RU2690161C1 - 3,5-substituted thiazolidine-2,4-dione derivatives, having antimicrobial activity - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula (I) or a pharmaceutically acceptable salt thereof, where R₁ is selected independently and is H, halogen; R₂ is selected independently and is H, halogen; R₃ is selected independently and is H, halogen; X is independently selected and represents OH, halogen, 6-member heterocyclyl containing 2 N atoms, optionally containing a substitute R₄; R₄ is independently selected and represents -C_1-6-alkyl, -C_1-6-alkyl-OH, 4-hydroxy-phenyl, -COCH₃-, -COO-tBu or represents a substitute of following structural formula (a) or (b), wherein the wavy line shows the place of attachment of substitute to fragment X, R₅ is selected independently and is H or phenyl substituted with a halogen atom.

formula (I),

(a),

(b).

EFFECT: compounds of the invention are intended for treating and/or preventing an infectious disease of a microbial aetiology caused by a fungal infection.

13 cl, 11 tbl, 9 ex

Description

Technical field

The invention relates to the chemistry of organic compounds, pharmacology and medicine and relates to new chemical compounds characterized by high antimicrobial activity, which, in particular, can be used for the prevention and treatment of infectious diseases in a subject, in particular diseases caused by candida and filamentous pathogens.

The level of technology

The lack of effectiveness of modern antimicrobial therapy is largely due to the development of resistance in pathogens to existing drugs. That is why throughout the world an intensive search and development of new effective medicinal compounds is carried out. Despite all efforts, the modern arsenal of medical devices is insufficient and does not allow for the effective treatment of many diseases, including fungal infections. The currently available antifungal drugs, polyenes and azoles, affecting the main component of the fungal membrane, ergosterol, do not provide adequate selectivity of action. They are very toxic, moreover, many strains of pathogens become resistant to the drugs of the azoles group.

Compounds having a thiazolidinedione moiety and characterized by antifungal activity US7105554, WO2002022612, Thiazolidine and benzylidene thiazolidinedione inhibitors of mannosyltransferease as antifungal agents are known in the prior art // Expert Opinion Ther.pat., Patent. These documents describe substituted derivatives of 5-benzylidene-2,4-thiazolidin-3 acetic acid as antimycotic agents active against many pathogenic fungi. The prior art also known as azole derivatives, characterized by antifungal activity WO2005006860. In addition, methods for the preparation and antifungal activity of acyl derivatives of azoles, a widely known group of antifungal agents, and in particular, compounds obtained by acylation of azole heterocycles on the oxygen atom of the alcohol part of the molecule, are described (Y.Wahbi et al. Aliphatic ethers and esters of 1- (2,4-dichlorophenyl) -2- (lH-imidazolyl) ethanol: study of antifungal activity against yeasts and hydrophobic character // Eur.J.Med.Chem, 1994, 29, 701-6; D. De Vita et al. Synthesis and antifungal activity of the 2- (1H-imidazol-1-yl-1-phenylethanol derivatives // Eur.J.Med.Chem., 2012, 49, 334-342). However, as mentioned above, the main disadvantage of drugs, based on azoles derivatives, is the growing resistance, which can negate all the treatment efforts. The problem is further aggravated by the fact that cross-resistance to all drugs of the azole group is developing (J.E.Parker. Resistance to antifungals that target CYP51 // J.Chem.Biol, 2014.).

Therefore, there remains a high need for the development of new effective agents against infectious diseases, in particular, antifungal agents, for the treatment of a wide range of diseases, in particular, caused by fungal infections.

DISCLOSURE OF INVENTION

The present invention is the development and creation of new effective antimicrobial agents that are promising for use in clinical practice for the treatment and / or prevention of infectious diseases.

The technical result of the invention is the development and production of new chemical compounds with high antimicrobial activity, low toxicity and promising for use in the treatment of infectious diseases in a subject, in particular diseases caused by fungal infections, for example, caused by candidal and filamentous pathogens, in particular for the treatment of dermatophytosis , superficial mycosis, candidiasis of the skin and nails, vaginal candidiasis, candidal stomatitis, endocarditis and other diseases human and animal. The compounds of the invention used for prophylactic purposes may also reduce the risk of developing serious candidal infections in immunocompromised people as a result of therapy (eg chemotherapy), organ transplantation or in people with infectious diseases caused by other pathogens (in particular HIV).

The activity of the claimed compounds investigated in cultures of microbial cells. The compounds of the invention with respect to Candida parapsilosis are not inferior or superior to the activity of Fluconazole and are close to Ketoconazole. In addition, the compounds of the invention, unlike fluconazole, inhibit the growth of filamentous fungi M.canis B-200 and T.rubrum 2002 and are active against fluconazole - resistant pathogens . These types of pathogenic fungi cause various lesions of both internal organs and mucous surfaces, and the outer integument of the skin and its appendages.

Revealed a high anti-candidiasis activity in relation to both typical Candida albinans and Fluconazole-resistant strains of Candida non-albicans microorganisms.

A comparative animal experiment on Candida albicans in vivo on a model of intraperitoneal infection of mice (express method) with a commercial drug Voriconazole revealed a clear superiority of the compounds according to the invention both in terms of doses used and in the effect of suppressing growths (growth tubes) of Candida albicans yeast cells .

This technical result is achieved through the development and creation of compounds of General formula (I):

формула (I),

formula (I)

or its stereoisomer or enantiomer, a pharmaceutically acceptable salt, solvate or hydrate, where:

R ₁ is selected independently and represents H or halogen;

R ₂ is selected independently and represents H or halogen;

R ₃ is selected independently and represents H or halogen;

X is chosen independently and is OH, halogen, 6-membered heterocyclyl containing 2 N atoms, optionally containing an R ₄ substituent;

R ₄ is chosen independently and represents –C _1-6 -alkyl, –C _1-6 –alkyl-OH, –phenyl, 4-hydroxy-phenyl, —COCH ₃ –COO-tBu or is a substituent with the following structural formula:

,

,

,

,

moreover, the wavy line shows the place of attachment of the substituent to fragment X.

R ₅ is independently selected and is H or phenyl substituted by a halogen atom.

A separate subclass of compounds of interest includes compounds of formula (I) in which:

R ₁ is selected independently and represents H, F or Cl;

R ₂ is chosen independently and represents H, F or Cl.

R ₃ is independently selected and is F or Cl;

R ₄ is independently selected and is methyl, isopropyl or - (CH ₂ ) ₂ —OH;

X is selected independently and is chlorine or piperazine;

R ₅ is selected independently and represents H or phenyl substituted by a halogen atom.

In particular embodiments of the invention, the compounds of interest can be selected from the following compounds of general formula (I):

(E) tert -butyl 4- [2- (5- (4-chlorobenzylidene) thiazolidin-2,4-dione-3-yl) -2- (4 chlorophenyl) ethyl] piperazine-1-carboxylate;

(E) t -butyl 4- [2- (5- (4-fluoro-benzylidene) thiazolidin-2,4-dione-3-yl) -2- (4-fluorophenyl) ethyl] piperazine-1-carboxylate;

(E) - t -butyl-4- [2- (5- (4-chlorobenzylidene) thiazolidin-2,4-dione-3-yl) -2- (4-fluorophenyl) ethyl] piperazine-1-carboxylate;

(E) -4 - [(2- (5- (4-chlorobenzylidene) -thiazolidin-2,4-dione-3-yl-1- (phenyl) ethyl] piperazin-1-ium) 2,2,2- trifluoroacetate;

(E) -4 - [(2- (5- (4-chlorobenzylidene) -thiazolidin-2,4-dione-3-yl-1- (4-chlorophenyl) ethyl] piperazin-1-yum) 2,2, 2-trifluoroacetate;

(E) -4 - [(2- (5- (4-fluorobenzylidene) -thiazolidin-2,4-dione-3-yl-1- (4-fluorophenyl) ethyl] piperazin-1-ium) 2.2, 2-trifluoroacetate;

(E) -4 - [(2- (5- (4-chlorobenzylidene) -thiazolidin-2,4-dione-3-yl-1- (2,4-dichlorophenyl) ethyl] piperazin-1-yum) hydrochloride;

(Z) -5- (4-chlorobenzylidene) -3- (2- (2,4-dichlorophenyl) -2-piperazin-yl) ethyl) thiazolidin-2,4-dione;

(Z) -5- (4-fluorobenzylidene) -3- (2- (4-fluorophenyl) -2-piperazin-yl) ethyl) thiazolidin-2,4-dione;

(Z) -5- (4-chlorobenzylidene) -3- (2- (4-chlorophenyl) -2-piperazin-yl) ethyl) thiazolidin-2,4-dione;

(Z) -5- (4-fluorobenzylidene) -3- (2- (4-chlorophenyl) -2-piperazin-yl) ethyl) thiazolidin-2,4-dione;

(Z) -5- (4-chlorobenzylidene) -3- (2- (4-fluorophenyl) -2-piperazin-yl) ethyl) thiazolidin-2,4-dione;

(Z) -5- (4-chlorobenzylidene) -3- (2-phenyl-2- (4-methylpiperazin-1-yl) ethyl) thiazolidin-2,4-dione;

(Z) -5- (4-fluorobenzylidene) -3- (2- (4-chlorophenyl) -2- (4-methoxypiperazin-1-yl) ethyl) thiazolidin-2,4-dione;

