RU2703997C1 - Hybrid amides based on triazole and thiazolidine having antimicrobial activity - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: invention relates to compounds of general formula (I) or a pharmaceutically acceptable salt thereof, where Z is independently selected and represents a fragment whose structural formula is given below, wherein the asterisk indicates an attachment point; X is independently selected and represents O or S; Ris independently selected and represents a benzylidene moiety optionally containing 1–3 substituents R', which is independently selected and represent -C-alkyl, -OC-alkyl, halogen, -OH, -C-cycloalkyl, -piperazinyl, optionally containing a substitute selected from -C-alkyl; wherein the asterisk indicates the substitution attachment point; Ris independently selected and represents H, -C-alkyl, phenyl; said phenyl in fragment Ris optionally substituted with at least two substitutes, which are halogen; Ris independently selected and represents halogen; Ris independently selected and represents halogen; n take values from 0 to 3.Z:,,,,,;R:.EFFECT: disclosed compounds are intended for treating and/or preventing an infectious disease of microbial aetiology in a subject caused by a fungal infection, wherein the disease of the microbial aetiology is caused by fungi of the genus Candida speciales, Aspergillus speciales, Microsporum speciales, Trichophyton speciales and/or Epidermophyton speciales.13 cl, 5 tbl, 56 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 antifungal 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 phylomentosis pathogens.

State of the art

The lack of effectiveness of modern antimicrobial therapy is largely due to the development of resistance in pathogens to existing drugs. That is why an intensive search and development of new effective drug compounds is carried out all over the world. 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. Currently available antifungal drugs - polyenes and azoles, affecting the main component of the fungal membrane - ergosterol, do not provide proper selectivity of action. They are very toxic, moreover, many strains of pathogens become resistant to drugs of the azole group.

Compounds having a thiazolidinedione moiety and characterized by antifungal activity US7105554, WO2002022612 WO2002022612, Thiazolidine and benzylidene thiazolidinedione inhibitors of mannosyltransferease as antifungal agents // Expert Opinion Ther.pat., 12, 12, 2002, 12, 2002 are known in the art. These documents describe substituted derivatives of 5-benzylidene-2,4-thiazolidin-3 acetic acid as antimycotic agents active against many pathogenic fungi. Derivatives of azole characterized by the antifungal activity of WO2005006860 are also known in the art. In addition, methods for the preparation and antifungal activity of acyl derivatives of azoles, a well-known group of antifungal agents, and, in particular, compounds obtained by acylation of azole heterocycles at the oxygen atom of the alcohol part of a 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 a new series of 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 azole derivatives is the growing resistance, which can negate all the efforts made to treat. The problem is further exacerbated by the fact that cross-resistance to all used drugs of the azole group develops (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 those caused by fungal infections.

Disclosure of invention

The present invention is the development and creation of new effective antimicrobial agents, promising for use in clinical practice for the treatment and / or prevention of infectious diseases, in particular for the treatment of diseases caused by fungal infection.

The technical result of the invention is the development and production of new chemical compounds with high antimicrobial activity, reduced 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 candida 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. Compounds of the invention for prophylactic purposes may also reduce the risk of developing serious candidiasis infections in people with weakened immune systems as a result of therapy (e.g. chemotherapy), organ transplants, or people with infectious diseases caused by other pathogens (particularly HIV). In addition, the compounds of the invention are characterized by high antimicrobial activity against resistant strains of fungi.

The activity of the claimed compounds was investigated on cultures of microbial cells. The compounds of the invention in relation toCandida parapsilosis ATCC 22019many times superior to the activity of Fluconazole and Amphotericin B, not inferior to or superior to the activity of Ketoconazole (for example, compounds 9, 10, 11). With respect to C. albicans ATCC 24433, the compounds of the invention (in particular compound 24, 29, 41) have shown advantages over ketoconazole. Regarding mushroomA.niger the compounds of the invention, in particular compounds 9, 14, 41 were more active than ketoconazole, and were comparable in activity to amphotericin B. In addition, the compounds of the invention, in contrast to fluconazole, inhibit the growth of filamentous fungiM.canis B-200 and T.rubrum 2002and are active against fluconazole-resistant pathogens.High activity in relation toCryptococcus neoformans,exceeding for compounds according to the invention, in particular for compounds 8, 9, 17, 37 ketoconazole, fluconazole and itraconazole activity.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. High anti-candidiasis activity in relation to typical mushrooms was revealed.Candida albinans, and fluconazole-resistant microorganism strainsCandida non-albicans.

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

формула (I),

formula (I),

or a stereoisomer or enantiomer thereof, a pharmaceutically acceptable salt, solvate or hydrate thereof, where

Z is independently selected and represents a fragment selected from:

,

,

,

,

,

;

,

,

,

,

,

;

moreover, the asterisk indicates the point of accession;

X is independently selected and is O or S;

R ¹ is independently selected and is hydrogen or a moiety representing:

, необязательно содержащий 1-3 заместителя R’, который выбираются независимо и представляют собой -С_1-7-алкил, -О-С_1-7-алкил, галоген, -ОН, -С_5-7-циклоалкил, -С_5-7-гетероциклил, содержащий 1-2 атома N, необязательно содержащий заместитель, выбранный из -С_1-7-алкила, -О-С_1-7-алкила, галогена, -ОН;

optionally containing 1 to 3 substituents R ′ , which are independently selected and are —C _1-7 -alkyl, —O — C _1-7 -alkyl, halogen, —OH, —C _5-7 -cycloalkyl, —C _{5 -7-} heterocyclyl containing 1-2 N atoms, optionally containing a substituent selected from -C _1-7 -alkyl, -O-C _1-7 -alkyl, halogen, -OH;

moreover, the asterisk indicates the place of attachment of the substituent;

R ² is independently selected and is H, C _1-7 alkyl, phenyl;

said R ² moiety is optionally substituted with at least one halogen substituent, —C _1-7 alkyl, —C _2-7 alkenyl, —O — C _1-7 alkyl, —O — C _{2- 7-} alkenyl, -C _1-7 -alkyl-OH, -C _2-7- alkenyl-OH;

R ³ is selected independently and represents halogen;

R ^four  is selected independently and represents halogen;

n take values from 0 to 3.

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

R ³ independently selected and represents chlorine or fluorine;

R ⁴ is independently selected and is chloro or fluoro.

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

2- (2,4-difluorophenyl) -1- (4- (3-carboxymethyl-1,3-thiazolidin-2,4-dione) piperazin-3- (1H-1,2,4-triazolyl-1-yl ) propan-2-ol;

3- (1- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -1 -oxopropan-2-yl) thiazolidin-2,4-dione;

3- (1-2,4-dichlorophenyl) -2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl ) piperazin-1-yl) -2-hydroxyethyl) thiazolidin-2,4-dione;

2- (2,4-difluorophenyl) -1- (4- (3-carboxymethyl-2-thio-1,3-thiazolidin-4-one) piperazin-3- (1H-1,2,4-triazolyl-1 -yl) propan-2-ol;

2- (2,4-dichlorophenyl) -1- (4- (3-carboxymethyl-2-thio-1,3-thiazolidin-4-one) piperazin-3- (1H-1,2,4-triazolyl-1 -yl) propan-2-ol;

3- (4- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -4 -oxobutyl) thiazolidine-2,4-dione;

3- (5- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -4 -oxopentyl) thiazolidine-2,4-dione;

5- (2,4-dichlorobenzylidene) -3- (2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -2-oxoethyl) thiazolidine-2,4-dione;

5- (4-chlorobenzylidene) -3- (2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -2-oxoethyl) thiazolidine-2,4-dione;

