0.8 mmol) of copper (II) acetate. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed in a vacuum

a rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

1H NMR spectrum (400 MHz, CDCl ₃ ) δ 1.43 (t, J = 7.0, 3H, OEt), 3.84 (s, 3H, ОМе), 3.86 (s, 3Н, ОМе), 4.06 (q, J = 6.9, 2H, OEt), 6.81 (d, J = 8.7, 2H, Ha _r ), 6.97 (s, 1H, CH), 7.01 (d, J = 8.7, 2H, Na), 7.28-7.35 (m, 5H, Ha _r ), 7.97 (d, J = 8.7, 2H, Ha _r ). 13С NMR spectrum (101 MHz, CDCl ₃ ) δ 14.8, 31.0, 55.65, 63.6, 114.6 (2С), 114.9 (2С), 124.7, 125.7, 125.9, 127.2, 128.7 (2С), 129.3 (2С), 129.45, 134.1 (2C), 136.5 (2C), 136.9, 160.2, 160.3, 160.7, 169.1. ⁷⁷ Se NMR (76 MHz, CDCl ₃ ) δ 407.9. IR spectrum (KBr, cm ^-1 ): 561, 600, 637, 683, 734, 772, 830, 894, 947, 1025, 1038, 1109, 1153, 1177, 1208, 1241, 1255, 1299, 1348, 1425 , 1476, 1490, 1510, 1595, 1634, 1713, 2846, 2935, 2975, 3210, 3412. High resolution mass spectrum (FTMS + cESI): M + H, found 509.0975. C ₂₆ H ₂₄ N ₂ O ₄ Se calculated 508.0901. Yellow crystals. Yield: 66%. m.p. 177-178 ° C.

Example 7. Preparation of (Z) -3- (4-methoxyphenyl) -5- (4-ethoxybenzylidene) -2- (phenylselanyl) -imidazol-4-one (1.7)

To a solution of 0.25 g (0.6 mmol) (Z) -3- (4-methoxyphenyl) -5- (4-ethoxybenzylidene) -2-selenoxoimidazol-4-one in 5 ml of 1,2-dichloroethane add 0, 36 g (2.5 mmol) of phenylboronic acid, 0.22 g (1.2 mmol) of 1,10-phenanthroline and 0.14 g (0.7 mmol) of copper (II) acetate. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

1H NMR spectrum (400 MHz, CDCl ₃ ) δ 1.43 (t, J = 6.9, 3H, OEt), 3.87 (s, 3H, ОМе), 4.06 (q, J = 6.8, 2Н, OEt), 6.77 (d, J = 8.3, 2H, Ha _r ), 6.95 (s, 1H, CH), 7.02 (d, J = 8.7, 2H, Ha _r ), 7.30 (d, J = 8.7, 2H, Ha _r ), 7.42-7.51 (m, 3H, Ha _r ), 7.76 (d, J = 7.9, 2H, Ha _r ), 7.90 (d, J = 8.4, 2H, Ha _r ). 13С NMR spectrum (101 MHz, CDCl ₃ ) δ 14.9, 55.7, 63.7, 114.6 (2С), 115.0 (2С), 124.8, 125.8, 125.9, 127.25, 128.8 (2С), 129.4 (2С), 129.5, 134.2 (2С ), 136.5 (2C), 136.9, 160.25, 160.4, 160.75, 169.2. IR spectrum (KBr, cm-1): 566, 594, 635, 659, 685, 704, 734, 755, 811, 837, 901,

941, 1024, 1047, 1068, 1112, 1153, 1179, 1210, 1254, 1299, 1312, 1350, 1361, 1391, 1425, 1442, 1470, 1496, 1509, 1563, 1598, 1628, 1715, 2935, 2973, 3076, 3212, 3423. High Resolution Mass Spectrum (FTMS + cESI): M + H found 479.0871. C ₂₅ H ₂₂ N ₂ O ₃ Se calculated 478.0796. Yellow crystals. Yield: 49%. m.p. 179-180 ° C

Example 8 (Z) -3- (4-methoxyphenyl) -5- (2-chlorobenzylidene) -2 - ((4-chlorophenyl) selanyl) imidazol-4-one (1.8)

To a solution of 0.25 g (0.6 mmol) (Z) -3- (4-methoxyphenyl) -5- (2-chlorobenzylidene) -2-selenoxoimidazol-4-one in 5 ml of 1,2-dichloroethane add 0, 4 g (2.6 mmol) of (4-chlorophenyl) boric acid, 0.23 g (1.3 mmol) of 1,10-phenanthroline and 0.15 g (0.8 mmol) of copper (II) acetate. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

1H NMR spectrum (400 MHz, CDCl ₃ ) δ 3.88 (s, 3H, ОМе), 7.03 (d, J = 8.7, 2H, Ha _r ), 7.12 (t, J = 7.6, 1Н, Ha _r ), 7.23 ( d, J = 7.9, 1H, Ha _r ), 7.30 (d, J-8.7, 2H, Ha _r ), 7.38 (d, J = 8.0, 1H, Ha _r ), 7.42 (d, J = 8.3, 2H, Ha _r ), 7.46 (s, 1H, CH), 7.67 (d, J = 8.3, 2H, Ha _r ), 8.48 (d, J = 8.0, 1H, Ha _r ). 13С NMR spectrum (101 MHz, CDCl ₃ ) δ 56.04, 113.71, 127.21, 127.46, 127.47, 127.92, 128.55, 128.71, 129.16, 131.28, 131.47, 131.65, 133.05, 133.25, 134.56, 137.42, 151.64, 159.03, 166.34 IR- spectrum (ZnSe, cm ^-1 ): 572, 600, 634, 654, 672, 698, 712, 729, 759, 815, 829, 888, 948, 1012, 1025, 1051, 1089, 1123, 1162, 1187, 1205 , 1228, 1256, 1289, 1361, 1389, 1439, 1484, 1519, 1587, 1607, 1628, 1723, 2843, 2946, 3012, 3052. High resolution mass spectrum (FTMS + cESI): M + H, found 502.9825 ... C ₂₃ H ₁₆ Cl ₂ N ₂ O ₂ Se calculated 501.9754. Yellow crystals. Yield: 68%. m.p. 236-237 ° C.

Example 9. Preparation of (Z) -3- (4-methoxyphenyl) -5- (2-chlorobenzylidene) -2- (p-tolylselanyl) -imidazol-4-one (1.9)

To a solution of 0.25 g (0.6 mmol) (Z) -3- (4-methoxyphenyl) -5- (2-chlorobenzylidene) -2-selenoxoimidazol-4-one in 5 ml of 1,2-dichloroethane add 0, 35 g (2.6 mmol) p-

tolylboronic acid, 0.23 g (1.3 mmol) of 1,10-phenanthroline and 0.15 g (0.8 mmol) of copper (II) acetate. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

1Н NMR spectrum (400 MHz, CDCl ₃ ) δ 2.45 (s, 3Н, СН ₃ ), 3.87 (s, 3Н, ОМе), 7.02-7.07 (m, 3Н, Ha _r ), 7.21 (t, J = 7.7, 1H, Ha _r ), 7.25 (d, J = 5.9, 2H, Ha _r ), 7.30 (d, J = 8.7, 2H, Ha _r ), 7.36 (d, J = 8.1, 1H, Ha _r ), 7.44 ( s, 1H, CH), 7.61 (d, J = 8.0, 2H, Ha _r ), 8.55 (d, J = 8.0, 1H Ha _r ). 13С NMR spectrum (101 MHz, CDCl ₃ ) δ 21.13, 56.04, 113.71, 127.21, 127.46, 127.92, 128.55, 128.71, 131.28 127.47, 131.47, 131.51, 131.65, 132.48, 133.05, 134.56, 138.95, 151.64, 159.03, 166.34. IR spectrum (ZnSe, cm- ¹ ): 541, 654, 669, 694, 712, 743, 757, 802, 826, 949, 1016, 1025, 1051, 1122, 1164, 1176, 1187, 1203, 1226, 1258 , 1376, 1437, 1457, 1481, 1519, 1724, 2850, 2920, 2953. High resolution mass spectrum (FTMS + cESI): M + H, found 483.0365. C ₂₄ H ₁₉ ClN ₂ O ₂ Se calculated 482.0300. Yellow crystals. Yield: 12%. m.p. 191-192 ° C.