(Z) -5- (4-chlorobenzylidene) -3- (2- (4-chlorophenyl) -2- (4- (2-hydroxyethyl) piperazin-1-yl) ethyl) thiazolidin-2,4-dione;

(Z) -5- (4-chlorobenzylidene) -3- (2- (4-chlorophenyl) -2- (4-methylpiperazin-1-yl) ethyl) thiazolidin-2,4-dione;

(Z) -5- (4-chlorobenzylidene) -3- (2- (4-chlorophenyl) -2- (4-isopropyl) piperazin-1-yl) ethyl) thiazolidin-2,4-dione;

(Z) -5- (4-chlorobenzylidene) -3- (2- (4-chlorophenyl) -2- (4- (4-hydroxyphenyl) piperazin-1-yl) ethyl) thiazolidin-2,4-dione;

(Z) -5- (4-chlorobenzylidene) -3- (2- (4-fluorophenyl) -2- (4-methoxypiperazin-1-yl) ethyl) thiazolidin-2,4-dione;

(Z) -3- (2- (4-chlorophenyl) -2- (4- (2- (1- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) ethoxy) acetyl) piperazine -1-yl) ethyl) -5- (4-fluorobenzylidene) thiazolidin-2,4-dione;

(Z) -3- (2- (4-chlorophenyl) -2- (4- (2- (1- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) ethoxy) acetyl) piperazine -1-yl) ethyl) -5- (4-chlorobenzylidene) thiazolidin-2,4-dione;

(Z) -3- (2- (4-fluorophenyl) -2- (4- (2- (1- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) ethoxy) acetyl) piperazine -1-yl) ethyl) -5- (4-fluorobenzylidene) thiazolidin-2,4-dione;

(Z) -5- (4-chlorobenzylidene) -3- (2- (4-chlorophenyl) -2- (4- (2- (2-chlorophenyl) -2- (1- (2,4-dichlorophenyl) - 2- (1H-imidazol-1-yl) ethoxy) acetyl) piperazin-1-yl) ethyl) thiazolidin-2,4-dione;

(Z) -5- (4-fluorobenzylidene) -3- (2- (4-fluorophenyl) -2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1, 2,4-triazol-1-yl) propyl) piperazin-1-yl) ethyl) thiazolidin-2,4-dione;

(Z) -5- (4-chlorobenzylidene) -3- (2- (4-fluorophenyl) -2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1, 2,4-triazol-1-yl) propyl) piperazin-1-yl) ethyl) thiazolidin-2,4-dione.

The present invention relates to the use of the compounds of the invention as an antimicrobial drug.

The present invention relates to the use of the compounds of the invention as an antifungal drug.

This invention also relates to the use of the compounds of the invention for the treatment and / or prevention of infectious diseases, in particular those caused by a fungal infection in a subject. In particular embodiments of the invention, the subject is a human or an animal.

The compounds of the invention exhibit high antifungal activity, in particular with respect to fungi of the genus Candida spp, Aspergillus, Microsporum, Trichophyton and Epidermophyton. The compounds of the invention exhibit high antifungal activity, in particular with respect to fungi of the species Aspergillus fumigatus, Aspergillus niger, Microsporum canis, Trichophyton rubrum and / or Epidermophyton floccosum .

The invention also relates to the use of the compounds of the invention for the preparation of a pharmaceutical composition for the treatment and / or prevention of infectious diseases of microbial etiology. In private embodiments, an infectious disease of microbial etiology is caused by a fungal infection. In private embodiments of the invention, the infectious disease is a disease of the skin, nails or internal organs, in particular such as dermatophytosis, superficial mycosis, candidiasis of the skin and / or nails, vaginal candidiasis, candidal stomatitis, endocarditis and other diseases of a person or animal.

In addition, the invention provides pharmaceutical compositions for the treatment and / or prevention of infectious diseases of microbial etiology, including a therapeutically effective amount of at least one compound that is the subject of the invention, and at least one pharmaceutically acceptable excipient.

In some embodiments, embodiments of the invention, the auxiliary substance may be a carrier, filler and / or solvent.

In some embodiments of the invention, the microbial etiology of the infection is caused by a fungal infection.

In particular embodiments of the invention, the pharmaceutical composition is intended for the treatment of infectious diseases caused by a fungus of the genus Candida spp, Aspergillus, Microsporum, Trichophyton and / or Epidermophyton. In particular embodiments, the pharmaceutical composition is intended to treat infectious diseases caused by a fungus of the species Aspergillus fumigatus, Aspergillus niger, Microsporum canis, Trichophyton rubrum or Epidermophyton floccosum.

In private embodiments of the invention, the pharmaceutical composition is intended for the treatment and / or prevention of a disease that is a disease of the skin, nails or internal organs, in particular dermatophytosis, superficial mycosis, candidiasis of the skin and / or nails, vaginal candidiasis, candidal stomatitis, endocarditis and other human or animal diseases.

The present invention also relates to a method of treating and / or preventing infectious diseases, including administering (as monotherapy or in combination with one or more agents) a therapeutically effective amount of a compound of the invention into a human or animal organism in need of treatment and / or prevention of such diseases. The term “administering” the compound of the present invention includes the delivery to the recipient of the compound described in the present invention, a prodrug, or other pharmacologically acceptable derivative of such a compound, using any acceptable drugs or routes of administration to the body that are well known to specialists.

The invention also includes the preparation of compounds of general formula (I).

Detailed disclosure of the invention

Definitions (terms)

For a better understanding of the present invention, here are some terms used in the present description of the invention. In addition, unless otherwise indicated, all occurrences of functional groups are selected independently; two occurrences can be either the same or different.

In the description of this invention, the terms " includes " and " including " are interpreted to mean "includes, among other things." These terms are not intended to be interpreted as “consists only of”.

The term "alkyl" , by itself or as part of another substituent, refers to straight or branched saturated hydrocarbon groups, including hydrocarbon groups having a specified number of carbon atoms (i.e., C _1-6 means from one to six carbon atoms). Examples of alkyls include methyl, ethyl, n-propyl, iso-propyl.

The term "halogen" by itself or in part of another term refers to a fluorine, chlorine, bromine or iodine atom.

The term "benzylidene" , unless otherwise specified, means a hydrocarbon residue = CH-C ₆ H _5:

.

.

The term "heterocycle" or "heterocyclyl" means herein non-aromatic cyclic systems (saturated or partially unsaturated) having six atoms, containing 2 N heteroatoms. Examples of heterocyclic rings include, but are not limited to, piperazine.

This invention contains only such combinations of substituents and derivatives, which form a stable or chemically possible compound. A stable or chemically feasible compound is a compound whose stability is sufficient for its synthesis and analytical detection. Preferred compounds of this invention are fairly stable and do not decompose at temperatures up to 40 ° C in the absence of chemically active conditions for at least one week.

Unless otherwise indicated, the compound structures described in the application materials also imply all stereoisomers, that is, the R and S isomers for each asymmetric center. In addition, individual stereochemical isomers, as well as enantiomers and diastereomeric mixtures of the present compounds, are also the subject of this invention. Thus, this invention encompasses each diastereomer or enantiomer free to a large extent from other isomers (> 90%; more preferably> 95% molar purity), as well as a mixture of such isomers.

A specific optical isomer can be obtained by separation of the racemic mixture in accordance with standard procedures, for example, by preparing diastereoisomeric salts by treating with an optically active acid or base, followed by separating the mixture of diastereomers with crystallization, followed by separation of the optically active bases from these salts. Examples of suitable acids are tartaric, diacetyl tartaric, dibenzoyl tartaric, ditoluoic tartaric and camphorsulfonic acid. Another technique for separating optical isomers is to use a chiral chromatographic column. In addition, another separation method involves the synthesis of covalent diastereomeric molecules by reacting the compounds of the invention with an optically pure acid in activated form or an optically pure isocyanate. The resulting diastereomers can be separated by conventional methods, for example, by chromatography, distillation, crystallization, or sublimation, and then hydrolyzed to obtain an enantiomerically pure compound.

Optically active compounds of this invention can be obtained using optically active starting materials. Such isomers may be in the form of the free acid, free base, ester or salt.

The term “solvate” refers to an association or complex of one or more solvent molecules and a compound of the invention. Examples of solvents forming solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

The term "hydrate" refers to a complex where the solvent molecules are water.

The compounds of the present invention may exist in free form or, if desired, in the form of a pharmaceutically acceptable salt or other derivative. As used herein, the term "pharmaceutically acceptable salt" refers to such salts that, within the framework of a medical report, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, etc., and meet a reasonable ratio of benefits. and risk. Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates, and other types of compounds are well known in medicine. Salts can be obtained in situ during the isolation or purification process of the compounds of the invention, and can also be obtained separately by reacting the free acid or free base of the compound of the invention with a suitable base or acid, respectively. Examples of pharmaceutically acceptable, non-toxic salts of acids include amino group salts formed with inorganic acids, such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids, or organic acids, such as acetic, oxalic, maleic, tartaric, succinic, or malonic acids, or prepared other methods used in this field, for example, using ion exchange. Other pharmaceutically acceptable ones include adipate and alfat heptanate, hexanate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, symphiduate, polyamide ulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanate, valerate and the like. Typical salts of alkali and alkaline earth metals include sodium, lithium, potassium, calcium, magnesium, and others. In addition, pharmaceutically acceptable salts may contain, if required, non-toxic ammonium, quaternary ammonium and amine cations, obtained using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.