5- (4-methoxybenzylidene) -3- (2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -2-oxoethyl) thiazolidine-2,4-dione;

5- (4-ethylbenzylidene) -3- (2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -2-oxoethyl) thiazolidine-2,4-dione;

5- (4-isopropyl-benzylidene) - 3- (2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -2-oxoethyl) thiazolidine-2,4-dione;

5- (4-tert-butylbenzylidene) -3- (2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -2-oxoethyl) thiazolidine-2,4-dione;

5- (2,4-dichlorobenzylidene) -3- (2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -2-oxoethyl) -2-thio-1,3-thiazolidin-4-one;

5- (4-chlorobenzylidene) -3- (2- (4- (2- (2,4-dichlorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -2-oxoethyl) -2-thio-1,3-thiazolidin-4-one;

3- (2- (4- (2- (2,4-dichlorophenyl) -2-hydroxy-3- (1H-1,2,4-tyrazol-1-yl) propyl) piperazin-1-yl) -2 -oxoethyl) -5- (4-methoxybenzylidene) -2-thio-1,3-thiazolidin-4-one;

5- (4-chlorobenzylidene) -3- (1- (4- (2- (2,4-difluorophenyl-2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazine -1-yl) -1-oxopropan-2-yl) thiazolidine -2,4-dione;

5- (2-hydroxy-3,5-dichlorobenzylidene) -3- (2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazole- 1-yl) propyl) piperazin-1-yl) -2-oxoethyl) thiazolidine -2,4-dione;

3- (1- (2,4-dichlorophenyl) -2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -2-oxoethyl) -5- (4-fluorobenzylidene) thiazolidine -2,4-dione;

3- (3- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -3 -oxopropyl) -5- (4-methoxybenzylidene) thiazolidine -2,4-dione;

5- (2,4-dichlorobenzylidene) -3- (3- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -3-oxopropyl) thiazolidine -2,4-dione;

5- (4-chlorobenzylidene) -3- (3- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -3-oxopropyl) thiazolidin-2,4-dione;

5- (2-chloro-6- (4-methylpiperazin-1-yl) benzylidene) -3- (4- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1 2,4-triazol-1-yl) propyl) piperazin-1-yl) -4-oxobutyl) thiazolidine -2,4-dione;

5- (4-chlorobenzylidene) -3- (4- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -4-oxobutyl) thiazolidine -2,4-dione;

3- (4- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -4 -oxobutyl) -5- (4-fluorobenzylidene) thiazolidine-2,4-dione;

5- (2,4-dichlorobenzylidene) -3- (4- (4- (2- (2,4-difluorenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -4-oxobutyl) thiazolidin-2,4-dione;

5- (3,5-dichloro-2-hydroxybenzylidene) -3- (4- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazole- 1-yl) propyl) piperazin-1-yl) -4-oxobutyl) thiazolidin-2,4-dione;

5- (3,5-dichlorochloro-2-hydroxybenzylidene) -3- (5- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazole- 1-yl) propyl) piperazin-1-yl) -5-oxopentyl) thiazolidin-2,4-dione;

5- (4-chlorobenzylidene) -3- (5- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -5-oxopentyl) thiazolidin-2,4-dione;

5- (2,4-dichlorobenzylidene) -3- (5- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -5-oxopentyl) thiazolidin-2,4-dione;

5- (2-chloro-6- (4-methylpiperazin-1-yl) benzylidene) -3- (5- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1 2,4-triazol-1-yl) propyl) piperazin-1-yl) -5-oxopentyl) thiazolidin-2,4-dione;

3- (5- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -5 -oxopentyl) -5- (4-fluorobenzylidene) thiazolidine-2,4-dione;

N-cyclopropyl-2- (5- (2,4-dichlorobenzylidene) -2,4-dioxothiazolidin-3-yl) -N- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H- 1,2,4-triazol-1-yl) propyl) acetamide;

N-cyclopropyl-2- (5- (4-chlorobenzylidene) -2,4-dioxothiazolidin-3-yl) -N- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1, 2,4-triazol-1-yl) propyl) acetamide;

N-cyclopropyl-2- (5- (4-fluorobenzylidene) -2,4-dioxothiazolidin-3-yl) -N- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1, 2,4-triazol-1-yl) propyl) acetamide;

2- (5- (2,4-dichlorobenzylidene) -2,4-dioxothiazolidin-3-yl) -N- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2, 4-triazol-1-yl) propyl) -N-propylacetamide;

2- (5- (4-chlorobenzylidene) -2,4-dioxothiazolidin-3-yl) -N- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4- triazol-1-yl) propyl) -N-propylacetamide;

2- (5- (4-fluorobenzylidene) -2,4-dioxothiazolidin-3-yl) -N- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4- triazol-1-yl) propyl) -N-propylacetamide.

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.

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

The compounds of the invention exhibit high antifungal activity, in particular against fungi of the genus Candida spp., Aspergillus spp., Cryptococcus neoformans, Microsporum, Trichophyton and Epidermophyton. The compounds of the invention exhibit high antifungal activity, in particular against fungi of the species Aspergillus fumigatus, Aspergillus niger, Cryptococcus neoformans, 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 particular embodiments, the infectious disease of microbial etiology is caused by a fungal infection. In particular 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 humans or animals.

In addition, the invention provides pharmaceutical compositions for treating and / or preventing infectious diseases of microbial etiology, comprising a therapeutically effective amount of at least one compound of the invention and at least one pharmaceutically acceptable excipient.

In some embodiments, the excipient may be a carrier, excipient and / or solvent.

In some embodiments, an infectious disease of microbial etiology is caused by a fungal infection.

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

In particular embodiments of the invention, the pharmaceutical composition is intended to treat and / or prevent 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 others diseases of humans or animals.

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

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

Detailed Disclosure of Invention

Definitions (terms)

For a better understanding of the present invention, the following are some of the 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 the same or different.

In the description of the present invention, the terms “ includes ” and “ including ” are interpreted as meaning “includes, inter alia,”. These terms are not intended to be construed as “consists of only”.

The term “alkyl” , alone or as part of another substituent, refers to straight or branched chain saturated hydrocarbon groups, including hydrocarbon groups having a specified number of carbon atoms (i.e., C _1-7 means from one to seven 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 an atom of fluorine, chlorine, bromine or iodine.

This invention contains only those combinations of substituents and derivatives that 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 sufficiently 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 structure of compounds given in the application materials also implies all stereoisomers, i.e., 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 substantially free of other isomers (> 90%; more preferably> 95% molar purity), as well as a mixture of such isomers.

A particular optical isomer can be obtained by resolving a racemic mixture in accordance with a standard procedure, for example, by preparing diastereoisomeric salts by treatment with an optically active acid or base, followed by crystallization of the diastereomer mixture, followed by isolation of the optically active bases from these salts. Examples of suitable acids are tartaric, diacetyl tartaric, dibenzoyl tartaric, ditoluolvic 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 optically pure acid in an activated form or optically pure isocyanate. The resulting diastereomers can be separated by conventional methods, for example, chromatography, distillation, crystallization or sublimation, and then hydrolyzed to obtain an enantiomerically pure compound.