Example 10. Preparation of (Z) -3- (4-methoxyphenyl) -5- (4-chlorobenzylidene) -2 - ((4-chlorophenyl) selanyl) imidazol-4-one (1.10)

To a solution of 0.25 g (0.6 mmol) (Z) -3- (4-methoxyphenyl) -5- (4-chlorobenzylidene) -2-selenoxoimidazol-4-one in 5 ml of 1,2-dichloroethane add 0, 40 g (2.6 mmol) of (4-chlorophenyl) boric acid, 0.23 g (1.3 mmol) of 1,10-phenanthroline and 0.15 g (0.8 mmol) of copper (II) acetate. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

1H NMR spectrum (400 MHz, CDCl ₃ ) δ 3.87 (s, 3H, OMe), 6.90 (s, 1H, CH), 7.03 (d, J-8.5, 2H, Ha _r ), 7.25-7.30 (m, 4H , Ha _r ), 7.44 (d, J = 8.1, 2H, Ha _r ), 7.67 (d, J = 8.1, 2H, Ha _r ), 7.85 (d, J = 8.2, 2H, Ha _r ). 13С NMR spectrum (101 MHz, CDCl ₃ ) δ 55.7, 115.1 (2С), 122.6, 124.1, 125.3, 128.7 (2С), 128.95 (2С), 129.7 (2С), 132.8, 133.3 (2С), 136.2, 136.4, 137.9 (2C), 138.8, 160.5, 162.75, 168.8. ⁷⁷ Se NMR (76 MHz, CDCl ₃ ) δ 408.12. IR spectrum (ZnSe, cm ^-1 ): 588, 644, 659, 700, 729, 748, 808, 828, 894, 940, 949, 1010, 1024, 1084, 1105, 1154, 1173, 1190, 1209, 1226 , 1257, 1279, 1304, 1343, 1366, 1385, 1406, 1445, 1472, 1490, 1512, 1558, 1583, 1606, 1628, 1722, 2845, 2941, 3079. High Resolution Mass Spectrum (FTMS + cESI): M + H, found 502.9823. C ₂₃ H ₁₆ Cl ₂ N ₂ O ₂ Se calculated 501.9754. Yellow crystals. Yield: 69%. m.p. 239-240 ° C

Example 11. Preparation of (Z) -3- (4-methoxyphenyl) -5- (4-cyanobenzylidene) -2 - ((4-tolyl) selanyl) imidazol-4-one (1.11)

To a solution of 0.25 g (0.7 mmol) (Z) -3- (4-methoxyphenyl) -5- (4-cyanobenzylidene) -2-selenoxoimidazol-4-one in 5 ml of 1,2-dichloroethane add 0, 35 g (2.6 mmol) of p-tolylboronic acid, 0.23 g (1.3 mmol) of 1,10-phenanthroline and 0.15 g (0.8 mmol) of copper (II) acetate. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

¹ Н NMR spectrum (400 MHz, CDCl ₃ ) δ = 2.49 (s, 3Н, Me), 3.88 (s, 3Н, ОМе), 6.86 (s, 1Н, СН), 7.04 (d, J = 8.8, 2Н, Ha _r ), 7.28-7.31 (m, 4H, Ha _r ), 7.50 (d, J = 8.3, 2H, Ha _r ), 7.61 (d, J = 7.9, 2H, Ha _r ), 8.01 (d, J = 8.2, 2H, Ha _r ). NMR ¹³ C (101 MHz, CDCl ₃₎ δ = 21.6, 55.7, 112.3, 115.2 (2C), 119.0, 120.6, 121.7, 125.2, 128.7 (2C), 130.4 (2C), 132.08 (2C), 132.13 (2C ), 136.6 (2C), 138.9, 140.3, 140.9, 160.6, 166.5, 168.7. IR spectrum (ZnSe, cm ^-1 ): 631, 649, 668,

702, 719, 759, 795, 823, 838, 854, 920, 950, 972, 1015, 1033, 1072, 1113, 1170, 1182, 1197, 1231, 1248, 1296, 1307, 1315, 1371, 1412, 1438, 1485, 1511, 1612, 1639, 1727, 2226, 2835, 2919, 3037. High resolution mass spectrum (FTMS + cESI): M + H, found 474.0709. C ₂₅ H ₁₉ N ₃ O ₂ Se calculated 473.0642. Yellow crystals. Yield: 62%. m.p. 231-232 ° C.

Example 12. Preparation of (Z) -3- (4-methoxyphenyl) -5- (4-cyanobenzylidene) -2 - ((3-methoxyphenyl) selanyl) imidazol-4-one (1.12)

To a solution of 0.25 g (0.7 mmol) (Z) -3- (4-methoxyphenyl) -5- (4-cyanobenzylidene) -2-selenoxoimidazol-4-one in 5 ml of 1,2-dichloroethane add 0, 40 g (2.6 mmol) of (3-methoxyphenyl) boric acid, 0.23 g (1.3 mmol) of 1,10-phenanthroline and 0.15 g (0.8 mmol) of copper (II) acetate. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

¹ H NMR spectrum (600 MHz, CDCl ₃ ) δ 3.86 (s, 3H, ОМе), 3.88 (s, 3Н, ОМе), 6.88 (s, 1H, СН), 7.04 (d, J = 8.7, 2Н, Ha _r ), 7.08 (d, J = 7.9, 1H, Ha _r ), 7.29-7.31 (m, 3H, Ha _r ), 7.34 (s, 1H, Ha _r ), 7.37 (t, J = 7.9, 1H, Ha _r ), 7.53 (d, J = 8.1, 2H, Ha _r ), 8.05 (d, J = 8.1, 2H, Ha _r ). ¹³ С NMR spectrum (101 MHz, CDCl ₃ ) δ = 55.6, 55.7, 112.4, 115.1 (2С), 115.9, 118.9, 121.7, 121.9, 124.9, 125.1, 128.4, 128.7 (2С), 130.2, 132.1 (2С), 132.1 (2C), 138.8, 140.8, 160.1, 160.6, 165.8, 168.6. IR spectrum (ZnSe, cm ^-1 ): 633, 656.675, 698, 727, 759, 770, 798, 813, 831, 858, 887, 948, 993, 1025, 1070, 1112, 1160, 1176, 1190, 1200 , 1228, 1245, 1296, 1316, 1347, 1363, 1419, 1479, 1515, 1575, 1590, 1632, 1719, 2224, 2840, 2938, 3076. High resolution mass spectrum (FTMS + cESI): M + H, found 490.0660. C ₂₃ H ₁₆ Cl ₂ N ₂ O ₂ Se calculated 489.059163. Yellow crystals. Yield: 47%. m.p. 212-213 ° C.

Example 13 Preparation of (Z) -4- (4-ethoxybenzylidene) -1- (4-methoxyphenyl) -2 - ((2-tolyl) selanyl) imidazol-4-one (1.13)

To a solution of 0.25 g (0.6 mmol) (Z) -4- (4-ethoxybenzylidene) -1- (4-methoxyphenyl) -2-selenosoimidazol-4-one in 5 ml of 1,2-dichloroethane add 0, 33 g (2.4 mmol) o-

tolylboronic acid, 0.22 g (1.2 mmol) of 1,10-phenanthroline and 0.13 g (0.7 mmol) of copper (II) acetate. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

¹ H NMR spectrum (600 MHz, CDCl ₃ ) δ 1.42 (t, J = 8.0, 3H, OEt), 2.51 (s, 3H, Me), 3.87 (s, 3H, ОМе), 4.05 (q, J = 6.9 , 2H, OEt), 6.76 (d, J = 8.0, 2H, Ha _r ), 6.93 (s, 1H, CH), 7.02 (d, J = 8.0, 2H, Ha _r ), 7.23 (t, J = 4.0 , 1H, H _Ar ), 7.31 (d, J = 8.8, 1H, Ha _r ), 7.37-7.43 (m, 2H, Ha _r ), 7.77 (d, J = 8.0, 1H, Ha _r ), 7.86 (d , J = 8.0, 2H, Ha _r ). ¹³ C NMR spectrum (101 MHz, CDCl ₃ ) δ 14.9, 23.1, 55.7, 63.7, 114.6 (2C), 115.0 (2C), 125.8, 125.9, 126.0, 126.8, 127.3, 128.7 (2C), 130.2, 130.5, 134.1 (2C), 137.0, 137.9, 143.0, 159.7, 160.2, 160.7, 169.2. IR spectrum (kW, cm ^-1 ): 560, 595, 635, 658, 683, 735, 851, 806, 829, 901, 947, 1115, 1156, 1176, 1204, 1253, 1300, 1313, 1348, 1362 , 1393, 1421, 1443, 1483, 1511, 1597, 1638, 1656, 1719, 1767, 2925, 2979. High resolution mass spectrum (FTMS + cESI): M + H, found 493.1019. C ₂₆ H ₂₄ N ₂ O ₃ Se calculated 492.09521. Yellow crystals. Yield: 70%. m.p. 172-173 ° C.