The present invention includes all pharmaceutically acceptable isotopically labeled compounds of the present invention in which one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include hydrogen isotopes, such as ² H and ³ H, carbon, such as ¹¹ C, ¹³ C and ¹⁴ C, chlorine, such as ³⁶ CI, fluorine, such as ¹⁸ F, iodine, such as ¹²³ I and ¹²⁵ I, nitrogen, such as ¹³ N and ¹⁵ N, oxygen, such as ¹⁵ O, ¹⁷ O and ¹⁸ O, phosphor, such as ³² P, and sulfur, such as ³⁵ S.

Some isotopically labeled compounds of formula (I), for example, those that include a radioactive isotope, are used in studies of the distribution of a drug and / or substrate in tissues. In particular, radioactive isotopes, such as tritium, i.e. ³ H, and carbon-14, i.e. ¹⁴ C, are used for this purpose because of their ease of introduction and the availability of means of their detection.

Substitution with heavier isotopes, such as deuterium, i.e. ² H, can provide certain therapeutic effects due to metabolic stability, for example, an increase in half-life in vivo or lower dosage rates, and therefore may be preferable in some cases.

The isotopically labeled compounds of the invention can be obtained by conventional methods known to the person skilled in the art or by methods similar to those described in the attached examples of synthetic methods, using appropriate isotopically labeled reagents instead of the previously unlabeled reagent previously used.

Pharmaceutically acceptable solvates in accordance with the invention include solvates, where the crystallization solvent can be isotopically substituted, for example, D ₂ O, d6-acetone, d6-DMSO.

The term " microbe ", including in the composition of complex words (for example, antimicrobial, antimicrobial), in this document includes, for example, bacteria, fungi, yeast and protozoa.

The implementation of the invention

Overview of Methods for Preparing Compounds of the Invention

The compounds that are the subject of the present invention, can be obtained using the following synthetic methods. The listed methods are not exhaustive and allow the introduction of reasonable modifications. These reactions should be carried out using suitable solvents and materials. When implementing these general methods for the synthesis of specific substances, it is necessary to take into account the functional groups present in the substances and their influence on the course of the reaction. To obtain certain substances, it is necessary to change the order of the stages or to give preference to one of several alternative synthesis schemes. It should be understood that these and all the examples given in the application materials are not limiting and are given only to illustrate the present invention.

General method for producing 3- (2- (R _one R ₂ -phenyl) -2-X-piperazin-1-yl) ethyl) 5-arylidene thiazolidin-2,4-dione derivatives:

1. Preparation of the potassium salt of 5- (R ₃ -benzylidene) thiazolidin-2,4-dione (1)

The potassium salt of 5-arylidene thiazolidine-2,4-dione is obtained in a known manner by reacting 5-arylidene thiazolidine-2,4-dione with potassium hydroxide in dry ethanol (Scheme 1).

Scheme 1. General scheme for the synthesis of potassium salts of 5- (R ₃ -benzylidene) thiazolidin-2,4-dione.

2. Preparation of 3- (2-R ₁ , R ₂ -phenyl-2-hydroxyethyl) substituted 5- (R3-benzylidene) thiazolidine-2,4-dione derivatives (3).

The potassium salt of 5-arylidene thiazolidine-2,4-dione is condensed in DMF with heating with the corresponding α-bromoethyl- (R ₁ , R ₂ ) -phenyl ethanol (2). As a result of the reaction, 3- (2-phenyl-2-hydroxyethyl) substituted 5- (R ₃ -benzylidene) thiazolidine-2,4-dione derivatives are obtained (Scheme 2).

Scheme 2. General scheme for the synthesis of 3- (2- (R ₁ , R ₂ -phenyl) -2-hydroxyethyl) substituted derivatives of 5- (R ₃ -benzylidene) thiazolidin-2,4-dione.

3. Preparation of 3- (2-R ₁ , R ₂ -phenyl-2-chloroethyl) substituted derivatives of 5- (R ₃ -benzylidene) thiazolidin-2,4-dione (4)

Alcoholic hydroxyl of 3- (2-R ₁ , R ₂ -phenyl-2-hydroxyethyl) substituted derivatives of 5- (R ₃ -benzylidene) thiazolidine-2,4-dione as a result of interaction with thionyl chloride is replaced by a chlorine atom with a quantitative yield of c obtaining previously described 3- (2-phenyl-2-chloroethyl) substituted derivatives of 5- (R ₃ -benzylidene) thiazolidin-2,4-dione (Scheme 3).

Scheme 3. General scheme for the synthesis of 3- (2- (R ₁ , R ₂ -phenyl) -2-chloroethyl) substituted derivatives of 5- (R ₃ -benzylidene) thiazolidin-2,4-dione.

4. Preparation of (Z) -5- (R ₃ -benzylidene) -3- (2- (R ₁ , R ₂ -phenyl) -2- (piperazin-1-yl) ethyl) substituted thiazolidin-2,4-dione (5-8)

Chlorinated derivatives of 3- (2-R ₁ , R ₂ -phenyl-2-chloroethyl) substituted derivatives of 5- (R ₃ -benzylidene) thiazolidin-2,4-dione are aminated with Boc-protected piperazine or N-substituted piperazine to give compounds ( 6) and (8) respectively. After removal of the Boc-protection with trifluoroacetic acid or with a solution of hydrogen chloride in ethyl acetate, the desired products (6) are obtained or, after appropriate treatment with sodium carbonate, a base is obtained - the compound (7).

Scheme 4. General scheme for the synthesis of (Z) -5- (R ₃ -benzylidene) -3- (2- (R ₁ , R ₂ -phenyl) -2- (piperazin-1-yl) ethyl) substituted thiazolidin-2, 4-dione.

5. Preparation of amides of (Z) -5- (R ₃ -benzylidene) -3- (2- (R ₁ , R ₂ -phenyl) -2- (piperazin-1-yl) ethyl) substituted thiazolidin-2,4- Dione (10,11).

When interacting salts of (Z) -5- (R ₃ -benzylidene) -3- (2- (R ₁ , R ₂ -phenyl) -2- (piperazin-1-yl) ethyl) substituted thiazolidin-2,4-dione with imidazole acetic acid chloride (9.1), or phenylacetic acid (9.2), the corresponding amides (Z) -5- (R ₃ -benzylidene) -3- (2- (R ₁ , R ₂ -phenyl) -2- (piperazine -1-yl) ethyl) substituted thiazolidine-2,4-dione (10,11).

Scheme 5. General scheme for the synthesis of amides of imidazolyl acetic and phenylacetic acids (Z) -5- (R ₃ -benzylidene) -3- (2- (R ₁ , R ₂ -phenyl) -2- (piperazin-1-yl) ethyl ) thiazolidin-2,4-dione (10,11).

6. Preparation of (Z) -5- (R ₃ -benzylidene) -3- (2- (R ₁ , R ₂ -phenyl) -2- (4- (2- (2,4-difluorophenyl) -2-hydroxy -3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) ethyl) thiazolidin-2,4-dione (13)

In the reaction of the hydrochloric acid or trifluoroacetic salt of (Z) -5- (R ₃ -benzylidene) -3- (2- (R ₁ , R ₂ -phenyl) -2- (piperazin-1-yl) ethyl) substituted thiazolidin-2, 4-dione (6) with a mixture of oxirane methanesulfonate and triethylamine when boiling in ethanol, (Z) -5- (R ₃ -benzylidene) -3- (2- (R ₁ , R ₂ -phenyl) -2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) ethyl) thiazolidin-2,4-diones.

Scheme 6. The general scheme of the synthesis of (Z) -5- (R ₃ -benzylidene) -3- (2- (R ₁ , R ₂ -phenyl) -2- (4- (2- (2,4-difluorophenyl) - 2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) ethyl) thiazolidin-2,4-dione.

Intermediates for the preparation of certain compounds of the invention can be prepared by the procedures in the following examples.

1. An example of obtaining potassium salt of (Z) -5- (4-fluorobenzylidene) thiazolidin-2,4-dione (Scheme 1).

In a 100 ml conical flask equipped with a calcium chloride tube and cooling, 1.12 g of (Z) -5- (4-fluorobenzylidene) thiazolidine-2,4-dione (0.0049 mol) is suspended in 25 ml of dry methanol. At a temperature of 20 ° ^C is made 0.279 g KOH (1.00 mol. Equiv.) In solution in 5 ml of dry methanol. The reaction mass is stirred at 20 ^o C for 1.5 hours, evaporated on a rotary evaporator (FIR) to 1/3 of the volume. The bottom precipitate is filtered and washed with 5 ml of cold dry methanol and 5 ml of diethyl ether. The precipitate is dried under reduced pressure on a rotary evaporator.

1.15 g of (Z) -5- (4-fluorobenzylidene) thiazolidine-2,4-dione potassium salt was obtained. The yield was 89.29%.

Similarly, potassium salts of the other 5-substituted benzylidene thiazolidine-2,4-dione are obtained.