The optically active compounds of this invention can be prepared using optically active starting materials. Such isomers may be in the form of a 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 solvate forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

The term “hydrate” refers to a complex wherein 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 those salts which, within the framework of a medical opinion, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, etc., and correspond to a reasonable balance 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 prepared in situ during the isolation or purification of the compounds of the invention, and can also be prepared separately by reacting the free acid or free base of the compound of the invention with a suitable base or acid, respectively. An example of pharmaceutically acceptable, non-toxic acid salts is the amino group formed by 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 the resulting other methods used in this field, for example, using ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, heptofluorosulfonate, glucose gluconate, formate glucose phosphate heptane, hexanate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec ulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecane, valerate and the like. Typical alkali and alkaline earth metal salts contain sodium, lithium, potassium, calcium, magnesium and others. In addition, pharmaceutically acceptable salts may contain, if desired, non-toxic cations of ammonium, quaternary ammonium and amine 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 is replaced by atoms having the same atomic number but an atomic mass or mass number other than the atomic mass or mass number commonly 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, philosophore, 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, due to the ease of their introduction and the availability of detection tools.

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 a decrease in dosing rates, and therefore may be preferred in some cases.

Isotopically labeled compounds of the invention can be prepared by conventional methods known to one skilled in the art or by methods similar to those described in the accompanying examples of synthetic methods using appropriate isotopically labeled reagents instead of the unlabeled previously used reagent.

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

The term " microbe ", including as part 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 the methods for producing compounds of the invention

The compounds of the present invention can be prepared using the synthetic methods described below. The listed methods are not exhaustive and allow the introduction of reasonable modifications.

General method for producing hybrid amide derivatives of thiazolidin-4-one and triazole

The preparation of hybrid amide derivatives of thiazolidin-4-one and triazole is carried out by acylation of the piperazinyl derivative of triazole with an acid chloride of the corresponding 3-substituted carboxylic acid thiazolidin-4-one in an organic solvent and the presence of triethylamine as an acceptor of hydrogen halide.

Scheme 1. Scheme of a general method for producing hybrid amide derivatives of thiazolidin-4-one and triazole, where Hal is halogen

1. An example of obtaining 2- (2,4-difluorophenyl) -1- (4- (3-carboxymethyl-1,3-thiazolidine-2,4-dione) piperazine-3- (1 H -1,2,4- triazolyl-1-yl) propan-2-ol (1).

2- (2,4-Difluorophenyl) -4- (piperazin-1-yl) -3- (1H-1,2,4-triazolyl-1-yl) propan-2-ol hydrochloride (300 mg, 0.83 mmol, 1 equiv) was suspended in methylene chloride (10 ml), then triethylamine (253 mg, 2.50 mmol, 3 equiv) was added. The reaction mass was cooled in an ice bath, then a solution of thiazolidine-2,4-dione acetic acid chloride in methylene chloride (194 mg, 1 mmol, 1.2 equiv) was added dropwise. Upon completion of the addition of the acid chloride, the pH of the mixture was controlled; it should be at least 8. The reaction mass was gradually heated to room temperature and stirred overnight at room temperature. Then it was washed with a saturated solution of citric acid until acidic, the organic layer was separated, dried over sodium sulfate and methylene chloride was distilled off on a rotary evaporator. The resulting residue was dissolved in methylene chloride and the substance was purified by silica gel chromatography; the methylene chloride system was a 3% solution of methanol in methylene. Yield 52% (210 mg) as a crystalline dark brown foam. C ₂₀ H ₂₂ F ₂ N ₆ O ₄ S. m / z 480.48. NMR and LCMS data confirming the structure of the compounds are shown in table 1

Scheme 2. Scheme for the synthesis of 2- (2,4-difluorophenyl) -1- (4- (3-carboxymethyl-1,3-thiazolidine-2,4-dione) piperazine-3- (1 H -1,2,4 triazolyl-1-yl) propan-2-ol.

Preparation of 3- (1- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) - 1-oxopropan-2-yl) thiazolidin-2,4-dione (2) .

Obtained analogously to (1) from the acid chloride of thiazolidine-2,4-dione 3-propionic acid. Physico-chemical characteristics are shown in table 1.

Preparation of 3- (1- (2,4-dichlorophenyl) -2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl ) propyl) piperazin-1-yl) -2-oxoethyl) thiazolidine-2,4-dione (3)

Obtained analogously to (1) from thiazolidine-2,4-dione 3- (2,4-dichlorophenyl) acetic acid chloride. Physico-chemical characteristics are shown in table 1.

1. An example of obtaining 2- (2,4-difluorophenyl) -1- (4- (3-carboxybutyl-1,3-thiazolidine-2,4-dione) piperazine-3- (1 H -1,2,4- triazolyl-1-yl) propan-2-ol (6) .

2- (2,4-Difluorophenyl) -4- (piperazin-1-yl) -3- (1H-1,2,4-triazolyl-1-yl) propan-2-ol hydrochloride (1 g, 2.78 mmol, 1 equiv) are suspended in methylene chloride (30 ml), then triethylamine (844 mg, 8.34 mmol, 3 equiv) is added. The reaction mass is cooled with ice, then a solution of acid chloride (739 mg, 3.34 mmol, 1.2 equiv) in methylene chloride (30 ml) is added dropwise with stirring. Upon completion of the addition of the acid chloride solution, the cooling bath was removed and the reaction mass was stirred for 16 hours at room temperature. Then the reaction mass is evaporated in a rotary solvent by half and washed with a saturated aqueous solution of citric acid until acidic. The organic layer was separated, dried over sodium sulfate and applied to silica gel. The resulting substance is isolated by flash chromatography on silica gel, the system for eluting with methylene chloride is a 5% solution of methanol in methylene chloride. The result is a pale yellow oil, 970 mg, yield 69%. C ₂₂ H ₂₆ F ₂ N ₆ O ₄ S, m / z 508.54.

Data confirming the structure of the compounds, NMR and LCMS are shown in table 1.

Scheme 4. Scheme for the preparation of 2- (2,4-difluorophenyl) -1- (4- (3-carboxybutyl-1,3-thiazolidine-2,4-dione) piperazine-3- (1 H -1,2,4 -triazolyl-1-yl) propan-2-ol.

In a similar manner, 2- (2,4-difluorophenyl) -1- (4- (3-carboxypentyl-1,3-thiazolidine-2,4-dione) piperazine-3- (1 H -1,2,4-triazolyl) was obtained -1-yl) propan-2-ol ( 7 ) The physicochemical characteristics are given in table 1.

2. An example of obtaining 2- (2,4-difluorophenyl) -1- (4- (3-carboxymethyl-2-thio-1,3-thiazolidin-4-one) piperazin-3- (1 N -1,2,4-triazolyl-1-yl) propan-2-ol (four) .

In methylene chloride (3 ml), rhodanine-3-acetic acid (80 mg, 0.42 mmol, 1 equiv) and the 2,4-difluorophenyl hydrochloride of the triazole derivative (181 mg, 0.50 mmol, 1.2 equiv) were suspended, then the calculated amount was added triethylamine (169 mg, 1.67 mmol, 4 equiv). The resulting solution was stirred for 30 minutes, then TBTU (161 mg, 0.50 mmol, 1.2 equiv) was added. After pH control (pH should be at least 8), the reaction mass was stirred at room temperature for 16 hours. Then the organic layer was washed with water, methylene chloride was separated and dried over sodium sulfate. Methylene chloride was evaporated on a rotary evaporator. The resulting material was isolated by flash chromatography on silica gel (ethyl acetate: hexane 3: 1 elution system). Received 41 mg of the target substance in the form of a dry foam, yield 20%. C ₂₀ H ₂₂ F ₂ N ₆ O ₃ S ₂ . m / z 496.55. Data confirming the structure, NMR and LCMS spectroscopy are shown in table 1.

Scheme 3. Scheme for the preparation of 2- (2,4-difluorophenyl) -1- (4- (3-carboxymethyl-2-thio-1,3-thiazolidin-4-one) piperazin-3- (1 H -1.2 , 4-triazolyl-1-yl) propan-2-ol.