Example 14. (Z) -4 - ((4- (4-ethoxybenzylidene) -1- (4-methoxyphenyl) -5-oxo-4,5-dihydro-imidazol-2-yl) selanyl) benzonitrile (1.14)

To a solution of 0.25 g (0.6 mmol) (Z) -4 - ((4- (4-ethoxybenzylidene) -5-oxo-4,5-dihydro-imidazol-2-yl) selenoxo) benzonitrile in 5 ml 1,2-dichloroethane, 0.35 g (2.4 mmol) of (4-cyanophenyl) boric acid, 0.22 g (1.2 mmol) of 1,10-phenanthroline and 0.13 g (0.7 mmol) copper (II) acetate. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

¹ H NMR spectrum (600 MHz, CDCl ₃ ) δ 11.44 (t, J = 7.0, 3H, OEt), 3.87 (s, 3H, ОМе), 4.09 (q, J = 6.9, 2H, OEt), 6.82 (d , J = 8.9, 2H, Ha _r ), 7.00 (s, 1H, CH), 7.02 (d, J = 9.0, 2H, Ha _r ), 7.28 (d, J = 8.9, 2H, Ha _r ), 7.70 ( d, J = 8.4, 2H, Ha _r ), 7.88 (d, J = 8.9, 2H, Ha _r ), 7.91 (d, J = 8.4, 2H, Ha _r ). ¹³ C NMR spectrum (101 MHz, CDCl ₃ ) δ 14.8, 55.7, 63.8, 113.1, 114.8 (2C), 115.1 (2C), 118.4, 125.3, 126.8, 127.0, 128.8 (2C), 131.5, 132.5 (2C), 134.2 (2C), 136.4, 136.5 (2C), 158.5, 160.5, 161.2, 168.8. IR spectrum (KBr, cm ^-1 ): 566, 596, 629, 652, 683, 702, 738, 799, 824, 845, 910, 950, 1015, 1028, 1048, 1067, 1113, 1168, 1204, 1245 , 1257, 1311, 1371, 1391, 1425, 1475, 1491, 1513, 1569, 1602, 1641, 1724, 2225, 2833, 2876, 2935, 2978. High resolution mass spectrum (FTMS + cESI): M + H, found 504.0836. C ₂₆ H ₂₁ N ₂ O ₃ Se calculated 503.07481. Yellow crystals. Yield: 82% m.p. 220-221 ° C.

Example 15 (Z) -4- (4-ethoxybenzylidene) -1- (4-methoxyphenyl) -2 - ((4-nitrophenyl) selanyl) imidazol-5-one (1.15)

To a solution of 0.25 g (0.6 mmol) (Z) -4- (4-ethoxybenzylidene) -2 - ((4-nitrophenyl) selenoxo) imidazol-5-one in 5 ml of 1,2-dichloroethane add 0, 40 g (2.4 mmol) of (4-nitrophenyl) boric acid, 0.22 g (1.2 mmol) of 1,10-phenanthroline and 0.13 g (0.7 mmol) of copper (II) acetate. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 1.43 (t, J = 6.9, 3H, OEt), 3.87 (s, 3H, ОМе), 4.07 (q, J = 6.9, 2Н, OEt), 6.81 (d , J = 8.7, 2H, Ha _r ), 7.01-7.03 (m, 3H, CH + Ha _r ), 7.29 (d, J = 8.8, 2H, Ha _r ), 7.90 (d, J = 8.7, 2H, Ha _r ), 7.98 (d, J = 8.7, 2H, Ha _r ), 8.26 (d, J = 8.7, 2H, Ha _r ) ¹³ C NMR spectrum (101 MHz, CDCl ₃ ) δ 14.8, 55.7, 63.8, 114.8 (2C ), 115.1 (2C), 123.9 (2C), 125.3, 126.7,

127.2, 128.8 (2C), 133.7, 134.2 (2C), 136.3, 136.5 (2C), 148.4, 158.2, 160.5, 161.2, 168.7. IR spectrum (KBr, cm ^-1 ): 567, 596, 628, 651, 682, 736, 799, 823, 851, 910, 949, 1013, 1026, 1050, 1065, 1113, 1164, 1179, 1203, 1248 , 1259, 1294, 1311, 1352, 1395, 1424, 1490, 1512, 1572, 1600, 1639, 1727, 2868, 2957, 3099. High resolution mass spectrum (FTMS + cESI): M + H, found 524.0721. C ₂₅ H ₂₁ N ₃ O ₅ Se calculated 523.06464. Yellow crystals. Yield: 74%. m.p. 206-207 ° C.

Example 16 (Z) -4-benzylidene-1- (4-methoxyphenyl) -2- (p-tolylselanyl) imidazol-5-one (1.16)

To a solution of 0.25 g (0.7 mmol) of (Z) -4-benzylidene-1- (4-methoxyphenyl) -selenoxoimidazol-5-one in 5 ml of 1,2-dichloroethane add 0.38 g (2.8 mmol) of p-tolylboronic acid, 0.25 g (1.4 mmol) of 1,10-phenanthroline and 0.15 g (0.84 mmol) of copper (II) acetate. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

¹ Н NMR spectrum (400 MHz, CDCl ₃ ) δ 2.45 (s, 3Н, Me), 3.86 (s, 3Н, ОМе), 6.96 (s, 1H, СН), 7.02 (d, J = 8.8, 2H, Ha _r ), 7.24-7.32 (m, 7H, Ha _r ), 7.63 (d, J = 8.0, 2H, Ha _r ), 7.95 (d, J = 7.2, 2H, Ha _r ). ¹³ С NMR spectrum (101 MHz, CDCl ₃ ) δ 21.5, 55.7, 115.0 (2С), 121.0, 125.4, 125.6, 128.6 (2С), 128.8 (2С), 130.0, 130.2 (2С), 132.3 (2С), 134.5 , 136.5 (2C), 138.7, 139.9, 160.3, 162.8, 169.2. IR spectrum (KBr, cm ^-1 ): 562, 597, 634, 657, 688, 740, 762, 802, 835, 924, 948, 1027, 1049, 1113, 1160, 1177, 1203, 1230, 1254, 1303 , 1350, 1362, 1447, 1489, 1516, 1608, 1634, 1721, 2975, 3021, 3061. High resolution mass spectrum (FTMS + cESI): M + H, found 449.0757. C ₂₄ H ₂₀ N ₂ O ₂ Se calculated 448.06899. Yellow crystals. Yield: 69%. m.p. 144-145 ° C.

Example 17 (Z) -1- (4-methoxyphenyl) -4- (4-methylbenzylidene) -2- (p-tolylselanyl) imidazol-5-one (1.17)

To a solution of 0.25 g (0.7 mmol) (Z) -1- (4-methoxyphenyl) -4- (4-methylbenzylidene) -2-selenoxoimidazol-5-one in 5 ml of 1,2-dichloroethane add 0, 38 g (2.8 mmol) of p-tolylboronic acid, 0.25 g (1.4 mmol) of 1,10-phenanthroline and 0.15 g (0.84 mmol) of copper (II) acetate. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 2.36 (s, 3H, Me), 2.47 (s, 3H, Me), 3.87 (s, 3H, ОМе), 6.96 (s, 1Н, СН), 7.02 ( d, J = 8.7, 2H, Ha _r ), 7.08 (d, J = 7.9, 2H, Ha _r ), 7.26-7.31 (m, 4H, Ha _r ), 7.63 (d, J = 7.9, 2H, Ha _r ), 7.85 (d, J = 7.9, 2H, Ha _r ). ¹³ C NMR spectrum (101 MHz, CDCl ₃ ) δ 20.9, 21.2, 55.5, 114.8 (2C), 120.9, 123.8, 125.3, 129.1 (2C), 129.2 (2C), 129.9 (2C), 131.4, 131.9 (2C) , 135.9 (2C), 137.7, 139.4, 140.2, 159.8, 162.2, 168.0. IR spectrum (KBr, cm ^-1 ): 592, 703.4 734, 755, 776, 797, 818, 836, 900, 940, 949, 1025, 1065, 1106, 1153, 1173, 1184, 1211, 1230, 1257, 1298, 1313, 1345, 1366, 1446, 1492, 1512, 1603, 1631, 1721, 2848, 2917. High resolution mass spectrum (FTMS + cESI): M + H, found 463.0897. C ₂₅ H ₂₂ N ₂ O ₂ Se calculated 462.08464. Yellow crystals. Yield: 66%. m.p. 200-201 ° C.