2. An example of obtaining 2-bromo-1- (4-chlorophenyl) ethanol (Scheme 2).

In a 100 ml conical flask equipped with a calcium chloride tube and cooling, 10.00 g of 2-bromoacetophenone (0.045 mole) is dissolved in 50 ml of dry methanol. At a temperature of 0-3 ^{° C} contribute 0.95 g NaBH ₄ (0.55 mol. Eq.), Intense foaming observed. The reaction mass is stirred at 0 ⁰ C for 0.5 hours, the cooling is removed and stirred for another 0.5 hour. The reaction mass is acidified with 0.1 ml of concentrated hydrochloric acid, evaporated on FIR. The bottoms are dissolved in 100 ml of methylene chloride, washed twice with 50 ml of distilled water. The organic layer is dried with Na ₂ SO ₄ and evaporated on a rotary evaporator.

8.16 g of 2-bromo-1- (4-chlorophenyl) ethanol was obtained. The yield was 74.90%

3. An example of obtaining 2- (1- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) ethoxy) acetic acid (9.1), (Schemes 5, 7).

Sodium hydride, 60% suspension in mineral oil (653 mg, 2.1 eq.) Is added to a solution of secondary alcohol (2 g, 1 eq.) In 30 ml of DMF under argon atmosphere, and the mixture is stirred for 20 minutes. Chloroacetic acid (808 mg, 1.1 eq.) Is then added in portions, and the reaction mixture is stirred for 24 hours at room temperature. To the mixture is added 10 ml of water, after which it is acidified with conc. HCl to pH 7 and evaporated under vacuum to dryness. The dry residue is extracted with 30 ml of methanol, filtered, evaporated under vacuum to dryness. The crystalline residue is triturated with ether. Yield 2.45 g (99%).

Scheme 7. Scheme for the synthesis of 2- (1- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) ethoxy) acetic acid.

4. An example of obtaining 2- (1- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) ethoxy) - (2-chlorophenyl) acetic acid (9.2), (schemes 5, 8)

Sodium hydride, 60% suspension in mineral oil (321 mg, 2 eq.) Is added to a solution of secondary alcohol (1 g, 1 eq.) In 30 ml of DMF under argon, after which the mixture is stirred for 20 minutes. Then bromoacid (1 g, 1 eq.) Is added in portions, after which the reaction mixture is stirred for 24 hours at room temperature. To the mixture is added 10 ml of water, after which it is concentrated under vacuum. The residue is diluted with 50 ml of water, the solution is washed with ether and acidified with stirring. HCl to pH 7. The precipitated white substance crystallizes on standing, is filtered, washed with water and ether. Yield 1.36 g of 2- (1- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) ethoxy) - (2-chlorophenyl) acetic acid (80%).

Scheme 8. Scheme for the synthesis of 2- (1- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) ethoxy) - (2-chlorophenyl) acetic acid

5. An example of obtaining 1 - ((2- (2,4-difluorophenyl) oxiran-2-yl) methyl) -1H-1,2,4-triazole methanesulfonate (12) (schemes 6, 9)

To a mixture of 2,4-difluoro-2- (1,2,4-triazol-1-yl) acetophenone (5 g, 1 eq.), Trimethylsulfoxonium iodide (4.93 g, 1 eq.) And hexadecyltrimethylammonium bromide (204 mg, 0.025 eq.) In 40 ml of toluene, 9 ml of 20% NaOH (1.79 g, 2 eq.) Is added. The mixture is stirred at 60 ° C overnight. The emulsion is filtered, the toluene phase is separated, evaporated, the residue is diluted with ethyl acetate. Under stirring, methanesulfonic acid (4.3 g, 2 eq.) Is added dropwise to the resulting solution. The precipitated salt is filtered and washed with ethyl acetate. Yield 4.9 g (66%) of 1 - ((2- (2,4-difluorophenyl) oxirane-2-yl) methyl) -1H-1,2,4-triazole methanesulfonate.

Scheme 9. Synthesis scheme for 1 - ((2- (2,4-difluorophenyl) oxirane-2-yl) methyl) -1H-1,2,4-triazole methanesulfonate.

Examples of obtaining compounds according to the invention

1. An example of obtaining (E) -3- (2-phenyl-2-hydroxyethyl) -5- (4 – chlorobenzylidene) thiazolidin-2,4-dione (3.1)

In a 100 ml conical flask equipped with a calcium chloride tube, 5.55 g of the potassium salt of 5- (4-chlorobenzylidene) thiazolidin-2,4-dione (0.019 mol) is suspended in 25 ml of dry DMF . Making 4.12 g of 2-bromo-1-phenylethanol (1.05 mol. Eq.). The reaction mixture was stirred at ⁷⁵ ° C for 18 hours, removed heat and cooled to 25 ^C. The reaction mixture was poured into 150 ml of distilled water, waiting for the formation of stable precipitate. The precipitate is filtered off, pressed on the filter, washed with 2 portions of 10 ml of diethyl ether, the remaining precipitate is dried in air for 24 hours. Obtained 5.8 g (E) -3- (2-phenyl-2-hydroxyethyl) -5- (4-chlorobenzylidene) thiazolidine-2,4-dione. The dried precipitate is heated in 20 ml of methanol to boiling point and incubated for 1 hour, cooled to room temperature, the precipitate is filtered off and dried.

5.6 g of (E) -3- (2-phenyl-2-hydroxyethyl) -5- (4-chlorobenzylidene) thiazolidine-2,4-dione was obtained . The yield was 74.6%. The structure of the compound was confirmed by a combination of NMR and mass spectrometry data. C ₁₈ H ₁₄ ClNO ₃ S.LCMS [M + H] ⁺ = 361.

1H NMR (500 MHz, DMSO-d6) δ ppm 3.23 (br s, 1 H) 3.66 (dd, J = 13.42, 4.46 Hz, 1 H) 3.83 (dd, J = 13.42, 9.08 Hz, 1 H) 4.88 ( dt, J = 8.96, 4.39 Hz, 1 H) 5.69 (d, J = 4.46 Hz, 1 H) 7.25 - 7.39 (m, 5 H) 7.54 - 7.67 (m, 5 H) 7.90 (s, 1 H)

The following examples of compounds according to the invention, presented in Table 1, were prepared in accordance with the synthesis procedure described for compound 3.1, using the appropriate starting materials: potassium salts of 5-arylidentiazolidine-2,4-dione and 2-bromo-1-aryl ethanol.

Table 1. Examples of compounds according to the invention.

2. An example of obtaining (E) -3- (2-phenyl-2-chloroethyl) - 5- (4-chlorobenzylidene) thiazolidin-2,4-dione (4.1)

In a 50 ml conical flask in 25 ml of methylene chloride, 1.33 g (0.0037 mol) of (E) -3- (2-phenyl-2-hydroxyethyl) -5- (4-chlorobenzylidene) thiazolidine-2,4- dion, to the suspension with stirring, add 1.6 g (4 mol. eq.) of thionyl chloride, and stirred for 18 hours at a temperature of 45 ^o C.

After completion of the reaction, the reaction mixture is evaporated on a rotary evaporator, the resulting residue is washed with 10 ml of cold hexane.

1.37 g of (E) -3- (2-phenyl-2-chloroethyl) -5- (4-chlorobenzylidene) thiazolidine-2,4-dione was obtained. The yield was 98.0%. The structure of the compound is confirmed by a combination of NMR and mass spectrometry data. C ₁₈ H ₁₃ Cl ₂ NO ₂ S. M + 1 = 379.28

¹ H NMR (500 MHz, CHLOROFORM- d ) δppm 3.91 (brd, J = 19.75 Hz, 1 H) 3.91 (brd, J = 7.76 Hz, 1 H) 4.13 (brd, J = 9.17 Hz, 1 H) 4.05 - 4.24 (m, 1 H) 4.06 - 4.14 (m, 1 H) 5.15 (dd, J = 8.41, 6.51 Hz, 1 H) 7.05 - 7.24 (m, 5 H) 7.25 - 7.29 (m, 2 H) 7.42 ( s, 1 H) 7.43 - 7.47 (m, 1 H) 7.51 (s, 1 H) 7.58 - 7.72 (m, 1 H) 7.79 (s, 1 H) 11.95 (brs, 1 H)

The following examples of compounds according to the invention, presented in Table 2, were prepared in accordance with the synthesis procedure described for compound 4.1, using suitable starting materials: (E) -3- (2-aryl-2-hydroxyethyl) -5-arylidene thiazolidin-2 , 4-diones and thionyl chloride

Table 2. Examples of compounds according to the invention.

3. An example of obtaining (E) - tert -butyl 4- [2- (5- (4-chlorobenzylidene) thiazolidin-2,4-dione-3-yl) -2-phenylethyl] piperazine-1-carboxylate (5.1)

In a 50 ml conical flask, 1.37 g (0.0028 mol) of (E) -3- (2-phenyl-2-chloroethyl) -5- (4-chlorobenzylidene) thiazolidin-2,4-dione is dissolved in 25 ml of DMF , 0.65 g (1 mol. equiv.) tert -butyl piperazine-1-carboxylate is added to the solution with stirring, and 0.693 g of calcined potassium carbonate is stirred for 18 hours at 60 ^o C.

After passing through the reaction, the reaction mixture is filtered from inorganic salts and evaporated on a rotary evaporator, the resulting residue is purified on a column (2: 1, hexane-ethyl acetate). Obtained 0.81 g of (E) - tert -butyl 4- [2- (5- (4-hlorobenziliden) thiazolidine-2,4-dione-3-yl) 2- (phenyl-ethyl)] piperazin-1- carboxylate. The yield was 55.1%. C ₂₇ H ₃₀ ClN ₃ O ₄ S. M + 1 = 529.06.