In a similar manner, 2- (2,4-dichlorophenyl) -1- (4- (3-carboxymethyl-2-thio-1,3-thiazolidin-4-one) piperazin-3- ( 1 H -1,2,4-triazolyl-1-yl) propan-2-ol (5) The physicochemical characteristics of this compound are shown in Table 1.

Table 1. Physico-chemical characteristics of the hybrid piperazinyl amide derivatives of thiazolidin-4-one and triazole according to the invention, including data confirming the structure of the compounds.

General methods for the preparation of hybrid 5-arylidene amide derivatives of thiazolidin-4-one and triazole

Option A. The preparation of hybrid 5-arylidene piperazinyl amide derivatives of thiazolidin-4-one and triazole is carried out by acylation of the piperazinyl derivative of triazole with the corresponding 3-substituted carboxylic acid thiazolidin-4-one in an organic solvent and the presence of triethylamine as an acceptor of hydrogen halide.

Scheme 6. General scheme for the preparation of hybrid 5-arylidene amide derivatives of thiazolidin-4-one and triazole by the method according to option A, where Hal is halogen.

Option B.

The preparation of hybrid 5-arylidene piperazinyl amide derivatives of thiazolidin-4-one and triazole is carried out by condensation of the 3-piperazinyl amide derivative of thiazolidin-4-one and the corresponding halogen triazoloxirane in an organic solvent in the presence of triethylamine as an acceptor of hydrogen halide.

Scheme 7. General scheme for the preparation of hybrid 5-arylidene piperazinyl amide derivatives of thiazolidin-4-one and triazole by the method according to embodiment B, where Hal is halogen.

Option B.

The preparation of hybrid 5-arylidene piperazinyl amide derivatives of thiazolidin-4-one and triazole is carried out by condensation of 3-substituted thiazolidin-4-one according to Knevenagel with aromatic aldehydes in ethanol and the presence of piperidine as a reaction catalyst.

Scheme 8. General scheme for the preparation of hybrid 5-arylidene piperazinyl amide derivatives of thiazolidin-4-one and triazole by the method according to embodiment B, where Hal is halogen.

Option G.

The preparation of hybrid 5-arylidene piperazinyl amide derivatives of thiazolidin-4-one and triazole is carried out by alkylation of the potassium salt of 5-substituted thiazolidin-4-one 3-chloro-1- (4- (2- (2,4-Hal-phenyl) -2 -hydroxy-3- (1 H -1,2,4-triazol-1-yl) propyl) piperazin-1-yl) propan-1-one in dimethylformamide in the presence of potassium iodide.

Scheme 9. General scheme for the preparation of hybrid 5-arylidene piperazinyl amide derivatives of thiazolidin-4-one and triazole by the method according to embodiment D, where Hal is halogen.

An example of obtaining 3- (2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1 H -1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -2-oxoethyl) -5- (2,4-dichlorobenzylidene) thiazolidine-2,4-dione (8), variant A :

5- (2,4-Dichlorobenzylidene) thiazolidine-2,4-dione-3-acetic acid chloride (108 mg, 1 equiv.) Is added while cooling in an ice bath to a mixture of substituted alcohol piperazine hydrochloride (111 mg, 1 equiv.) and triethylamine (95 μl, 2.2 equiv.) in 1 ml of anhydrous (<0.01%) methylene chloride. The next day, the reaction mass is diluted with water, the organic phase is separated, washed with water, dried over Na ₂ SO ₄ and evaporated. The product was obtained as a mixture of diastereomers. Yield 132 mg (67%). C ₂₇ H ₂₅ ClF ₂ N ₆ O ₄ S, m / z 603.05. The structure was confirmed by NMR spectrometry and LC-MS. Physico-chemical characteristics are given in table 2.

In a similar manner, from the appropriate starting reagents, the compounds were obtained: 5- (4-methoxybenzylidene) -3- (2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4 triazol-1-yl) propyl) piperazin-1-yl) -2-oxoethyl) thiazolidin-2,4-dione (10),

5- (4-ethylbenzylidene) -3- (2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -2-oxoethyl) thiazolidin-2,4-dione (11) ,

5- (4-isopropyl-benzylidene) -3- (2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1 H -1,2,4-triazol-1-yl ) propyl) piperazin-1-yl) -2-oxoethyl) thiazolidine-2,4-dione (12) ,

5- (4-tert-butylbenzylidene) -3- (2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -2-oxoethyl) thiazolidine-2,4-dione (13)

3. An example of obtaining 3- (2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1 H -1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -2-oxoethyl) -5- (4-methoxybenzylidene) thiazolidine-2,4-dione (9), option B

A mixture of oxirane (386 mg, 1.216 mmol, 1 equiv), 5- (4-chlorobenzylidene) substituted amide piperazinyl thiazolidine-2,4-dione in the form of hydrochloride (489 mg, 1.216 mol, 1 equiv.) And triethylamine (185 mg, 1.823 mmol, 1.5 equiv.) Boils in ethanol overnight. Ethanol is evaporated, the residue is dissolved in methylene chloride and washed with an aqueous solution of citric acid until acidic, then with water. The organic phase is dried over Na ₂ SO ₄ and evaporated. The residue is dissolved in methylene chloride and the substance is purified by flash chromatography on silica gel (methylene chloride elution system - 3% solution of methanol in methylene chloride). The yield of the target substance 25% (180 g), white powder. C ₂₇ H ₂₅ ClF ₂ N ₆ O ₄ S, m / z 603.05. The structure of the target compound was confirmed by NMR spectrometry and LC-MS. Physico-chemical characteristics are given in table 2.

3. An example of obtaining 5- (4-chlorobenzylidene) -3- (2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1 H -1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -2-oxoethyl) -2-thio-thiazolidin-4-one (14), option B :

To a solution of the derivative (2,4-difluorophenyl) triazole amide of rhodanine-3-acetic acid (380 mg, 0.77 mmol, 1 equiv) in 5 ml of ethanol was added 4-chlorobenzaldehyde (118 mg, 0.84 mmol, 1.1 equiv), piperidine (13 mg, 0.14 mmol, 0.2 eq) and boiled for 16 hours. The reaction mass was cooled, evaporated on a rotary evaporator and the residue was dissolved in methylene chloride. The resulting material was purified by flash chromatography on silica gel (methylene chloride elution system — 4% methanol in methylene chloride). Received 98 mg of the target substance in the form of a dry foam, yield 21% . C ₂₇ H ₂₅ F ₂ ClN ₆ O ₃ S ₂ , m / z 619.12.

The structure of the target compound is confirmed by a combination of NMR spectrometry and the LC-MS method. Physico-chemical characteristics are given in table 2.

5- (4-Chlorobenzylidene) -3- (2- (4- (2- (2,4-dichlorophenyl) -2-hydroxy-3- (1 H -1,2,4- triazol-1-yl) propyl) piperazin-1-yl) -2-oxoethyl) -2-thio-thiazolidin-4-one (15) , 3- (2- (4- (2- (2,4-dichlorophenyl) ) -2-hydroxy-3- (1H-1,2,4-tyrazol-1-yl) propyl) piperazin-1-yl) -2-oxoethyl) -5- (4-methoxybenzylidene) -2-thio-1 , 3-thiazolidin-4-one (16) . Physico-chemical characteristics are given in table 2.