Example 18 (Z) -4- (4-chlorobenzylidene) -1- (4-methoxyphenyl) -2- (p-tolylselanyl) imidazol-5-one (1.18)

To a solution of 0.25 g (0.6 mmol) (Z) -4- (4-chlorobenzylidene) -1- (4-methoxyphenyl) -2-selenoxoimidazol-5-one in 5 ml of 1,2-dichloroethane add 0, 33 g (2.4 mmol) of p-tolylboronic acid, 0.22 g (1.2 mmol) of 1,10-phenanthroline and 0.14 g (0.72 mmol) of copper (II) acetate. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

¹ Н NMR spectrum (400 MHz, CDCl ₃ ) δ 2.45 (s, 3Н, Me), 3.85 (s, 3Н, ОМе), 6.86 (s, 1Н, СН), 7.00 (d, J = 8.8, 2H, Ha _r ), 7.60 (d, J = 8.1, 2H, Ha _r ), 7.86 (d, J = 8.7, 2H, Ha _r ), 7.19 (d, J = 8.6, 2H, Ha _r ), 7.24-7.29 (m , 4H, Ha _r ). ¹³ С NMR spectrum (101 MHz, CDCl ₃ ) δ 21.6, 55.7, 115.0 (2С), 120.8, 123.5, 125.5, 128.7 (2С), 128.8 (2С), 130.2 (2С), 133.0, 133.3 (2С), 135.8 , 136.5 (2C), 139.0, 140.0, 160.4, 168.9. IR spectrum (KBr, cm ^-1 ): 645, 657, 696, 747, 794, 812, 825, 834, 889, 914, 949, 1013, 1025, 1085, 1112, 1159, 1179, 1192, 1202, 1233 , 1253, 1277, 1307, 1346, 1363, 1406, 1439, 1487, 1517, 1585, 1608, 1634, 1724, 2843, 2919, 3081. High-resolution mass spectrum (FTMS + cESI): M + H, found 483.0371 ... C ₂₄ H ₁₉ ClN ₂ O ₂ Se calculated 482.03002. Yellow crystals. Yield: 77%. m.p. 199-200 ° C.

Example 19 (Z) -4- (3-chlorobenzylidene) -1- (4-methoxyphenyl) -2- (p-tolylselanyl) -1-imidazol-5-one (1.19)

To a solution of 0.25 g (0.6 mmol) (Z) -4- (3-chlorobenzylidene) -1- (4-methoxyphenyl) -2-selenoxoimidazol-5-one in 5 ml of 1,2-dichloroethane add 0, 33 g (2.4 mmol) of p-tolylboronic acid, 0.22 g (1.2 mmol) of 1,10-phenanthroline and 0.14 g (0.72 mmol) of copper (II) acetate. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 2.38 (s, 3H, Me), 3.84 (s, 3H, ОМе), 6.87 (s, 1H, СН), 7.11 (d, J = 8.9, 2H, Ha _r ), 7.31-7.43 (m, 6H, Ha _r ), 7.63 (d, J = 8.0, 2H, Ha _r ), 7.76 (d, J = 7.6, 1H, Ha _r ), 8.27 (s, 1H, NH ). ¹³ C NMR spectrum (101 MHz, CDCl ₃ ) δ 21.0, 55.5, 114.8 (2C), 120.5, 121.2, 125.0, 129.2 (2C), 129.5, 130.2 (3C), 130.3, 130.7, 133.4, 136.0 (2C), 136.1, 139.3,

139.5, 160.0, 165.0, 167.8. IR spectrum (KBr, cm ^-1 ): 564, 598, 654, 691, 744, 783, 828, 948, 1031, 1102, 1162, 1203, 1225, 1246, 1276, 1296, 1367, 1423, 1492, 1508 , 1558, 1609, 1635, 1725, 2839, 2914, 3041. High resolution mass spectrum (FTMS + cESI): M + H, found 483.0376. C ₂₄ H ₁₉ ClN ₂ O ₂ Se calculated 482.03002. Yellow crystals. Yield: 70%. m.p. 186-187 ° C.

Example 20 (Z) -1- (4-methoxyphenyl) -2- (p-tolylselanyl) -4- (4-trifluoromethyl) benzylidene-imidazol-5-one (1.20)

To a solution of 0.25 g (0.6 mmol) (Z) -1- (4-methoxyphenyl) -2-selenoxo-4- (4-trifluoromethyl) benzylidene-imidazol-5-one in 5 ml of 1,2-dichloroethane 0.33 g (2.4 mmol) of p-tolylboronic acid, 0.22 g (1.2 mmol) of 1,10-phenanthroline and 0.14 g (0.72 mmol) of copper (II) acetate are added. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 2.44 (s, 3H, Me), 3.84 (s, 3H, ОМе), 6.88 (s, 1H, СН), 7.00 (d, J = 8.9, 2H, Ha _r ), 7.22-7.28 (m, 4H, Ha _r ), 7.44 (d, J = 8.3, 2H, Ha _r ), 7.59 (d, J = 8.1, 2H, Ha _r ), 7.99 (d, J = 8.1 , 2H, Ha _r ). ¹³ С NMR spectrum (101 MHz, CDCl ₃ ) δ 21.6, 55.7, 115.1 (2С), 120.7, 122.6, 124.11 (120.05, 122.75, 125.46, 128.17, q, J = 272.2), 125.29 (125.23, 125.27, 125.31, 125.35, q, 3 = 4, 2C), 125.33, 128.7 (2C), 130.3 (2C), 130.86 (130.38, 130.70, 131.02, 131.34, q, J = 32.5), 132.1 (2C), 136.5 (2C), 137.8 (137.83, 137.84, d, J = 1.2), 140.2, 140.3, 160.5, 165.3, 168.9. IR spectrum (KBr, cm ^-1 ): 652, 698, 736, 764, 798, 826, 844, 922, 948, 1026, 1068, 1103, 1169, 1199, 1238, 1245, 1324, 1376, 1419, 1488 , 1511, 1608, 1643, 1731, 2838, 2959, 3047. High resolution mass spectrum (FTMS + cESI): M + H, found 517.0638. C ₂₅ H ₁₉ F ₃ N ₂ O ₂ Se calculated 516.05638. Yellow crystals. Yield: 64%. m.p. 205-206 ° C.

Example 21 (Z) -1- (4-methoxyphenyl) -4- (thiophen-2-ylmethylene) -2- (p-tolylselanyl) imidazol-5-one (1.21)

To a solution of 0.25 g (0.7 mmol) (Z) -1- (4-methoxyphenyl) -4- (thiophen-2-ylmethylene) -2-selenoxoimidazol-5-one in 5 ml of 1,2-dichloroethane is added 0.38 g (2.8 mmol) of p-tolylboronic acid, 0.25 g (1.4 mmol) of 1,10-phenanthroline and 0.15 g (0.84 mmol) of copper (II) acetate. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 2.39 (s, 3H, Me), 3.84 (s, 3H, ОМе), 7.10 (d, J = 8.9, 2H, Na), 7.11-7.12 (m, 1H , Ha _r ), 7.28 (s, 1H, CH), 7.30 (d, J = 8.2, 2H, Ha _r ), 7.39 (d, J = 8.9, 2H, Ha _r ), 7.61 (d, J = 3.6, 1H, H _Thio ), 7.68 (d, J = 8.1, 1H, Ha _r ), 7.81 (d, J = 5.1, 1H, H _Thio ). ¹³ C NMR spectrum (101 MHz, CDCl ₃ ) δ 20.9, 55.5, 114.7 (2C), 118.2, 120.9, 125.2, 127.5, 129.2 (2C), 130.0 (2C), 134.3, 134.5, 135.3 (2C), 135.8, 137.5, 139.0, 159.8, 160.7, 167.1. IR spectrum (KBr, cm ^-1 ): 576, 596, 634, 659, 702, 736, 753, 764, 798, 837, 855, 887, 908, 940, 1024, 1048, 1068, 1108, 1159, 1173 , 1188, 1203, 1240, 1258, 1310, 1368, 1418, 1443, 1478, 1512, 1624, 1717, 2844, 2939, 3073. High resolution mass spectrum (FTMS + cESI): M + H, found 455.0320. C ₂₅ H ₁₉ F ₃ N ₂ O ₂ Se calculated 454.02542. Yellow crystals. Yield: 66%. m.p. 167-168 ° C.

Example 22 (Z) -4-ethoxybenzylidene) -1- (3-methoxyphenyl) -2- (p-tolylselanyl) imidazol-5-one (1.22)

To a solution of 0.25 g (0.6 mmol) of (Z) -4-ethoxybenzylidene-1- (3-methoxyphenyl) -2-selenoxoimidazol-5-one in 5 ml of 1,2-dichloroethane add 0.33 g (2 , 4 mmol) of p-tolylboronic acid, 0.22 g (1.2 mmol) of 1,10-phenanthroline and 0.14 g (0.72 mmol) of copper (II) acetate. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 1.44 (t, J = 7.0, 3H, OEt), 2.46 (s, 3H, Me), 3.85 (s, 3H, ОМе), 4.07 (q, J = 7.0 , 2H, OEt), 6.78 (d, J = 8.8, 2H, Ha _r ), 6.91 (t, J = 2.0, 1H, Ha _r ), 6.96 (s, 1H, CH), 6.97-7.01 (m, 2H , Ha _r ), 7.25 (d, J = 6.9, 2H, Ha _r ), 7.41 (t, J = 8.1, 1H, Ha _r ), 7.63 (d, J = 8.0, 2H, Ha _r ), 7.91 (d , J = 8.8, 2H, Ha _r ). ¹³ C NMR spectrum (101 MHz, CDCl ₃ ) δ 14.9, 21.5, 55.6, 63.6, 112.6, 114.6 (2C), 115.3, 119.2, 125.9, 127.3, 130.1 (2C), 130.4, 134.2 (2C), 134.4, 136.5 (2C), 136.9, 139.7, 159.8, 160.5, 160.7, 168.8. IR spectrum (KBr, cm ^-1 ): 559, 645, 686, 729, 781, 802, 834, 912, 980, 1042, 1111, 1151, 1183, 1253, 1312, 1359, 1395, 1453, 1498, 1566 , 1599, 1632, 1702, 2929, 2973. High resolution mass spectrum (FTMS + cESI): M + H, found 493.1035. C ₂₅ H ₁₉ F ₃ N ₂ O ₂ Se calculated 492.09521. Yellow crystals. Yield: 87%. m.p. 157-158 ° C.