¹ H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.83 - 0.95 (m, 1 H) 1.23 - 1.45 (m, 3H) 1.48 (s, 9 H) 2.05 (s, 1 H) 3.50 (br s, 8 H) 4.03 - 4.24 (m, 2H) 4.59 - 4.67 (m, 1 H) 7.08-7.20 (m, 4H) 7.28-7.32 (m, 4 H) 7.41-7.52 (m, 3H) 7.86-7.98 (m, 2H).

The following examples of compounds according to the invention, shown in Table 3, were prepared in accordance with the synthesis procedure described for compound 5.1, using suitable starting materials: (E) -3- (2-aryl-2-chloroethyl) -5-arylidene thiazolidin-2 , 4-diones and tert -butyl piperazine.

Table 3. Examples of compounds according to the invention.

4. An example of the preparation of (E) -4- [(2- (5- (4-chlorobenzylidene) -thiazolidin-2,4-dione-3-yl-1- (phenyl) ethyl] piperazin-1-yum) 2, 2,2-trifluoroacetate (6.1)

In a 50 ml conical flask, dissolve 0.750 g (0.0013 mol) of tert -butyl 4- [2- (5- (4-chlorobenzylidene) -thiazolidine-2,4-dione-3-yl) - 25 ml in 25 ml of methylene chloride. 1- (phenyl) ethyl] piperazine-1-carboxylate, then add 0.53 g (3.5 mol. Equiv.) Of trifluoroacetic acid (TFA), the reaction mixture is stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture is evaporated on a rotary evaporator, the resulting residue is washed with 10 ml of cold dry diethyl ether. The precipitate obtained is dried under vacuum and purged with argon.

0.762 g of (E) - 4 - [(2- (5- (4-chlorobenzylidene) -thiazolidin-2,4-dione-3-yl-1- (phenyl) ethyl] piperazin-1-ium 2.2, 2-trifluoroacetate.

The yield was 54%. The structure of the compound is confirmed by a combination of NMR spectroscopy and mass spectrometry data. M + 1 = 428. C ₂₄ H ₂₃ ClF ₃ N ₃ O ₄ S. ¹ HNMR (500 MHz, DMSO- d 6) δppm 2.89 - 4.23 (m, 34 H) 4.81- 5.00 (m, 1 H) 7.21 - 7.34 (m, 4H) 7.36 - 7.46 (m, 4 H) 7.55 -7.62 (m, 3 H) 8.82 - 9.04 (m, 2H).

5. An example of the preparation of (Z) -5- (4-chlorobenzylidene) -3- (2- (2,4-dichlorophenyl) -2- (piperazin-1-yl) ethyl) thiazolidin-2,4-dione hydrochloride (6.6 )

In a 50 ml conical flask in 25 ml of ethyl acetate and 25 ml of ethyl alcohol dissolve 0.68 g, (E) -tert-butyl-4- [2- (5- (4-chlorobenzylidene) -thiazolidin-2, 4-dione-3-yl) -1- (2,4-dichlorophenyl) ethyl] piperazine-1-carboxylate (0.0011 mol) then add 2 ml of 6N HCl solution in ethyl acetate, the reaction mass is stirred at room temperature temperature 18 hours.

After passing through the reaction, the reaction mixture is evaporated on a rotary evaporator, the resulting residue is washed with 10 ml of cold dry diethyl ether. The precipitate obtained is dried under vacuum and purged with argon.

Obtained 0.54 g of (Z) -5- (4-chlorobenzylidene) -3- (2- (2,4-dichlorophenyl) -2- (piperazin-1-yl) ethyl) thiazolidin-2,4-dione hydrochloride. The yield was 88.9%. Data confirming the structure of the compounds are presented in table 4.

6. An example of the preparation of (Z) -5- (4-chlorobenzylidene) -3- (2- (2,4-dichlorophenyl) -2-piperazin-yl) ethyl) thiazolidin-2,4-dione (7.1).

In a 100 ml conical flask, 1.7 g (0.0032 mol) of (Z) -5- (4-chlorobenzylidene) -3- (2- (2,4-dichlorophenyl) -2- (piperazin-1-yl) ethyl) are suspended ) thiazolidine-2,4-dione hydrochloride in 25 ml of distilled water and 25 ml of methylene chloride, 0.84 g (2.5 molar equivalent) of sodium carbonate dissolved in 10 ml of distilled water are added to the suspension with stirring and stirred for 1 hour. The organic phase is separated, the aqueous is washed with 25 ml of methylene chloride and the combined organic phase is further washed with 20 ml of distilled water, and then dried over 5 g of sodium sulfate. Methylene chloride is distilled off at the FIR, the resulting precipitate is dried under vacuum.

1.45 (Z) -5- (4-chlorobenzylidene) -3- (2- (2,4-dichlorophenyl) -2- (piperazin-1-yl) ethyl) thiazolidin-2,4-dione is obtained. Yield 86%. Data confirming the structure of the compounds are presented in table 4.

The following examples of compounds according to the invention, presented in Table 4, were prepared in accordance with the synthesis procedures described for compounds 6.1, 6.6 and 7.1 using the appropriate starting materials: (E) - tert -butyl 4- [2- (5-arylidentiazolidin-2, 4-dione-3-yl) -2-phenylethyl] piperazine-1-carboxylates, trifluoroacetic acid, hydrochloric acid, sodium carbonate.

Table 4. Examples of compounds according to the invention.

7. Example of obtaining (Z) -5- (4-chlorobenzylidene) -3- (2-phenyl-2- (4-methylpiperazin-1-yl) ethyl) thiazolidin-2,4-dione (8.1)

In a 50 ml conical flask, 0.5 g (0.0013 mol) of (E) -3- (2-phenyl-2-chloroethyl) -5- (4-chlorobenzylidene) thiazolidine-2,4-dione is dissolved in 25 ml of DMF, to the solution with stirring was added 0.134 g (1 mol. eq.) of 4-methylpiperazine and 0.274 g of calcined potassium carbonate, stirred for 18 hours at ⁶⁰ ° C.

After passing through the reaction, the reaction mixture is filtered from inorganic salts and evaporated on a rotary evaporator, the resulting residue is purified on a column (2: 1, hexane-ethyl acetate). 0.15 g of (Z) -5- (4-chlorobenzylidene) -3- (2-phenyl-2- (4-methylpiperazin-1-yl) ethyl) thiazolidin-2,4-dione is obtained.

The yield was 25.69%. The structure of the compound is confirmed by a combination of NMR spectroscopy and mass spectrometry data.

¹ H NMR (500 MHz, CHLOROFORM- d ) δ ppm 2.32 (s, 3 H) 2.35-2.65 (m, 4 H) 3.25-3.85 (m, 4 H) 4.10-4.15 (m, 1 H) 4.67 (m , 1 H) 7.33-739 (m, 5H) 7.45 (d, J = 10Hz, 2H) 7.59 (d, J = 5Hz, 2H) 7.76 (s, 1H). M + 1 = 443. C ₂₃ H ₂₄ ClN ₃ O ₂ S.

The following examples of compounds according to the invention, presented in Table 5, were prepared in accordance with the synthesis procedure described for compound 5.1, using the appropriate starting materials: (E) -3- (2-aryl-2-chloroethyl) -5-arylidene thiazolidin-2 , 4-diones and the corresponding N-substituted piperazines.

Table 5. Examples of compounds according to the invention.

8. An example of the preparation of (Z) -3- (2- (4-chlorophenyl) -2- (4- (2- (1- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) ethoxy ) acetyl) piperazin-1-yl) ethyl) -5- (4-fluorobenzylidene) thiazolidin-2,4-dione (10.1).

In a test tube with a screw cap and a 15 ml magnetic stirrer in 7 ml of methylene chloride, 0.200 g of ((Z) -3- (2- (4-chlorophenyl) -2- (piperazin-1-yl) ethyl) -5- (4-fluorobenzylidene) thiazolidine-2,4-dione 2,2,2-trifluoroacetate (0.34 mmol). Add 0.120 g (1.1 mmol. Eq.) 2- (1- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) ethoxy) acetic acid, 0.155 ml (3.2 mmol. Eq.) Triethylamine (TEAL), and 0.128 g (1.1 mmol. Eq.) TBTU.

The reaction mass is maintained under stirring at room temperature for 18 hours, the methylene is washed with 5 ml of sodium bicarbonate solution, 5 ml of citric acid solution, 5 ml of water and evaporated in an FIR. To the distillation residue add 10 ml of dry diethyl ether, the precipitate formed is filtered off and dried under vacuum.

0.108 g of (Z) -3- (2- (4-chlorophenyl) -2- (4- (2- (1- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) ethoxy) is obtained acetyl) piperazin-1-yl) ethyl) -5- (4-fluorobenzylidene) thiazolidin-2,4-dione. The yield was 41.25%. Data confirming the structure of the obtained compounds are presented in table 6. The following examples of compounds according to the invention, presented in table 6, are obtained in a similar way.

Table 6. Examples of compounds according to the invention.

9. An example of the preparation of (Z) -5- (4-fluorobenzylidene) -3- (2- (4-fluorophenyl) -2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- ( 1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) ethyl) thiazolidin-2,4-dione, (13.1).