4. Production Example 5- (4-chlorobenzylidene) -3- (1- (4- (2- (2,4-difluorophenyl-2-hydroxy-3- (1H-1,2,4-triazol-1-yl) ) propyl) piperazin-1-yl) -1-oxopropan-2-yl) thiazolidine -2,4-dione (17) option a

To a suspension of piperazine hydrochloride (190 mg, 0.53 mmol, 1 equiv) in methylene chloride (2 ml) was added the calculated amount of triethylamine (160 mg, 1.58 mmol, 3 equiv), then the resulting solution was cooled in an ice bath. A solution of 2- (5- (4-chlorobenzylidene) -2,4-dioxothiazalidin-3-yl) propanoic acid (209 mg, 0.63 mmol, 1.2 equiv) in methylene chloride (2 ml) was added dropwise to the reaction mass while cooling. . After the addition of the acid chloride, the pH of the reaction mass should be at least 8. The resulting solution was stirred for 16 hours at room temperature, then washed with an aqueous solution of citric acid until acidic, the methylene layer was separated, washed with water, and separated again. The methylene chloride was dried over sodium sulfate, the solvents were evaporated on a rotary evaporator. The obtained residue was dissolved in methylene chloride and the target compound was purified by flash chromatography on silica gel (methylene chloride elution system — 3% methanol in methylene chloride). The yield of the target compound 71% (231 mg). C ₂₈ H ₂₇ ClF ₂ N ₆ O ₄ S, m / z 617.08.

The compound 5- (2-hydroxy-3,5-dichlorobenzylidene) -3- (2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1) , 2,4-triazol-1-yl) propyl) piperazin-1-yl) -2-oxoethyl) thiazolidin-2,4-dione (18) , variant A.

5. An example of obtaining 3- (1- (2,4-dichlorophenyl) -2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazole- 1-yl) propyl) piperazin-1-yl) -2-oxoethyl) -5- (4-fluorobenzylidene) thiazolidin-2,4-dione (19) , variant A.

The acid chloride (550 mg, 1 equiv.) Is added while cooling in an ice bath to a mixture of piperazine hydrochloride (445 mg, 1 equiv.) And triethylamine (207 μl, 1.2 equiv.) In 10 ml of methylene chloride. The next day, the reaction mixture is diluted with water, the organic phase is separated, dried over sodium sulfate and applied to a pad of silica gel. Purification of the target compound is carried out with ethyl acetate as an eluent. The product was obtained as a mixture of diastereoisomers. Yield 304 mg (33%). C ₃₃ H ₂₇ Cl ₂ F ₃ N ₆ O ₄ S, m / z 731.59. Physico-chemical characteristics are given in table 2.

6. Production Example 3- (3- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1- il) -3-oxopropyl) -5- (4-methoxybenzylidene) thiazolidine-2,4-dione (20), option G .

The potassium salt of 5- (4-methoxybenzylidene) thiazolidine-2,4-dione (220 mg, 0.8 mmol, 1 equiv) is suspended in DMF (4 ml), then the calculated amounts of the alkylating agent 2- (2,4-difluorophenyl) - are added 4- (3-chloroethylcarbonylpiperazin-1-yl) -3- (1H-1,2,4-triazolyl-1-yl) propan-2-ol (322 mg, 0.8 mmol, 1 equiv) and potassium iodide (134 mg , 0.8 mmol, 1 equiv). The resulting suspension was kept in a flask for 12 hours at 80 ^about C. Then the reaction mass was diluted with water (20 ml) and extracted three times with ethyl acetate (3 × 3 ml). The organic layer was separated, dried over sodium sulfate and the ethyl acetate was evaporated on a rotary evaporator. The resulting residue was dissolved in methylene chloride, and the substance was purified on silica gel (methylene chloride elution system — 5% methanol in methylene chloride). Received 42 mg of the substance as a pale yellow foam, yield 8.55%. C ₂₉ H ₃₀ F ₂ N ₆ O ₅ S. m / z 612.66. The structure of the target compound was confirmed by NMR spectrometry and LC-MS. Physico-chemical characteristics are given in table 2.

Similarly, from the appropriate starting reagents, 3- (3- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1 H -1,2,4-triazol-1-yl) propyl) was obtained) piperazin-1-yl) -3-oxopropyl) -5- (2,4-dichlorobenzylidene) thiazolidine-2,4-dione (21) . Physico-chemical characteristics are given in table 2.

Similarly, from the appropriate starting reagents, 3- (3- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1 H -1,2,4-triazol-1-yl) propyl) was obtained) piperazin-1-yl) -3-oxopropyl) -5- (4-chlorobenzylidene) thiazolidine-2,4-dione (22) . Physico-chemical characteristics are given in table 2.

7. An example of obtaining 5- (2-chloro-6- (4-methylpiperazin-1-yl) benzylidene) -3- (5- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (one H -1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -4-oxobutyl) thiazolidin-2,4-dione (23), option B.

To a solution of substituted thiazolidine-2,4-dione (166 mg, 0.33 mmol, 1 equiv) in 3 ml of ethanol was added 2-chloro-6- (4-methylpiperazine) benzaldehyde (86 mg, 0.36 mmol, 1.1 equiv), piperidine ( 6 mg, 0.07 mmol, 0.2 eq) and boiled for 16 hours. The reaction mass was cooled, evaporated on a rotary evaporator and the residue was dissolved in methylene chloride. The resulting material was isolated by flash chromatography on silica gel (methylene chloride elution system — 15% methanol in methylene chloride). Received 109 mg of the substance in the form of a dry foam, yield 46%. C ₃₄ H ₃₉ ClF ₂ N ₈ O ₄ S, m / z 729.25.

The structure was confirmed by NMR spectrometry and LC-MS. Physico-chemical characteristics are given in table 2.

Similarly, from the appropriate starting reagents, 3- (5- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1 H -1,2,4-triazol-1-yl) propyl) was obtained) piperazin-1-yl) -4-oxopentyl) -5- (4-chlorobenzylidene) thiazolidine-2,4-dione (24). The structure was confirmed by NMR spectrometry and LC-MS. Physico-chemical characteristics are given in table 2.

Similarly, from the appropriate starting reagents, 3- (5- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1 H -1,2,4-triazol-1-yl) propyl) was obtained) piperazin-1-yl) -4-hydroxybutyl) -5- (4-fluorobenzylidene) thiazolidine-2,4-dione (25). The structure was confirmed by NMR spectrometry and LC-MS. Physico-chemical characteristics are given in table 2.

Similarly, from the appropriate starting reagents, 3- (5- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1 H -1,2,4-triazol-1-yl) propyl) was obtained) piperazin-1-yl) -4-oxopentyl) -5- (2,4-dichlorobenzylidene) thiazolidine-2,4-dione (26). The structure was confirmed by NMR spectrometry and LC-MS. Physico-chemical characteristics are given in table 2.

5- (2-Hydroxy-3,5-dichlorobenzylidene) -3- (4- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1 H - 1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -4-oxobutyl) thiazolidin-2,4-dione (27). The structure was confirmed by NMR spectrometry and LC-MS. Physico-chemical characteristics are given in table 2.

8. An example of obtaining 3- (4- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1 H -1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -5-oxopentyl) -5- (2-hydroxy-3,5-dichlorobenzylidene) thiazolidin-2,4-dione (28) , option B.

To a solution of substituted thiazolidine-2,4-dione (176 mg, 0.34 mmol, 1 equiv) in 3 ml of ethanol was added 3,5-dichlorosalicylic aldehyde (71 mg, 0.37 mmol, 1.1 equiv), piperidine (6 mg, 0.07 mmol, 0.2 eq) and boiled for 16 hours. The reaction mass was cooled, evaporated on a rotary evaporator and the residue was dissolved in methylene chloride. The resulting material was purified by flash chromatography on silica gel (methylene chloride elution system — 15% methanol in methylene chloride). Received 131 mg of the target substance in the form of a dry foam. The yield of the target compound is 55.92%. C ₃₀ H ₃₀ Cl ₂ F ₂ N ₆ O ₅ S, m / z 695.58. The structure of the target compound was confirmed by NMR spectrometry and LC-MS. Physico-chemical characteristics are given in table 2.