Example 23 (Z) -4- (ethoxybenzylidene) -1- (2-methoxyphenyl) -2- (p-tolylselanyl) imidazol-5-one (1.23)

To a solution of 0.25 g (0.6 mmol) (Z) -4- (ethoxybenzylidene) -1- (2-methoxyphenyl) -2-selenoxoimidazol-5-one in 5 ml of 1,2-dichloroethane add 0.33 g (2.4 mmol) p-tolylboronic acid, 0.22 g (1.2 mmol) 1,10-phenanthroline and 0.14 g (0.72 mmol) copper (II) acetate. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent was removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture was redissolved in ethyl acetate, after which hexane was added dropwise until the characteristic turbidity. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 1.43 (t, J = 7.0, 3H, OEt), 2.43 (s, 3H, Me), 3.83 (s, 3H, ОМе), 4.07 (q, J = 7.0 , 2H, OEt), 6.79 (d, J = 8.9, 2H, Ha _r ), 6.95 (s, 1H, CH), 7.02-7.07 (m, 2H, Ha _r ), 7.22 (d, J = 7.9, 2H , Ha _r ), 7.26-7.29 (m, 1H, Ha _r ), 7.45 (td, J = 8.3, 1.6, 1H, Ha _r ), 7.62 (d, J = 8.1, 2H, Ha _r ), 7.95 (d , J = 8.8, 2H, Ha _r ). ¹³ C NMR spectrum (101 MHz, CDCl ₃ ) δ 14.9, 21.5, 55.9, 63.6, 112.4, 114.6 (2C), 121.0, 121.2, 121.8, 125.5, 127.4, 130.07 (2C), 130.09, 131.3, 134.1 (2C) , 136.3 (2C), 137.1, 139.5, 150.2, 155.8, 160.6, 169.2. IR spectrum (KBr, cm ^-1 ): 572, 634, 661, 713, 750, 765, 802, 831, 840, 862, 889, 920, 942, 1023, 1043, 1070, 1111, 1152, 1174, 1203 , 1234, 1249, 1283, 1304, 1342, 1358, 1394, 1463, 1491, 1504, 1566, 1598, 1634, 1718, 2932, 2975. High resolution mass spectrum (FTMS + cESI): M + H, found 493.1030 ... C ₂₆ H ₂₄ N ₂ O ₃ Se calculated 492.09521. Yellow crystals. Yield: 70%. m.p. 190-191 ° C.

Example 24 (Z) -4- (4-ethoxybenzylidene) -1-phenyl-2- (p-tolylselanyl) imidazol-5-one (1.24)

To a solution of 0.25 g (0.7 mmol) of (Z) -4- (4-ethoxybenzylidene) -1-phenyl-2-selenoxoimidazol-5-one in 5 ml of 1,2-dichloroethane add 0.38 g (2 , 8 mmol) of p-tolylboronic acid, 0.25 g (1.4 mmol) of 1,10-phenanthroline and 0.15 g (0.84 mmol) of copper (II) acetate. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 1.44 (t, J = 7.0, 3H, OEt). 2.45 (s, 3H, Me), 4.07 (q, J = 7.0, 2H, OEt), 6.78 (d, J = 8.8, 2H, Ha _r ), 6.96 (s, 1H, CH), 7.24-7.26 (m , 2H, Ha _r ), 7.39 (d, J = 7.3, 2H, Ha _r ), 7.44-7.54 (m, 3H, Ha _r ), 7.63 (d, J = 8.0, 2H, Ha _r ), 7.91 (d , J = 8.7, 2H, Ha _r ). ¹³ C NMR spectrum (101 MHz, CDCl ₃ ) δ 14.9, 21.6, 63.7, 114.6 (2C), 121.1, 126.0, 127.3 (2C), 127.3, 129.3, 129.7 (2C), 130.2 (2C), 133.4, 134.2 ( 2C), 136.5 (2C), 136.9, 139.8, 159.9, 160.7, 169.0. IR spectrum (KBr, cm ^-1 ): 567, 626, 649, 733, 753, 798, 828, 913, 944, 1015, 1048, 1066, 1094, 1109, 1157, 1197, 1239, 1264, 1312, 1349 , 1363, 1405, 1494, 1564, 1601, 1635, 1713, 2927, 2977. High resolution mass spectrum (FTMS + cESI): M + H, found 463.0930. C ₂₆ H ₂₄ N ₂ O ₃ Se calculated 462.084649. Yellow crystals. Yield: 79%. m.p. 146-147 ° C.

Example 25 (Z) -4- (4-ethoxybenzylidene) -1- (4-fluorophenyl) -2- (p-tolylselanyl) imidazol-5-one (1.25)

To a solution of 0.25 g (0.6 mmol) (Z) -4- (4-ethoxybenzylidene) -1- (4-fluorophenyl) -2-selenoxoimidazol-5-one in 5 ml of 1,2-dichloroethane add 0, 33 g (2.4 mmol) of p-tolylboronic acid, 0.22 g (1.2 mmol) of 1,10-phenanthroline and 0.14 g (0.72 mmol) of copper (II) acetate. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 1.43 (t, J = 7.0, 3H, OEt), 2.45 (s, 3H, Me), 4.07 (q, J = 7.0, 2H, OEt), 6.78 (d , J = 8.8, 2H, Ha _r ), 6.96 (s, 1H, CH), 7.19 (t, J = 8.5, 2H, Ha _r ), 7.25 (d, J = 7.9, 2H, Ha _r ), 7.36 ( dd, J = 8.7, 4.8, 2H, Ha _r ), 7.61 (d, J = 8.0, 2H, Ha _r ), 7.91 (d, J = 8.7, 2H, Ha _r ). ¹³ C NMR spectrum (101 MHz, CDCl ₃ ) δ 14.9, 21.6, 63.7, 114.6 (2C), 116.8 (116.64, 116.87, d, J = 23.0, 2C), 120.9, 126.3, 127.2, 129.2, 129.3 (2C) , 130.2 (2C), 134.3 (2C), 136.4 (2C), 136.6, 139.9, 159.5, 160.9, 162.8 (161.6, 164.1, d, J = 249.5), 168.9. IR spectrum (KBr, cm ^-1 ): 564, 588, 628, 650, 683, 735, 754, 794, 805, 837, 915, 945, 1014, 1048, 1066, 1111, 1157, 1178, 1197, 1221 , 1236, 1253, 1308, 1362, 1389, 1497, 1510, 1568, 1600, 1638, 1716, 2868, 2923, 2986, 3067. High resolution mass spectrum (FTMS + cESI): M + H, found 481.0821. C ₂₆ H ₂₄ N ₂ O ₃ Se calculated 480.07522. Yellow crystals. Yield: 96%. m.p. 184-185 ° C.

Example 26 (Z) -1- (4-chlorophenyl) -4- (4-ethoxybenzylidene) -2- (p-tolylselanyl) imidazol-5-one (1.26)

To a solution of 0.25 g (0.6 mmol). (Z) -1- (4-chlorophenyl) -4- (4-ethoxybenzylidene) -2-selenoxoimidazol-5-one in 5 ml of 1,2-dichloroethane add 0.33 g (2.4 mmol) of p-tolylboronic acid , 0.22 g (1.2 mmol) of 1,10-phenanthroline and 0.14 g (0.72 mmol) of copper (II) acetate. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 1.44 (t, J = 6.9, 3H, OEt), 2.45 (s, 3H, Me), 4.07 (q, J = 13.7, 6.8, 2H, OEt), 6.78 (d, J = 8.4, 2H, Ha _r ), 6.96 (s, 1H, CH), 7.25-7.26 (m, 2H, Ha _r ), 7.33 (d, J = 8.4, 2H, Ha _r ), 7.48 ( d, J = 8.2, 2H, Ha _r ), 7.60 (d, J = 7.7, 2H, Ha _r ), 7.91 (d, J = 8.2, 2H, Ha _r ). ¹³ C NMR spectrum (101 MHz, CDCl ₃ ) δ 14.9, 21.6, 63.7, 114.6 (2C), 120.9, 126.5, 127.1, 128.5 (2C), 129.9 (2C), 130.2 (2C), 131.9, 134.3 (2C) , 135.1, 136.5 (2C), 136.5, 139.9, 159.0, 160.9, 168.8. IR spectrum (ZnSe, cm ^-1 ): 567, 626, 649, 733, 753, 798, 828, 913, 944, 1015, 1048, 1066, 1094, 1109, 1157, 1197, 1239, 1264, 1312, 1349 , 1363, 1405, 1494, 1564, 1601, 1635, 1713, 2927, 2977. High resolution mass spectrum (FTMS + cESI): M + H, found 497.0533. C ₂₅ H ₂₁ ClN ₂ O ₂ Se calculated 496.04567. Yellow crystals. Yield: 89%. m.p. 169-170 ° C.