A mixture of oxirane methanesulfonate (123 mg, 1 eq.), (Z) -5- (4-fluorobenzylidene) -3- (2- (4-fluorophenyl) -2-piperazin-yl) ethyl) thiazolidin-2,4-dione trifluoroacetate (200 mg, 1 eq.) and triethylamine (128 μl, 2.5 eq.) are boiled in ethanol for 8 hours. Ethanol is evaporated, the residue is dissolved in methylene chloride and washed with aqueous and citric acid until acidic, then again with water. The organic phase is dried with Na ₂ SO ₄ and evaporated. The product is obtained in the form of oil, which gradually crystallizes on standing. Yield 207 mg (83.9%).

The following examples of compounds according to the invention, presented in table 7, obtained in a similar way.

Table 7. Examples of compounds according to the invention

The use of chemical compounds according to the invention

Medication Use

The compounds described in this invention can be used for the treatment and / or prevention of infectious diseases.

The method of therapeutic use of compounds

The subject matter of this invention also includes the administration to a subject in need of appropriate treatment of a therapeutically effective amount of a compound of general formula (I).

By a therapeutically effective amount is meant that amount of a compound administered or delivered to a patient at which the patient is most likely to display the desired response to treatment (prophylaxis). The exact amount required may vary from subject to subject, depending on the age, body weight and general condition of the patient, the severity of the disease, the method of administering the drug, the combined treatment with other drugs, etc.

A compound of the invention or a pharmaceutical composition comprising the compound may be administered to a patient in any amount and by any route of administration effective for treating or preventing a disease.

After mixing the drug with a particular suitable pharmaceutically acceptable carrier in the desired dosage, the formulations may be administered orally, parenterally, topically, and the like into the body of a human or other animals.

In the case where the compound of the invention is used as part of a combination therapy regimen, the dose of each of the components of the combination therapy is administered during the desired treatment period. The compounds that make up the combination therapy can be administered into the patient's body as a lump sum, in the form of a dosage containing all the components, and in the form of individual dosages of the components.

Pharmaceutical compositions

The invention also relates to pharmaceutical compositions which contain a compound of the general formula (I) (or a prodrug form, a pharmaceutically acceptable salt or another pharmaceutically acceptable derivative) and one or more pharmaceutically acceptable carriers, adjuvants, solvents and / or excipients, such as introduced into the patient’s body together with the compound constituting the essence of the present invention, and which do not destroy the pharmacological activity of this compound, and are non-toxic administered in doses sufficient to deliver a therapeutic amount of the compound.

The pharmaceutical compositions claimed in this invention contain the compounds of this invention together with pharmaceutically acceptable carriers, which may include any solvents, diluents, dispersions or suspensions, surfactants, isotonic agents, thickeners and emulsifiers, preservatives, astringents, lubricants materials, etc., suitable for a particular dosing form. Materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, mono- and oligosaccharides, as well as their derivatives; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut, cottonseed, saffrole, sesame, olive, corn and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic solution, ringer's solution; ethyl alcohol and phosphate buffer solutions. Other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as dyes, release agents, film-forming agents, sweeteners, flavorings and flavoring agents, preservatives and antioxidants can also be included in the composition.

The subject of this invention are also dosage forms - a class of pharmaceutical compositions, whose composition is optimized for a particular route of administration into the body in a therapeutically effective dose, for example, for oral administration, orally, topically, intraocularly, pulmonary, for example, in the form of an inhalation spray, or intravascular by the method, intranasally, subcutaneously, intramuscularly, and also by the infusion method, in the recommended dosages.

Dosage forms of this invention may contain formulations obtained by the use of liposomes, microencapsulation techniques, the preparation of nanoform of the drug, or other methods known in the pharmaceutical industry.

When preparing the composition, for example, in tablet form, the active principle is mixed with one or more pharmaceutical excipients, such as gelatin, starch, lactose, magnesium stearate, talc, silica, gum arabic, mannitol, microcrystalline cellulose, hypromellose, or similar compounds.

Tablets may be coated with sucrose, a cellulosic derivative, or other substances suitable for coating. Tablets can be prepared in a variety of ways, such as direct compression, dry or wet granulation, or hot melt fusion.

A pharmaceutical composition in the form of a gelatin capsule can be obtained by mixing the active principle with a solvent and filling the resulting mixture with soft or hard capsules.

For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions are used which contain pharmacologically compatible agents, for example, propylene glycol or butylene glycol.

Characterization of the biological activity of compounds

Comparative study of the spectrum of antifungal action of the compounds according to the invention in the experience in vitro  by the method of double microdilution in broth.

Experiments were performed using standard strains and clinical isolates. Sensitivity to reference strains and standard preparations used in the study is normalized according to GOST R ISO 16256-2015 and serves as a criterion for the accuracy of the experiment performed.

To control the ongoing research and comparative activity of the synthesized compounds, standard preparations Fluconazole (Fluconazole, Sigma-Aldrich), antifungal antibiotic Nystatin and the control strain Candida parapsilosis (ATCC 22019 ) were used.

The analysis was carried out by the method of serial microdilution in accordance with GOST R ISO 16256-2015 "Clinical laboratory studies and in vitro diagnostic test systems. Reference method for testing the activity of in vitro antimicrobial agents against yeast fungi that cause infectious diseases ”and recommendations of the World Non-Profit Organization for the Development of Standards and Recommendations in the Field of Medicine Reference method for broth dilution antifungal susceptibility testing of filamentous fungi; approved standard, 2nd ed. CLSI document M38-A, Antifungal Susceptibility Testing of Yeasts: M27-A2. 2008. Clinical and Laboratory Standards Institute, Wayne, PA.).

All studied samples of compounds were dissolved in dimethyl sulfoxide (DMSO), the concentration of the basic solutions was 10,000 μg / ml. To obtain working solutions, the main solutions were diluted in a nutrient medium to a concentration of 64 μg / ml. The range of values of the studied concentrations ranged from 32.0 to 0.015 μg / ml.

The inoculum of yeast cultures contained 10 ³ CFU / ml, filamentous fungi - 10 ⁴ CFU / ml.

A series of twofold dilutions of the test samples was prepared in 96-well immunological test plates in a volume of 100 μl of RPMI-1640 medium with L-glutamine (FGUP PIPVE na Chumakov, Russia) containing 0.2% glucose.

After seeding yeast cultures, the plates were incubated for 24-48 hours at 35 ° C, filamentous - 48-96 hours.

For the minimum inhibitory concentration (MIC), the lowest concentration of sample solutions was taken, at which no less than 80% growth inhibition was observed. All experiments were repeated three times.

The research results are presented in table 8.

Table 8. The results of an in vitro study of the antifungal spectrum of the compounds according to the invention by the method of twofold microdilutions in broth

No. of compounds according to the invention The minimum inhibitory concentration (MIC) µg / ml In relation to the strain C.parapsilosis ATCC 22019 24 h 48 h 5.2 1-2 2 5.3 0.5 one 5.5 one one 6.1 <0.125 0.5 6.2 2 2 6.4 one 2 6.6 <0.125 0.5 7.1 0.125 0.5 7.2 0.5 one 7.3 0.5 one 7.4 0.25 0.5 7.5 0.5 one 8.1 0.5 one 8.2 2 four 8.3 one 2 8.4 0.5 one 8.5 0.5 one 8.7 0.5 1-2 8.8 2 2-4 10.1 0.5 one 10.2 one 2 10.3 0.5 2 11.1 2 four 13.1 0.125 0.25 13.2 0.25 0.5 Fluconazole 2 four Nystatin four four In relation to the strain C.albicans ATCC 24433 24 h 48 h 6.4 eight eight 6.6 <0.125 0.25 7.1 0.125 0.25 10.1 2-4 four 13.1 four eight Fluconazole 2 four Nystatin eight eight Ketoconazole eight eight In relation to the strain A. niger 137a 7.1 1-2 8.8 2-4 Fluconazole > 32 Nystatin four In relation to the strain A.fumigatis ATCC 46645 6.6 0.5-1 7.1 0.5 Fluconazole > 32 Nystatin four In relation to the strain T.rubrum 2002 6.2 4-8 6.6 1-2 7.1 one 7.3 four 8.4 four 13.2 four Fluconazole 32 Nystatin eight In relation to the strain M.canis B-200 6.6 0.5-1.0 6.7 0.5 8.4 four 13.2 four 13.1 2 Fluconazole 32 Nystatin eight

Comparative evaluation of the activity of the claimed compounds according to the invention in vitro with respect to fungal strains of dermatophytes and comparison preparations (fluconazole and nystatin, as well as ketoconazole) showed that the compounds according to the invention are not inferior to widely used commercial preparations. The compounds of the invention have a broad spectrum of antifungal activity, which confirms their potential for use in clinical practice for the treatment of infectious diseases caused by fungal infections, particularly in dermatology.

The activity of the majority of the claimed compounds according to the invention in relation to Candida parapsilosis is not inferior to or exceeds the activity of Fluconazole and approaches Ketoconazole. In addition, the compounds of the invention, in contrast to Fluconazole, inhibit the growth of filamentous fungi M.canis B-200 and T.rubrum 2002. High activity is shown, in particular, by 3- (2,4-dichlorophenyl) ethyl) derivatives- (compounds 6.6 and 7.1), which, unlike Fluconazole, affects both yeast and filamentous fungi. Hybrid compounds with triazole (13.1 and 13.2) had a similar effect. Compounds obtained by combination with an imidazole fragment, in particular compounds 10.1 - 10.3., Show high activity only in relation to candidal pathogens. Moreover, hybrids with a triazole derivative exhibit the best activity (compounds 13.1 and 13.2)

Comparative study of the antifungal activity of the compounds according to the invention on clinical isolates Candida spp.  micromethod double serial dilutions in vitro

The antifungal activity of the compounds according to the invention and the microbiological standards of ketoconazole and itraconazole were investigated by the spectrum of antifungal action in relation to clinical isolates of Candida sp . micromethod double serial dilutions in nutrient broth RPMI 1640 in relation to 10 clinical isolates and standard strains of Candida sp .