Similarly, from the appropriate starting reagents, 3- (4- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1 H -1,2,4-triazol-1-yl) propyl) was obtained) piperazin-1-yl) -5-oxopentyl) -5- (4-chlorobenzylidene) thiazolidine-2,4-dione (29). The structure was confirmed by NMR spectrometry and LC-MS. Physico-chemical characteristics are given in table 2.

Similarly, from the appropriate starting reagents, 3- (4- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1 H -1,2,4-triazol-1-yl) propyl) was obtained) piperazin-1-yl) -4-oxopentyl) -5- (2,4-dichlorobenzylidene) thiazolidine-2,4-dione (30). The structure was confirmed by NMR spectrometry and LC-MS. Physico-chemical characteristics are given in table 2.

Similarly, from suitable starting reagents, 5- (2-chloro-6- (4-methylpiperazyl-1-yl) benzylidene) -3- (4- (4- (2- (2,4-difluorophenyl) -2-hydroxy -3- (1 H -1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -5-oxopentyl) thiazolidin-2,4-dione (31). The structure was confirmed by NMR spectrometry and LC-MS. Physico-chemical characteristics are shown in table 2

Similarly, from the appropriate starting reagents, 3- (4- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazine was obtained -1-yl) -5-oxopentyl) -5- (4-fluorobenzylidene) thiazolidin-2,4-dione (32). The structure was confirmed by NMR spectroscopy and LC-MS. Physico-chemical characteristics are shown in table 2

2. An example of obtaining N-cyclopropyl-2- (5- (2,4-dichlorobenzylidene) -2,4-dioxothiazolidin-3-yl) -N- (2- (2,4-difluorophenyl) -2-hydroxy-3 - (1H-1,2,4-triazol-1-yl) propyl) acetamide (33)

5- (2,4-Dichlorobenzylidene) -2- (2,4-dioxothiazolidin-3-yl) acetic acid chloride (249 mg, 1 eq.) Is added while cooling in an ice bath to a mixture of 1- (1 H -1, 2,4-triazol-1-yl) -2- (2,4-difluorophenyl) -3-cyclopropylamino-2-propanol (209 mg, 1 equiv.) And triethylamine (119 μl, 1.2 equiv.) In 8 ml of anhydrous acetonitrile. The next day, the solvent is evaporated, the crystalline residue is triturated with water, filtered and washed with water and ether. The yield of the target compound 234 mg (54%). The structure of the target compound was confirmed by NMR spectrometry and LC-MS. Physico-chemical characteristics are given in table 2.

Similarly, from suitable starting reagents, N-cyclopropyl-2- (5- (4-chlorobenzylidene) -2,4-dioxothiazolidin-3-yl) -N- (2- (2,4-difluorophenyl) -2-hydroxy- 3- (1H-1,2,4-triazol-1-yl) propyl) acetamide (34). The structure was confirmed by NMR spectrometry and LC-MS. Physico-chemical characteristics are shown in table 2

Similarly, from suitable starting reagents, N-cyclopropyl-2- (5- (4-fluorobenzylidene) -2,4-dioxothiazolidin-3-yl) -N- (2- (2,4-difluorophenyl) -2-hydroxy- 3- (1H-1,2,4-triazol-1-yl) propyl) acetamide (35). The structure was confirmed by NMR spectrometry and LC-MS. Physico-chemical characteristics are shown in table 2

9. An example of obtaining N-propyl-2- (5- (2,4-dichlorobenzylidene) -2,4-dioxothiazolidin-3-yl) -N- (2- (2,4-difluorophenyl) -2-hydroxy-3 - (1H-1,2,4-triazol-1-yl) propyl) acetamide (36)

5- (2,4-Dichlorobenzylidene) -2- (2,4-dioxothiazolidin-3-yl) acetic acid chloride (150 mg, 1 equiv.) Is added while cooling in an ice bath to a mixture of 1- (1 N -1, 2,4-triazol-1-yl) -2- (2,4-difluorophenyl) -3-propylamino-2-propanol (127 mg, 1 equiv.) And triethylamine (72 μl, 1.2 equiv.) In 5 ml of anhydrous acetonitrile. The next day, the solvent is evaporated, the residue is distributed between ethyl acetate and water. The organic phase is separated, evaporated, the residue is purified on silica gel (system for elution with 20% hexane in ethyl acetate). The product after evaporation of the fractions was obtained as a dry foam. The yield of the target compound is 175 mg (67%). The structure of the target compound was confirmed by NMR spectrometry and LC-MS. Physico-chemical characteristics are given in table 2.

Similarly, from suitable starting reagents, N-propyl-2- (5- (4-chlorobenzylidene) -2,4-dioxothiazolidin-3-yl) -N- (2- (2,4-difluorophenyl) -2-hydroxy- 3- (1H-1,2,4-triazol-1-yl) propyl) acetamide (37). The structure was confirmed by NMR spectrometry and LC-MS. Physico-chemical characteristics are given in table 2.

Similarly, from suitable starting reagents, N-propyl-2- (5- (4-fluorobenzylidene) -2,4-dioxothiazolidin-3-yl) -N- (2- (2,4-difluorophenyl) -2-hydroxy- 3- (1H-1,2,4-triazol-1-yl) propyl) acetamide (38). The structure was confirmed by NMR spectrometry and LC-MS. Physico-chemical characteristics are shown in table 2

Table 2. Physico-chemical characteristics of the hybrid molecules of the invention, including data confirming the structure of the compounds.

Examples of the preparation of amides containing triazole (1H-1,2,3-triazole, 39) or piperidine (4-amino-piperidine, 40, 1-methylamino-piperidine, 41) fragments.

Production Example 2- (5- (4-chlorobenzylidene) -2,4-dioxothiazolidin-3-yl) -N - ((1- (2- (2,4-difluorophenyl) -2-hydroxy-3- ( 1H- 1,2,4-triazol-1-yl) propyl) -1H-1,2,3-triazol-4-yl) methyl) acetamide (39).

To a suspension of 1- (4- (aminomethyl) -1H-1,2,3-triazol-1-yl) -2- (2,4-difluorophenyl) -3- (1H-1,2,4-triazol-1 -yl) propan-2-ol (250 mg, 0.75 mmol, 1 equiv) and triethylamine (226 mg, 2.24 mmol, 3 equiv) in methylene chloride (4 ml) while cooling with an ice bath, a solution of acid chloride (283 mg, 0.89 mmol, 1.2 equiv) in methylene chloride (4 ml). The reaction mass was stirred for 16 hours at room temperature, then methylene chloride was washed with citric acid until acidic. The organic layer was separated, dried over sodium sulfate and purified by flash chromatography on silica gel (elution system for ethyl acetate: 3: 1 hexane - ethyl acetate - ethyl acetate: 3: 2 methanol). The fractions containing the desired product were evaporated on a rotary evaporator, the resulting yellowish crystalline solid was washed with ethyl acetate (3 ml), filtered and dried in air. White crystals, yield of the target compound 14% (64 mg). C ₂₆ H ₂₁ ClF ₂ N ₈ O ₄ S. [M + H] ⁺ 616.02.