Example 27 (Z) -1- (4-bromophenyl) -4- (4-ethoxybenzylidene) -2- (p-tolylselanyl) imidazol-5-one (1.27)

To a solution of 0.25 g (0.55 mmol) (Z) -1- (4-bromophenyl) -4- (4-ethoxybenzylidene) -2-selenoxoimidazol-5-one in 5 ml of 1,2-dichloroethane add 0, 30 g (2.2 mmol) of p-tolylboronic acid, 0.20 g (1.1 mmol) of 1,10-phenanthroline and 0.12 g (0.67 mmol) of copper (II) acetate. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 1.44 (t, 3 = 6.9, 3H, OEt), 2.46 (s, 3H, Me), 4.07 (q, J = 6.9, 2H, OEt), 6.78 (d , J = 8.7,2H, Ha _r ), 6.96 (s, 1H, CH), 7.24-7.28 (m, 4H, Ha _r ), 7.59-7.54 (m, 4H, Ha _r ), 7.91 (d, J = 8.7, 2H, Ha _r ). ¹³ C NMR spectrum (101 MHz, CDCl ₃ ) δ 14.9, 21.5, 63.7, 114.6 (2C), 120.9, 123.2, 126.5, 127.1, 128.7 (2C), 130.2 (2C), 132.5, 132.9 (2C), 134.3 ( 2C), 136.5 (2C), 136.5, 139.9, 158.9, 160.9, 168.7. IR spectrum (KBr, cm ^-1 ): 566, 624, 648, 731, 753, 799, 827, 911, 943, 1013, 1048, 1067, 1109, 1158, 1189, 1265, 1312, 1348, 1363, 1402 , 1500, 1564, 1601, 1635, 1714, 2928, 2976, 3427. High resolution mass spectrum (FTMS + cESI): M + H, found 541.0035. C ₂₅ H ₂₁ BrN ₂ O ₂ Se calculated 539.9951. Yellow crystals. Yield: 84%. m.p. 192-193 ° C.

Example 28 (Z) -1- (3-chloro-4-fluorophenyl) -4- (4-ethoxybenzylidene) -2- (p-tolylselanyl) imidazol-5-one (1.28)

To a solution of 0.25 g (0.6 mmol) (Z) -1- (3-chloro-4-fluorophenyl) -4- (4-ethoxybenzylidene) -2-selenoxoimidazol-5-one in 5 ml of 1,2- dichloroethane, 0.33 g (2.4 mmol) of p-tolylboronic acid, 0.22 g (1.2 mmol) of 1,10-phenanthroline and 0.14 g (0.72 mmol) of copper (II) acetate are added. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 1.44 (t, J = 7.0, 3H, OEt), 2.45 (s, 3H, Me), 4.07 (q, J = 6.9, 2H, OEt), 6.79 (d , J = 8.7, 2H, Ha _r ), 6.97 (s, 1H, CH), 7.23-7.27 (m, 4H, Ha _r ), 7.42 (d, J = 6.4, 1H, Ha _r ), 7.57 (d, J = 7.9, 2H, Ha _r ), 7.92 (d, J = 8.7, 2H, Ha _r ). ¹³ C NMR spectrum (101 MHz, CDCl ₃ ) δ 14.9, 21.5, 63.7, 114.7 (2C), 117.4 (d, J = 22.6), 120.8, 122.2 (d, J = 19.2), 126.9, 127.0,

127.3 (d, J = 7.7), 129.88, 129.9 (d, J = 2.9), 130.3 (2C), 134.4 (2C), 136.3, 136.4 (2C), 140.0,

158.4 (d, J = 252.3), 158.4, 161.0, 168.7. IR spectrum (ZnSe, cm ^-1 ): 557, 726, 800, 829, 873, 913, 972, 1050, 1110, 1162, 1192, 1254, 1313, 1367, 1405, 1501, 1565, 1599, 1634, 1713 , 2976, 3050. High Resolution Mass Spectrum (FTMS + cESI): M + H, found 515.0420.

C ₂₅ H ₂₀ ClFN ₂ O ₂ Se calculated 514.036255. Yellow crystals. Yield: 66%. m.p. 176-177 ° C.

Example 29 (Z) -4- (4-ethoxybenzylidene) -2- (p-tolylselanyl) -1- (4- (trifluoromethyl) phenyl) imidazol-5-one (1.29)

To a solution of 0.25 g (0.57 mmol) (Z) -4- (4-ethoxybenzylidene) -2-selenoxo-1- (4- (trifluoromethyl) phenyl) -imidazol-5-one in 5 ml 1.2 -dichloroethane, 0.31 g (2.3 mmol) of p-tolylboronic acid, 0.21 g (1.1 mmol) of 1.10-phenanthroline and 0.12 g (0.68 mmol) of copper (II) acetate are added. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

¹ H NMR spectrum (600 MHz, CDCl ₃ ) δ 1.44 (t, J = 7.0, 3H, OEt), 2.45 (s, 3H, ОМе), 4.08 (q, J = 7.0, 2H, OEt), 6.79 (d , J = 8.9, 2H, Ha _r ), 6.99 (s, 1H, CH), 7.24 (d, J = 7.8, 2H, Ha _r ), 7.52 (d, J = 8.2, 2H, Ha _r ), 7.59 ( d, J = 8.0, 2H, Ha _r ), 7.76 (d, J = 8.3, 2H, Ha _r ), 7.92 (d, J = 8.8, 2H, Ha _r ). ¹³ C NMR spectrum (101 MHz, CDCl ₃ ) δ 14.8, 21.5, 63.7, 114.7 (2C), 120.8, 123.8 (121.11, 122.92, 124.72, 126.53, q, J = 272.4), 126.8 (126.78, 126.80, d, J = 3.4, 2C), 126.9, 127.0, 127.3 (2C), 130.3 (2C), 130.9 (130.61, 130.83, 131.05, 131.27, q, J = 32.9), 134.4 (2C), 136.3, 136.5 (2C), 136.7, 140.0, 158.1, 161.0, 168.5. IR spectrum (KBr, cm ^-1 ): 563, 600, 629, 646, 660, 717, 742, 754, 812, 838, 848, 897, 944, 1015, 1043, 1059, 1072.1115, 1163, 1188 , 1254, 1326, 1364, 1394, 1422, 1482, 1509, 1567, 1600, 1634, 1723, 2884, 2981, 3071. High resolution mass spectrum (FTMS + cESI): M + H, found 531.0805. C ₂₆ H ₂₁ F ₃ N ₂ O ₂ Se calculated 530.07203. Yellow crystals. Yield: 72%. m.p. 207-208 ° C.

Example 30 (Z) -4- (4- (4-ethoxybenzylidene) -5-oxo-2- (p-tolylselanyl) -4,5-dihydroimidazol-1yl) benzonitrile (1.30)

To a solution of 0.25 g (0.6 mmol) (Z) -4- (4- (4-ethoxybenzylidene) -5-oxo-2-selenoxo-4,5-dihydroimidazol-1yl) benzonitrile in 5 ml of 1.2 -dichloroethane, 0.33 g (2.4 mmol) of p-tolylboronic acid, 0.22 g (1.2 mmol) of 1.10-phenanthroline and 0.14 g (0.72 mmol) of copper (II) acetate are added. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ 1.44 (t, J = 6.6, 3H, OEt), 2.46 (s, 3H, Me), 4.07 (q, J = 13.4, 6.5, 2H, OEt), 6.79 (d, J = 8.2, 2H, Ha _r ), 6.99 (s, 1H, CH), 7.25 (d, J = 7.6, 2H, Ha _r ), 7.54 (d, J = 7.9, 2H, Ha _r ), 7.58 (d, J = 7.7, 2H, Ha _r ), 7.79 (d, J = 8.0, 2H, Ha _r ), 7.90 (d, J = 8.3, 2H, Ha _r ). ¹³ C NMR spectrum (101 MHz, CDCl ₃ ) δ 14.8, 21.5, 63.7, 112.5, 114.7 (2C), 118.1, 120.7, 126.9, 127.3, 127.4 (2C), 130.3 (2C), 133.5 (2C), 134.5 ( 2C), 136.1, 136.5 (2C), 137.5, 140.1, 157.3, 161.1, 168.2. IR spectrum (ZnSe, cm ^-1 ): 570, 627, 652, 708, 738, 798, 841, 913, 947, 1014, 1046, 1067, 1111, 1160, 1192, 1267, 1313, 1350, 1366, 1498 , 1511, 1564, 1601, 1638, 1717, 2229, 2980, 3066. High resolution mass spectrum (FTMS + cESI): M + H, found 488.0865. C ₂₆ H ₂₁ N ₃ O ₂ Se calculated 487.0798. Yellow crystals. Yield: 56%. m.p. 213-214 ° C.