The activity was evaluated in accordance with the recommendations of the World Non-Profit Organization for the Development of Standards and Recommendations in the Field of Medicine - Clinical and Laboratory Standards Institute (CLSI). Used methods M27-A3 ( Clinical and Laboratory Standards Institute. Approved standard third edition M27-A3, Wayne, PA, USA, 2008 ) and ISO 16256: 2012 Clinical laboratory methods The activity of antimicrobial agents against yeast fungi involved in infectious diseases (IDT) to determine the value of the minimum inhibitory concentration (MIC), by micromethod of serial dilutions in RPMI 1640 medium with the addition of glucose to a concentration of 0.2%.

To obtain the inoculum, the strains were grown on agar timing 2 (VFS 42-3068-98, Biohold, Russia) at 35 ° C for 48 hours. The inoculum suspension was prepared in RPMIc medium with 0.2% glucose according to McFarland turbidity standard of 0.5 (~ 5x10 ⁶ CFU / ml for yeast cultures), the titer of microbial cells of the prepared suspension was evaluated densitometrically (Densimat, Biomerieux). The resulting suspension was diluted from 1: 1000 to ~ 2.5 x 10 ³ colonies forming units (CFU / ml) in RPMIc medium with 0.2% glucose.

To obtain basic solutions of samples with a concentration of 10,000 μg / ml of the sample was dissolved in dimethyl sulfoxide (DMSO). The substance of the compounds in the amount of 18 mg was dissolved in 1.8 ml of DMSO, ketoconazole in the amount of 1.8 mg was dissolved in 0.18 ml of DMSO. To obtain working solutions with a concentration of 64 μg / ml, the basic solutions in the amount of 0.64 ml were adjusted to 10 ml in nutrient broth RPMI 1640 with glucose of 0.2%.

We used 96 well plates for immunological studies (Medpolymer, St. Petersburg). 100 μl of a suspension of yeast cultures in a nutrient medium and samples in the concentration range of 32 - 0.125 μg / ml, a standard sample of ketoconazole in the range of 64-0.015 μg / ml were added to the wells. After making the samples under study, the density of the suspension of the test cultures was ~ 2.5 x 10 ³ CFU / ml. To control the growth of the culture, test microorganisms without samples were seeded into the nutrient broth.

To maintain the accuracy of the procedure for determining the MIC values of the studied strains, the test included the reference strain Candida parapsilosis ATCC 22019, for which the growth inhibitory concentration of ketoconazole (MIC) should not exceed the confidence limits provided by the document ( Clinical and Laboratory Standards Institute: References; informational supplement (M27-S3). Wayne, PA: 2007 ; ISO 16256: 2012 Clinical laboratory disease associated with infectious diseases (IDT) :

Evaluation of sensitivity was performed visually after incubation at 35 ° C for 24 and 48 hours.

The growth of the culture in the broth in the presence of drugs was evaluated in comparison with the growth rate without drugs (growth control).

Table 9. Comparative results of the compounds of the invention with respect to clinical strains of Candida spp.

No
connections MIC (µg / ml) C. parapsillosis ATCC 22019 C. utilis 84 C. tropicalis 3019 C. krusei 432M 24h 48h 24h 48h 24h 48h 24h 48h 6.1 0.125 0.5 four eight 0.5 0.5 eight 8-16 6.2 one 1-2 one one one one one one 6.6 0.125 0.5 0.25 0.5 0.25-0.5 1-2 2-4 four 7.1 0.125 0.5 0.25 0.5 0.25-0.25 one 2 2 7.3 0.125 0.125 0.125 0.25 0.125 0.25 one one 7.4 one 2 0.125 0.25 0.125 0.25 2 2-4 8.4 0.5 0.5 four four 1-2 1-2 eight eight 10.3 0.5 one four eight 0.5-1 2 sixteen 32 Fluconazole > 32 > 32 eight sixteen 32 32 eight sixteen Itraconazole 0.125 0.125 0.25 one 32 32 32 32 Ketoconazole 0.03 0.125 0.03 0.25 0.25 0.5 0.25 one

Table 10. Comparative results of some compounds of the invention against clinical isolates of Candida spp, including resistant. * - C. albicans 80R and C.albicans 604M.

No
connections MIC (µg / ml) C. albicans ATCC 24433 C. glabrata 61L C. albicans 80R * C. albicans 604M * 24h 48h 24h 48h 24h 48h 24h 48h 6.2 eight eight four four eight sixteen eight sixteen 6.6 four eight 2 2-4 1-2 eight 0.5 one 7.1 2 four one 2 one four 0.5 one 7.3 0.125 0.25 one 2 2 4-8 four four 7.4 2 four four 4-8 32 32 eight eight 8.4 0.5 0.5 four eight 32 32 sixteen 32 10.3 eight sixteen four 32 one sixteen eight sixteen Fluconazole > 32 > 32 eight sixteen 32 32 eight sixteen Itraconazole 0.125 0.125 0.25 one 32 32 32 32 Ketoconazole 8-16 sixteen 0.25 0.25 eight eight eight eight

A comparative analysis of the compounds according to the invention and comparison preparations (ketoconazole, itraconazole and fluconazole) revealed the advantages of the claimed compounds with respect to various strains of the fungi Candida spp. including resistant ( C.albicans 604M (R), C.albicans 80 (R) or not sensitive to fluconazole ( C. tropicalis 3019, C.glabrata 61L, C. krusei 432M). According to the activity rating, in relation to C. tropicalis 3019, compounds, in particular compounds 6.6, 7.1 and 7.3, showed better values than ketoconazole and itraconazole. In activity against C. albicans ATCC 24433, the compounds were comparable to ketoconazole, and considering that ketoconazole has significant toxicity, The claimed compounds can be a serious competitor, since the compounds according to the invention are characterized by low toxicity. Nost.

On the other hand, the claimed compounds are a serious competitor to fluconazole, to which constant growing resistance is fixed. And since the compounds according to the invention have a completely different mechanism of action on the pathogenic cell, the possibility of developing resistance to them is significantly reduced.

Comparative study in vivo compounds according to the invention (for example, compound No. 6.6) in relation to Candida albicans on the model of intraperitoneal infection of mice (express method) with a commercial drug Voriconazole.

Drug comparison

The substance of voriconazole (SIGMA-ALDRICH Co., USA.) Was used as a reference drug.

Solvent

Due to the insolubility in water of Compound No. 6.6 and voriconazole, dimethyl sulfoxide (DMSO) (LenReactive) was used as a solvent.

Test culture

The strain Candida albicans RCPG Y 1274 was obtained from the "Russian collection of pathogenic fungi" Institute of Medical Mycology. Pn Kashkina SZGMU them. I.I. Mechnikov. The strain is characterized by resistance to fluconazole and sensitivity to voriconazole.

Nutrient medium

Wednesday Saburo. Ingredients: distilled water - 1 liter, enzyme peptone - 10 g, glucose - 40 g, agar-agar - 18 g.

Laboratory animals

For the study used male outbred mice obtained in the nursery Rappolovo. Body weight at the beginning of the experiment - 20 g.

Animals were adapted within 7 days after admission to the laboratory. During this period, a daily inspection of the condition of the animals was carried out. Before inclusion in the study, the animals were examined by a veterinarian. Animals with abnormalities found during the inspection were not included in the study.

The distribution of animals in groups

For the experiment, five groups of animals were formed (6 mice in each group), including 3 experimental (No. 1, 2, 3), one group for the administration of voriconozole (B), and a control group (D - intraperitoneal administration of 0.5 ml 20% DMSO). Animals were divided into groups by random selection.

For a comparative assessment of the effectiveness of suppressing the germination of yeast C. albicans cells in glands of mice with different doses of compound No. 6.6 and voriconazole, we calculated the percentage of germination of yeast cells in each of these groups of animals relative to the control group D (20% DMSO). Then calculated the percentage of suppression of germination of cells of C. albicans: 100% -% germination (Table. 11).

Table 11. Suppression of the process of formation of C. albicans growth tubes ( strain RCPG Y 1274) in glands of mice with different doses of compound No. 6.6 and voriconazole.

Animal group number Input connection Dose of Compound % suppression * p ** one connection 6.6 5 mg / kg 34.86 0.00001 2 connection 6.6 12 mg / kg 23,16 0.00001 3 connection 6.6 25 mg / kg 15.61 0.14 AT voriconazole 12 mg / kg 17.00 <0.05 *% suppression - the proportion of cells that have not formed growth tubes;
** p - comparison with voriconazole.

As follows from the results presented in Table 11, Compound No. 6.6, when administered at a dose 2.4 times smaller (5 mg / kg) than voriconazole (12 mg / kg), inhibited the formation of growth tubes by C. albicans yeast cells 2 times more effective (34.86 vs. 17.00%). With the introduction of equal doses (12 mg / kg) compound number 6.6. it was also more effective than voriconazole (23.16 vs. 17.00%). Increasing the dose of Compound No. 6.6 to 25 mg / kg, which was 2.1 times higher than the dose of voriconazole (12 µg / kg), a comparable inhibitory effect was obtained on the germination process of yeast C. albicans cells (15.61 vs. 17.00) .