¹ H (DMSO-d ₆ ): 8.77 (m, 1H), 8.32 (s, 1H), 7.95 (s, 1H), 7.81 (s, 1H), 7.73 (s, 1H), 7.67 (d, 2H, J = 8.81 Hz), 7.62 (d, 2H, J = 8.81 Hz), 7.21 (m, 1H), 7.14 (m, 1H), 6.86 (m, 1H), 6.45 (s, 1H), 4.95 (m, 1H), 4.73 (m, 1H), 4.66 (m, 1H), 4.53 (m, 1H), 4.27 (s, 2H), 4.25 (m, 2H).

An example of obtaining 4- (5- (4-chlorobenzylidene) -2,4-dioxothiazolidin-3-yl) -N- (1- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1 , 2,4-triazol-1-yl) propyl) piperidin-4-yl) butanamide ( 40 ).

To a suspension of 4- (5- (4-chlorobenzylidene) -2,4-dioxothiazolidin-3-yl) -N- (piperidin-4-yl) butanamide hydrochloride (125 mg, 0.28 mmol, 1 equiv) in ethanol (5 ml ) triethylamine (114 mg, 1.13 mmol, 4 equiv) was added, then oxirane methanesulfonate (89 mg, 0.28 mmol, 1 equiv) was added. The reaction mass was stirred for 16 hours at 85 degrees, then cooled, ethanol was evaporated on a rotary evaporator. The resulting residue was poured with water (3 ml), the precipitate was filtered off, dried in air and purified by silica gel chromatography (elution system ethyl acetate: hexane 3: 1 - ethyl acetate - ethyl acetate: methanol 3: 2). The yield of the target compound is 31% (57 mg). C ₃₀ H ₃₁ ClF ₂ N ₆ O ₄ S. [M + H] ⁺ 646.13.

¹ H (CDCl ₃ ): 8.18 (s, 1H), 7.83 (s, 1H), 7.78 (s, 1H), 7.54 (m, 1H), 7.44 (m, 4H), 6.81 (m, 2H), 6.01 (bs, 1H), 4.53 (dd, 2H, J ₁ = 14.57 Hz, J ₂ = 29.73 Hz), 3.77 (m, 3H), 3.18 (m, 1H), 2.91 (m, 1H), 2.76 (m, 1H), 2.57 (m, 2H), 2.27 (m, 1H), 2.16 (m, 2H), 2.06 (s, 2H), 1.99 (m, 2H), 1.91 (m, 1H), 1.78 (m, 1H ), 1.46 (m, 1H).

An example of obtaining 5- (4-chlorobenzylidene) -3- (2- (4 - ((2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl ) propyl) (methyl) amino) piperidin-1-yl) -2-oxoethyl) thiazolidin-2,4-dione ( 41 ).

К суспензии дигидрохлорида пиперазина (200 мг, 0.47 ммоль, 1 экв) в хлористом метилене (2 мл) прибавили триэтиламин (191 мг, 1.89 ммоль, 3 экв), затем реакционную массу охладили до 0 градусов на ледяной бане. При охлаждении по каплям прибавили раствор хлорангидрида (164 мг, 0.52 ммоль, 1.1 экв) в дихлорметане (2 мл), затем проконтролировали рН полученной смеси (он должен быть не ниже 8). Реакционную массу перемешивали 16 часов при комнатной температуре, после чего промыли водным раствором лимонной кислоты до кислой реакции. Хлористый метилен отделили, промыли водой и высушили над сульфатом натрия. Полученный остаток почистили хроматографией на силикагеле (система для элюирования этилацетат – этилацетат : метанол 4:1). Выход целевого соединения 60% (177 мг). C₂₉H₂₉ClF₂N₆O₄S. [M+H]⁺ 632.11.

Triethylamine (191 mg, 1.89 mmol, 3 equiv) was added to a suspension of piperazine dihydrochloride (200 mg, 0.47 mmol, 1 equiv) in methylene chloride (2 ml), then the reaction mass was cooled to 0 degrees in an ice bath. While cooling, a solution of acid chloride (164 mg, 0.52 mmol, 1.1 equiv) in dichloromethane (2 ml) was added dropwise, then the pH of the resulting mixture was monitored (it should be at least 8). The reaction mass was stirred for 16 hours at room temperature, after which it was washed with an aqueous solution of citric acid until acidic. Methylene chloride was separated, washed with water and dried over sodium sulfate. The resulting residue was purified by silica gel chromatography (elution system ethyl acetate-ethyl acetate: methanol 4: 1). The yield of the target compound is 60% (177 mg). C ₂₉ H ₂₉ ClF ₂ N ₆ O ₄ S. [M + H] ⁺ 632.11.

¹ H (CDCl ₃ ): 8.30 (m, 1H), 7.91 (m, 2H), 7.69 (m, 1H), 7.46 (m, 4H), 6.88 (m, 2H), 4.66 (m, 2H), 4.53 (m, 3H), 3.86 (m, 1H), 3.33 (m, 2H), 3.05 (m, 1H), 2.80 (m, 1H), 2.51 (m, 1H), 2.27 (m, 2H), 2.10 ( s, 3H), 1.90 (m, 2H), 1.42 (m, 1H).

Examples of methods for the preparation of intermediates

To obtain 3-substituted thiazolidine-2,4-dione derivatives (TZD), the potassium salt of TZD was alkylated with various halide alkyl esters of carboxylic acids. Potassium salt is obtained in alcohol with potassium hydroxide.

An example of obtaining a potassium salt of thiazolidine-2,4-dione (01).

Thiazolidine-2,4-dione (3.51 g, 0.3 mol, 1 equiv) was suspended in 50 ml of ethanol, then a solution of potassium hydroxide (1.08 g, 0.3 mol, 1 equiv) in ethanol (15 ml) was added. The resulting suspension was stirred at room temperature for 3 hours. Then the precipitate was filtered, washed with ethanol (20 ml) and diethyl ether (2 * 30 ml) and transferred to a round bottom flask. The substance was dried on a rotary evaporator to constant weight. Yield 98% (4.56 g), white powder.

An example of the preparation of ethyl 2- (2,4-dioxothiazolidin-3-yl) acetate (02).

Equimolar amounts of the potassium salt of TZD (4.5 g, 0.28 mol, 1 equiv) and the alkylating agent ethyl bromoacetic acid (5.38 g, 0.3 mol, 1 equiv) were suspended in acetone and boiled for 16 hours. The resulting potassium bromide precipitate was filtered off, and the organic layer was evaporated on a rotary evaporator. The oil residue was used without further purification. Yield 92% (5.60 g). C ₇ H ₉ NO ₄ S. m / z 203.22. [M + H] ⁺ 204.22.

An example of the preparation of 2- (2,4-dioxothiazolidin-3-yl) acetic acid (03).

TZD ethyl acetate (5.60 g, 27.56 mmol, 1 equiv) was dissolved in a 3: 1 mixture of acetic and hydrochloric acids and refluxed for 16 hours. The solution was evaporated on a rotary evaporator and the residue was washed with diethyl ether and then filtered. Yield 93% (4.50 g).

C ₄ H ₅ NO ₄ S. m / z 175.16. [MH] ^- 174.16. ¹ H NMR (DMSO- d ₆ ): δ = 13.23 (1H, s, COOH), 4.32 (2H, s, NCH ₂ ), 4.20 (2H, s, CH ₂ ). According to TLC, the substance is individual, used further without further purification.

An example of obtaining 5- (4-methoxybenzylidene) thiazolidine-2,4-dione (04).