Example 31 (Z) -1-cyclopropyl-4- (4-ethoxybenzylidene) -2- (p-tolylselanyl) imidazol-5-one (1.31)

To a solution of 0.25 g (0.6 mmol) (Z) -1-cyclopropyl-4- (4-ethoxybenzylidene) -2-selenoxoimidazol-5-one in 5 ml of 1,2-dichloroethane add 0.33 g (2 , 4 mmol) of p-tolylboronic acid, 0.22 g (1.2 mmol) of 1,10-phenanthroline and 0.14 g (0.72 mmol) of copper (II) acetate. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

¹ H NMR spectrum (600 MHz, DMSO) δ 0.92-0.99 (m, 4H, CH ₂ Cycloprop.), 1.32 (t, J = 7.0, 3H, OEt), 2.42 (s, 3H, Me), 2.74-2.78 (m, 1H, CH Cycloprop.), 4.06 (q, J = 7.0.2H, OEt), 6.71 (s, 1H, CH), 6.80 (d, J = 8.9, 2H, Ha _r ), 7.33 (d, J = 8.3, 2H, Ha _r ), 7.66 (d, J = 8.1,2H, Ha _r ), 7.89 (d, J = 8.9, 2H, Ha _r ). ¹³ C NMR spectrum (151 MHz, DMSO) δ 6.0 (2C), 14.5, 20.8, 22.2, 63.2, 114.4 (2C), 121.0, 123.1, 126.7, 129.9 (2C), 133.6 (2C), 135.8 (2C), 137.0, 139.2, 159.9, 162.6, 168.6. IR spectrum (ZnSe, cm ^-1 ): 558, 698, 721, 759, 798, 835, 921, 1000, 1039, 1107, 1151, 1177, 1213, 1240, 1310, 1372, 1392, 1426, 1495, 1565 , 1632, 1707, 1727, 2924, 2971, 3024. High resolution mass spectrum (FTMS + cESI): M + H, found 427.0913. C ₂₂ H ₂₂ N ₂ O ₂ Se calculated 426.08464. Yellow crystals. Yield: 68%. m.p. 225-226 ° C.

Example 32 (Z) -1-benzyl-4- (4-ethoxybenzylidene) -2- (p-tolylselanyl) imidazol-5-one (1.32)

To a solution of 0.25 g (0.54 mmol) (Z) -1-benzyl-4- (4-ethoxybenzylidene) -2-selenoxoimidazol-5-one in 5 ml of 1,2-dichloroethane add 0.29 g (2 , 2 mmol) of p-tolylboronic acid, 0.19 g (1.1 mmol) of 1,10-phenanthroline and 0.12 g (0.65 mmol) of copper (II) acetate. The resulting mixture was stirred at room temperature for 2 hours, then placed in a microwave reactor and stirred for 30 minutes. at 80 ° C. After completion of the reaction (control: TLC), the reaction mixture was washed with saturated EDTA solution and extracted with ethyl acetate. The solvent is removed from the combined organic fractions on a vacuum rotary evaporator, and the resulting mixture is redissolved in ethyl acetate, after which hexane is added dropwise until it becomes cloudy. The resulting solution is applied to silica gel and washed with a mixture of ethyl acetate / hexane in a ratio of 1: 2. The fractions containing the target substance are combined, the solvent is removed on a vacuum rotary evaporator, and the resulting yellow substance is dissolved in dichloromethane and precipitated with hexane. The resulting precipitate is filtered and air-dried.

¹ H NMR (400 MHz, DMSO) δ 1.32 (t, J = 6.8, 3H, OEt), 2.39 (s, 3H, Me), 4.06 (q, J = 6.6, 2H, OEt), 4.81 (s, 2H, CH ₂ ), 6.83 (d, J = 8.5, 2H, Ha _r ), 6.90 (s, 1H, CH), 7.28-7.40 (m, 7H, Ha _r ), 7.59 (d, J = 7.7, 2H , Ha _r ), 7.96 (d, J = 8.5, 2H, Ha _r ). ¹³ C NMR spectrum (151 MHz, DMSO) δ 14.5, 20.9, 44.2, 63.3, 114.5 (2C), 120.7, 124.6, 126.6, 127.2 (2C), 127.8, 128.8 (2C), 130.1 (2C), 134.0 (2C ), 135.7 (2C), 136.2, 136.4, 139.4, 160.1, 160.3, 168.6. IR spectrum (ZnSe, cm ^-1 ): 551, 576, 616, 662, 698, 723, 759, 806, 831, 876, 905, 919, 951, 1016, 1039, 1073, 1106, 1124, 1168, 1249 , 1284, 1308, 1327, 1346, 1360, 1391, 1437, 1454, 1485, 1508, 1566, 1599, 1631, 1704, 2935, 2975. High resolution mass spectrum (FTMS + cESI): M + H, found 477.1065 ... C ₂₆ H ₂₄ N ₂ O ₂ Se calculated 476.10029. Yellow crystals. Yield: 64%. t. pl. 136-137 ° C.

Example 33. Obtaining salts (in the form of hydrochlorides).

To obtain salts of aryl-thiohydantoins of formula 1, the obtained compounds 1.1-1.32 are dissolved in alcohol, a saturated alcoholic solution of hydrogen chloride is added to them. After the end of the reaction, the precipitate formed is filtered off. Crystals of the hydrochlorides of compounds 1.1-1.32 are obtained.

Example 34. Biological tests

All of the aryl-2-selenohydantoins of formula 1 presented were tested for their ability to block cell growth and induce apoptosis in various strains of tumor cell lines. These models include embryonic kidney cells (Hek293), breast cancer cells (MCF-7), human lung fibroblasts (VA13), and human lung cancer cells (A549). The cytotoxicity of these substances was assessed using a standard MTT assay with (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyl tetrazolium bromide. The IC ₅₀ values obtained are shown in Table 1).

Основываясь на данных таблицы 1 можно сделать выводы, что соединение 1.6 проявило токсичность на клетках рака легкого, молочной железы и легочных фибропластах, при этом не затрагивая эмбриональные клетки почки, тогда как 1.10 не проявило токсичности на легочных фибропластах, что позволяет утверждать, что данные соединения проявляют специфичность к некоторым клеточным рецепторам. Работы по более подробному изучению биологического эффекта данного класса соединений, а также по изучению действия на клетки рака простаты, для которого, как предполагается, предназначены данные препараты, будет проводиться в дальнейшем.

Based on the data in Table 1, it can be concluded that compound 1.6 showed toxicity on lung cancer cells, breast cancer and lung fibroblasts, while not affecting embryonic kidney cells, whereas 1.10 did not show toxicity on lung fibroblasts, which suggests that these compounds show specificity for some cellular receptors. Work on a more detailed study of the biological effect of this class of compounds, as well as on the study of the effect on prostate cancer cells, for which these drugs are supposed to be intended, will be carried out in the future.

Example 35 Cytotoxicity Study Protocol

The cytotoxicity of the test substances was determined using the MTT assay (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) with some modifications. 2500 cells per well for cell lines PC3, LnCap, MCF7, HEK293T and A549 or 4000 cells per well for cell line VA-13 were seeded in 135 μl of DMEM-F12 medium (Gibco, USA) in a 96-well plate and incubated in 5% CO ₂ incubator for the first 16 hours without treatment. Then, 15 μL of solutions of test substances (DMSO) of medium-DMSO in media were added (final concentrations of DMSO in media were 1% or less) and the cells were treated for 72 h with 50 nM - 100 μM (eight dilutions) of our substances (three times each ) and doxorubicin and / or enzalutamide as a control. Then MTT reagent (Paneco LLC, Russia) was added to the cells to a final concentration of 0.5 g / L (10X stock solution in PBS was used) and incubated for 2 h at 37 ° C in an incubator in an atmosphere of 5% CO ₂ , Then the solution MTT was discarded and 140 μL of DMSO (PharmaMed LLC, Russia) was added. The plates were rocked on a shaker (60 rpm) to solubilize the formazan. Absorbance was measured using a microplate reader (VICTOR X5 Light Plate Reader, PerkinElmer, USA) with a wavelength of 565 nm (to measure the concentration of formazan). The results were used to plot a dose-response graph and estimate the IC ₅₀ value (GraphPad Software, Inc., San Diego, CA).

Example 36. Obtaining a medicinal product in the form of tablets.