Thus, as a result of a study performed on intraperitoneal infection of mice (express method), it was found that the compounds of the invention, in particular compound No. 6.6, when administered in doses of 5 mg / kg and 12 mg / kg more actively suppress the formation of growth tubes by Candida yeast cells albicans than voriconazole at a dose of 12 mcg / kg. When administered at a dose of 25 mg / kg, compound No. 6.6 had an inhibitory effect, not differing from the effects of voriconazole at a dose of 12 mg / kg.

Thus, the claimed compounds are of interest for medicine and can be used for the treatment and prevention of infectious diseases, in particular, caused by various fungal infections, such as diseases such as dermatophytosis, superficial mycosis, skin and nail candidiasis, vaginal candidiasis, candidal stomatitis, endocarditis and other human and animal diseases.

Although the invention has been described with reference to the disclosed embodiments, it should be obvious to those skilled in the art that the specific experiments described in detail are given only for the purpose of illustrating the present invention and should not be construed as limiting the scope of the invention in any way. It should be clear that it is possible to implement various modifications without departing from the gist of the present invention.

Claims (55)

1. Compound of general formula (I):

Formula (I): or its pharmaceutically acceptable salt, where R ₁ is selected independently and represents H, halogen; R ₂ is selected independently and represents H, halogen; R ₃ is selected independently and represents H, halogen; X is chosen independently and is OH, halogen, 6-membered heterocyclyl containing 2 N atoms, optionally containing an R ₄ substituent; R _four  is selected independently and represents –C_1-6-alkyl, -C_1-6–Alkyl-OH, 4-hydroxy-phenyl, —COCH₃-, -COO-tBu or is a Deputy with the following structural formula:

,

, moreover, a wavy line shows the place of attachment of the Deputy to the fragment X , R ₅ is selected independently and represents H or phenyl substituted by a halogen atom. 2. The compound according to claim 1, in which: R ₁ is selected independently and represents H, F or Cl; R ₂ is chosen independently and represents H, F or Cl; R ₃ is independently selected and is F or Cl; R ₄ is independently selected and is methyl, isopropyl or - (CH ₂ ) ₂ —OH; X is selected independently and is chlorine or piperazine; R ₅ is selected independently and represents H or phenyl substituted by a halogen atom. 3. The compound according to claim 1, selected from the group: (E) tert -butyl 4- [2- (5- (4-chlorobenzylidene) thiazolidin-2,4-dione-3-yl) -2- (4 chlorophenyl) ethyl] piperazine-1-carboxylate; (E) t -butyl 4- [2- (5- (4-fluoro-benzylidene) thiazolidin-2,4-dione-3-yl) -2- (4-fluorophenyl) ethyl] piperazine-1-carboxylate; (E) tert -butyl 4- [2- (5- (4-chlorobenzylidene) thiazolidin-2,4-dione-3-yl) -2- (4-fluorophenyl) ethyl] piperazine-1-carboxylate; (E) -4 - [(2- (5- (4-chlorobenzylidene) -thiazolidin-2,4-dione-3-yl-1- (phenyl) ethyl] piperazin-1-ium) 2,2,2- trifluoroacetate; (E) -4 - [(2- (5- (4-chlorobenzylidene) -thiazolidin-2,4-dione-3-yl-1- (4-chlorophenyl) ethyl] piperazin-1-yum) 2,2, 2-trifluoroacetate; (E) -4 - [(2- (5- (4-fluorobenzylidene) -thiazolidin-2,4-dione-3-yl-1- (4-fluorophenyl) ethyl] piperazin-1-ium) 2.2, 2-trifluoroacetate; (E) -4 - [(2- (5- (4-chlorobenzylidene) -thiazolidin-2,4-dione-3-yl-1- (2,4-dichlorophenyl) ethyl] piperazin-1-yum) hydrochloride; (Z) -5- (4-chlorobenzylidene) -3- (2- (2,4-dichlorophenyl) -2-piperazin-yl) ethyl) thiazolidin-2,4-dione; (Z) -5- (4-fluorobenzylidene) -3- (2- (4-fluorophenyl) -2-piperazin-yl) ethyl) thiazolidin-2,4-dione; (Z) -5- (4-chlorobenzylidene) -3- (2- (4-chlorophenyl) -2-piperazin-yl) ethyl) thiazolidin-2,4-dione; (Z) -5- (4-fluorobenzylidene) -3- (2- (4-chlorophenyl) -2-piperazin-yl) ethyl) thiazolidin-2,4-dione; (Z) -5- (4-chlorobenzylidene) -3- (2- (4-fluorophenyl) -2-piperazin-yl) ethyl) thiazolidin-2,4-dione; (Z) -5- (4-chlorobenzylidene) -3- (2-phenyl-2- (4-methylpiperazin-1-yl) ethyl) thiazolidin-2,4-dione; (Z) -5- (4-fluorobenzylidene) -3- (2- (4-chlorophenyl) -2- (4-methylcarbonylpiperazin-1-yl) ethyl) thiazolidin-2,4-dione; (Z) -5- (4-chlorobenzylidene) -3- (2- (4-chlorophenyl) -2- (4- (2-hydroxyethyl) piperazin-1-yl) ethyl) thiazolidin-2,4-dione; (Z) -5- (4-chlorobenzylidene) -3- (2- (4-chlorophenyl) -2- (4-methylpiperazin-1-yl) ethyl) thiazolidin-2,4-dione; (Z) -5- (4-chlorobenzylidene) -3- (2- (4-chlorophenyl) -2- (4-isopropyl) piperazin-1-yl) ethyl) thiazolidin-2,4-dione; (Z) -5- (4-chlorobenzylidene) -3- (2- (4-chlorophenyl) -2- (4- (4-hydroxyphenyl) piperazin-1-yl) ethyl) thiazolidin-2,4-dione; (Z) -5- (4-chlorobenzylidene) -3- (2- (4-fluorophenyl) -2- (4-methylcarbonylpiperazin-1-yl) ethyl) thiazolidin-2,4-dione; (Z) -3- (2- (4-chlorophenyl) -2- (4- (2- (1- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) ethoxy) acetyl) piperazine -1-yl) ethyl) -5- (4-fluorobenzylidene) thiazolidin-2,4-dione; (Z) -3- (2- (4-chlorophenyl) -2- (4- (2- (1- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) ethoxy) acetyl) piperazine -1-yl) ethyl) -5- (4-chlorobenzylidene) thiazolidin-2,4-dione; (Z) -3- (2- (4-fluorophenyl) -2- (4- (2- (1- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) ethoxy) acetyl) piperazine -1-yl) ethyl) -5- (4-fluorobenzylidene) thiazolidin-2,4-dione; (Z) -5- (4-chlorobenzylidene) -3- (2- (4-chlorophenyl) -2- (4- (2- (2-chlorophenyl) -2- (1- (2,4-dichlorophenyl) - 2- (1H-imidazol-1-yl) ethoxy) acetyl) piperazin-1-yl) ethyl) thiazolidin-2,4-dione; (Z) -5- (4-fluorobenzylidene) -3- (2- (4-fluorophenyl) -2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1, 2,4-triazol-1-yl) propyl) piperazin-1-yl) ethyl) thiazolidin-2,4-dione; (Z) -5- (4-chlorobenzylidene) -3- (2- (4-fluorophenyl) -2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1, 2,4-triazol-1-yl) propyl) piperazin-1-yl) ethyl) thiazolidin-2,4-dione. 4. The use of compounds according to any one of claims 1 to 3 as an antifungal agent. 5. The use of compounds according to any one of claims 1 to 3 to obtain a pharmaceutical composition for the treatment and / or prevention of an infectious disease of microbial etiology caused by a fungal infection in a subject. 6. The use of a compound according to claim 5, characterized in that the disease of microbial etiology is caused by a fungus of the genus Candida spp, Aspergillus spp., Microsporum spp. Trichophyton spp. and / or Epidermophyton spp. 7. The use according to claim 5, characterized in that the disease of microbial etiology is caused by a fungus of the species Aspergillus fumigatus, Aspergillus niger, Microsporum canis, Trichophyton rubrum or Epidermophyton floccosum . 8. The use according to claim 5, characterized in that the disease is a disease of the skin, nails and / or internal organs. 9. The use according to claim 8, wherein the disease is dermatophytosis, superficial mycosis, candidiasis of the skin and / or nails, vaginal candidiasis, candidal stomatitis or endocarditis. 10. Pharmaceutical composition for the treatment and / or prevention of an infectious disease of microbial etiology caused by a fungal infection in a subject, containing an effective amount of the compound according to claim 1-3 and at least one pharmaceutically acceptable excipient. 11. The pharmaceutical composition of claim 10, characterized in that the pharmaceutically acceptable excipient is a carrier, excipient and / or solvent. 12. The pharmaceutical composition of claim 10, characterized in that the disease is a disease of the skin, nails and / or internal organs. 13. The pharmaceutical composition according to item 12, characterized in that the disease is a dermatophytosis, superficial mycosis, candidiasis of the skin and / or nails, vaginal candidiasis, candidal stomatitis or endocarditis.