1600 mg of starch, 1600 mg of ground lactose, 400 mg of talc and 1000 mg of compound 1.1 are mixed and compressed into a bar. The resulting bar is crushed into granules and sieved through sieves, collecting granules with a size of 14-16 mesh. The resulting granules are tableted into a suitable tablet form, each weighing 560 mg.

Example 37. Obtaining a medicinal product in the form of capsules.

Compound 1.1 is thoroughly mixed with lactose powder in a 2: 1 ratio. The resulting powder mixture is packaged in 300 mg gelatin capsules of suitable size.

Example 38. Obtaining a medicinal product in the form of injectable compositions for intramuscular, intraperitoneal or subcutaneous injection.

500 mg of compound 1.1 is mixed with 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of injection water. The resulting solution is filtered and placed in 1 ml ampoules, which are sealed.

Thus, a number of new, previously not described derivatives of 2-selenohydantoin were obtained. For the first time, a technique was developed for the arylation of 2-selenohydantoins with arylboronic acids, catalyzed by copper (II) salts. A series of previously undescribed 3-aryl-5-arylidene-2- (arylselanyl) -imidazol-4-ones has been obtained. A study of the cytotoxicity of the obtained 3-aryl-5-arylidene-2- (arylselanyl) -imidazol-4-ones in the MTT / MTS test on the cell lines HEK-293, MCF-7, A-549 and VA-13 was carried out. Compounds have been synthesized that exhibit selective toxicity in relation to certain cell lines.

Claims (50)

1. A compound that is a 2-selenoxo-tetrahydro-4n-imidazol-4-one derivative of the general formula 1 or a pharmaceutically acceptable salt or optical isomer thereof,

Where R ₁ is phenyl, possibly substituted by 1-2 substituents selected from a halogen atom, a lower alkoxy group, methyl; R ₂ is phenyl, possibly substituted by 1-2 substituents selected from a halogen atom, a lower alkoxy group, a cyano group; R ₃ is phenyl optionally substituted with 1 substituent selected from a halogen atom, a lower alkoxy group, or methyl. 2. A compound according to claim 1, characterized in that it is a compound selected from the group consisting of: (Z) -3- (p-tolyl) -5- (4-ethoxybenzylidene) -2- (p-tolylselanyl) -imidazol-4-one (1.1) (Z) -3- (4-methoxyphenyl) -5- (4-fluorobenzylidene) -2- (p-tolylselanyl) -imidazol-4-one (1.2) (Z) -3- (4-methoxyphenyl) -5- (4-ethoxybenzylidene) -2 - ((3-fluorophenyl) selanyl) -imidazol-4-one (1.3) (Z) -3- (4-methoxyphenyl) -5- (4-ethoxybenzylidene) -2- (p-tolylselanyl) imidazol-4-one (1.4) (Z) -3- (4-methoxyphenyl) -5- (4-fluorobenzylidene) -2 - ((4-chlorophenyl) selanyl) -imidazol-4-one (1.5) (Z) -3- (4-methoxyphenyl) -5- (4-ethoxybenzylidene) -2 - ((3-methoxyphenyl) selanyl) imidazol-4-one (1.6) (Z) -3- (4-methoxyphenyl) -5- (4-ethoxybenzylidene) -2- (phenylselanyl) -imidazol-4-one (1.7) (Z) -3- (4-methoxyphenyl) -5- (2-chlorobenzylidene) -2 - ((4-chlorophenyl) selanyl) -imidazol-4-one (1.8) (Z) -3- (4-methoxyphenyl) -5- (2-chlorobenzylidene) -2- (p-tolylselanyl) -imidazol-4-one (1.9) (Z) -3- (4-methoxyphenyl) -5- (4-chlorobenzylidene) -2 - ((4-chlorophenyl) selanyl) -imidazol-4-one (1.10) (Z) -3- (4-methoxyphenyl) -5- (4-cyanobenzylidene) -2 - ((4-tolyl) selanyl) -imidazol-4-one (1.11) (Z) -3- (4-methoxyphenyl) -5- (4-cyanobenzylidene) -2 - ((3-methoxyphenyl) selanyl) -imidazol-4-one (1.12) (Z) -4-benzylidene-1 - (4-methoxyphenyl) -2- (p-tolylselanyl) -imidazol-5-one (1.16) (Z) -1- (4-methoxyphenyl) -4- (4-methylbenzylidene) -2- (p-tolylselanyl) -imidazol-5-one (1.17) (Z) -4- (4-chlorobenzylidene) -1- (4-methoxyphenyl) -2- (p-tolylselanyl) -imidazol-5-one (1.18) (Z) -4- (3-chlorobenzylidene) -1- (4-methoxyphenyl) -2- (p-tolylselanyl) -1-imidazol-5-one (1.19) (Z) -4-ethoxybenzylidene) -l- (3-methoxyphenyl) -2- (p-tolylselanyl) -imidazol-5-one (1.22) (Z) -4- (ethoxybenzylidene) -1- (2-methoxyphenyl) -2- (p-tolylselanyl) -imidazol-5-one (1.23) (Z) -4- (4-ethoxybenzylidene) -1-phenyl-2- (p-tolylselanyl) -imidazol-5-one (1.24) (Z) -4- (4-ethoxybenzylidene) -1- (4-fluorophenyl) -2- (p-tolylselanyl) -imidazol-5-one (1.25) (Z) -1- (4-chlorophenyl) -4- (4-ethoxybenzylidene) -2- (p-tolylselanyl) -imidazol-5-one (1.26) (Z) -1- (4-bromophenyl) -4- (4-ethoxybenzylidene) -2- (p-tolylselanyl) -imidazol-5-one (1.27) (Z) -1- (3-chloro-4-fluorophenyl) -4- (4-ethoxybenzylidene) -2- (p-tolylselanyl) -imidazol-5-one (1.28) (Z) -4- (4-ethoxybenzylidene) -2- (p-tolylselanyl) -1- (4- (trifluoromethyl) phenyl) imidazol-5-one (1.29) (Z) -4- (4- (4-ethoxybenzylidene) -5-oxo-2- (p-tolylselanyl) -4,5-dihydroimidazol-l-yl) benzonitrile (1.30) 3. A method for synthesizing a compound according to claim 1, characterized in that the starting compound from the 2-selenohydantoin group is dissolved in an organic solvent, then arylboronic acid, a copper salt and a ligand are added to dissolve the copper salt, in ratios that allow the reaction to proceed, after all components, the resulting solution is placed in a microwave reactor and stirred for 30 ± 15 min at the boiling point of the solvent, after the end of the reaction, inorganic impurities are removed from the reaction mixture, and the remaining organic fraction is concentrated by removing the solvent, the target product is isolated by column chromatography, after which the resulting the powder is dried in air to constant weight. 4. The method according to claim 3, characterized in that for 250 ± 50 mg of the starting 2-selenohydantoin, from 5 to 10 ml of an organic solvent are taken. 5. The method according to claim 3, characterized in that tetrahydrofuran, 1,2-dichloroethane, dimethylformamide are used as the organic solvent. 6. The method according to claim 3, characterized in that various aromatic boric acids with donor and acceptor substituents are used as arylboronic acid. 7. The method according to claim 3, characterized in that 1 to 5 molar equivalents of arylboronic acid are taken for 1 molar equivalent of 2-selenohydantoin. 8. The method according to claim 3, characterized in that for 1 molar equivalent of 2-selenohydantoin, 1.5 ± 0.4 molar equivalents of the copper salt and the ligand are taken. 9. The method according to claim 3, characterized in that divalent copper salts are used as copper salts. 10. The method according to claim 3, characterized in that compounds capable of forming strong mononuclear complexes with the copper (II) ion are used as the ligand. 11. The method according to claim 10, characterized in that 2,2'-bipyridyl, 1,10-phenanthroline or tetramethylethylenediamine are used as ligands. 12. The method according to claim 3, characterized in that the reaction mixture is washed with a saturated EDTA solution and extracted with ethyl acetate or dichloromethane to separate the inorganic components. 13. The method according to claim 3, characterized in that the solvent is removed on a vacuum rotary evaporator. 14. The method according to claim 3, characterized in that the reaction mixture is additionally stirred at room temperature for 2 to 3 hours before it is placed in the microwave reactor to ensure the passage of the reaction. 15. An active ingredient with antitumor activity, characterized in that it is a compound according to claim 1. 16. The use of a compound according to claim 1 as a compound having antitumor activity. 17. A pharmaceutical composition for the prevention and treatment of oncological disease, characterized in that it contains an active ingredient according to claim 15 in a therapeutically effective amount. 18. A pharmaceutical composition according to claim 17, characterized in that the cancer is prostate cancer. 19. A medicament for the prevention and treatment of proliferative diseases, characterized in that it is made in the form of tablets, capsules or injections placed in a pharmaceutically acceptable package containing in an effective amount the active ingredient according to claim 15 or a pharmaceutical composition according to claim 17. 20. A method for the prevention and treatment of oncological disease, characterized in that it includes the introduction into a cell of a compound of general formula 1 according to claim 1.