Thiazolidine-2,4-dione (2.7 g, 23.05 mmol, 1 equiv) was suspended in 50 ml of acetic acid. To the resulting reaction mass was added 4-methoxybenzaldehyde (3.14 g, 23.05 mmol, 1 equiv), then a 40% aqueous solution of methylamine (1.16 ml, 0.43 g in terms of methylamine, 13.83 mmol, 0.6 equiv). The reaction mass was stirred overnight at 100 degrees, then cooled to room temperature. The precipitate was filtered off, washed twice with water (2 * 30 ml), dried in air and washed once with diethyl ether (40 ml). Yield 89% (4.80 g), light yellow powder. C ₁₁ H ₉ NO ₃ S. m / z 235.26. [M + H] ⁺ 236.27. ¹ H NMR (DMSO- d ₆ ): δ = 12.4 (1H, s, NH) 7.75 (1H, m, CH = C), 7.09 (4H, m, Ph), 3.82 (3H, s, OCH ₃ ).

An example of the preparation of the potassium salt of 5- (4-methoxybenzylidene) thiazolidine-2,4-dione (05).

5- (4-Methoxybenzylidene) thiazolidine-2,4-dione (1.5 g, 6.38 mmol, 1 equiv) was suspended in 30 ml of ethanol, then a solution of potassium hydroxide (0.36 g, 6.38 mmol, 1 equiv) in ethanol (5 ml) was added ) The resulting suspension was intensively stirred at room temperature for 3 hours. Then the precipitate was filtered, washed with ethanol (20 ml) and diethyl ether (2 × 30 ml) and transferred to a round bottom flask. The substance was dried on a rotary evaporator to constant weight. Yield 81% (1.42 g), white powder.

An example of the preparation of ethyl 2- (5- (4-methoxybenzylidene) -2,4-dioxothiazolidin-3-yl) acetate (06).

To 2.73 g (0.01 mol, 1 equiv.) Of the potassium salt of 5- (4-methoxybenzylidene) thiazolidine-2,4-dione in 50 ml of DMF was added 1.67 g (0.01 mol, 1 equiv.) ethyl bromoacetic acid and kept for 16 hours at a temperature of 50 degrees. The resulting solution was cooled and poured into 200 ml of water, the precipitate was filtered off, then washed with 20 ml of diethyl ether and used further without purification. Yield 87% (2.79 g). C ₁₅ H ₁₅ NO ₅ S. m / z 321.35. [M + H] ⁺ 322.35.

An example of obtaining 2- (5- (4-methoxybenzylidene) -2,4-dioxothiazolidin-3-yl) acetic acid (07).

2- (5- (4-Methoxybenzylidene) -2,4-dioxothiazolidin-3-yl) acetic acid ethyl ester (3.70 g, 11.51 mmol,) was dissolved in a 3: 1 mixture of acetic and hydrochloric acids in reflux within 16 hours. The solution was evaporated on a rotary evaporator and the residue was washed with diethyl ether and then filtered. Yield 95% (3.21 g).

C ₁₃ H ₁₁ NO ₅ S. m / z 293.30. [MH] ^- = 292.30. ¹ H NMR (DMSO- d ₆ ): δ = 13.35 (1H, s, COOH), 7.94 (1H, s, CH = C), 7.61 (2H, d, J = 8.7 Hz , 2Ph), 7.11 (2H, d, J = 8.7 Hz, 2Ph), 4.39 (2H, s, NCH ₂ ), 3.84 (3H, s, OCH ₃ ). According to TLC, the substance is individual, used further without further purification.

An example of the preparation of 2- (5- (4-methoxybenzylidene) -2,4-dioxothiazolidin-3-yl) acetic acid chloride (08).

2- (5- (4-Methoxybenzylidene) -2,4-dioxothiazolidin-3-yl) acetic acid (4.1 g, 14 mmol, 1 equiv) was suspended in thionyl chloride (10 ml, 140 mmol, 10 equiv) at room temperature , then boiled under reflux for two hours. Thionyl chloride was evaporated on a rotary evaporator and the residue was used for further syntheses without purification. Received a light yellow oil. The yield is 100%. (4.36 g).

An example of obtaining 5- (4-chlorobenzylidene) thiazolidine-2,4-dione (09).

Thiazolidine-2,4-dione (3.22 g, 27.49 mmol, 1 equiv) was suspended in 50 ml of acetic acid. To the resulting reaction mass was added 4-chlorobenzaldehyde (3.86 g, 27.49 mmol, 1 equiv), then a 40% aqueous solution of methylamine (1.38 ml, 0.51 g in terms of methylamine, 16.49 mmol, 0.6 equiv). The reaction mass was stirred overnight at 100 degrees, then cooled to room temperature. The precipitate was filtered off, washed twice with water (2 × 30 ml), dried in air and washed once with diethyl ether (40 ml). Yield 96% (6.32 g), white powder. C ₁₀ H ₆ ClNO ₂ S. m / z 239.68. [M + H] ⁺ = 240.68. ¹ H NMR (DMSO- d ₆ ): δ = 12.7 (1H, s, NH) 7.8 (1H, m, CH = C), 7.6 (4H, m, Ph).

An example of the preparation of the potassium salt of 5- (4-chlorobenzylidene) thiazolidine-2,4-dione (010).

5- (4-Chlorobenzylidene) thiazolidine-2,4-dione (5 g, 20.86 mmol, 1 equiv) was suspended in 80 ml of ethanol, then a solution of potassium hydroxide (1.17 g, 20.86 mmol, 1 equiv) in ethanol (20 ml) was added ) The resulting suspension was intensively stirred at room temperature for 3 hours. Then the precipitate was filtered, washed with ethanol (50 ml) and diethyl ether (2 * 60 ml) and transferred to a round bottom flask. The substance was dried on a rotary evaporator to constant weight. Yield 90% (5.23 g), white powder.

An example of obtaining 5- (2,4-dichlorobenzylidene) thiazolidine-2,4-dione (011).

Thiazolidine-2,4-dione (3.0 g, 25.61 mmol, 1 equiv) was suspended in 50 ml of acetic acid. To the resulting reaction mass was added 2,4-dichlorobenzaldehyde (4.48 g, 25.61 mmol, 1 equiv), then a 40% aqueous solution of methylamine (1.30 ml, 0.48 g in terms of methylamine, 15.37 mmol, 0.6 equiv). The reaction mass was stirred overnight at 100 degrees, then cooled to room temperature. The precipitate was filtered off, washed twice with water (2 × 30 ml), dried in air and washed once with diethyl ether (40 ml). Yield 81% (5.70 g) , light yellow powder. C ₁₀ H ₅ Cl ₂ NO ₂ S. m / z 274.13. [M + H] ⁺ = 275.13. ¹ H NMR (DMSO- d ₆ ): δ = 12.65 (1H, s, NH), 7.8 (1H, s, C = CH), 7.71 (1H, m, Ph), 7.61 (1H, m , Ph) 7.55 (1H, m, Ph).

An example of the preparation of the potassium salt of 5- (2,4-dichlorobenzylidene) thiazolidine-2,4-dione (012).

5- (2,4-Dichlorobenzylidene) thiazolidine-2,4-dione (1.0 g, 3.65 mmol, 1 equiv) was suspended in 15 ml of ethanol, then a solution of potassium hydroxide (0.20 g, 3.65 mmol, 1 equiv) in ethanol was added ( 3 ml). The resulting suspension was stirred at room temperature for 3 hours. Then the precipitate was filtered, washed with ethanol (10 ml) and diethyl ether (2 × 15 ml) and transferred to a round bottom flask. The substance was dried on a rotary evaporator to constant weight. Yield 92% (1.05 g), white powder.

An example of the preparation of 2- (2,4-dioxothiazolidin-3-yl) acetic acid chloride (013).

2- (2,4-dioxothiazolidin-3-yl) acetic acid (4.2 g, 0.25 mol, 1 equiv) was suspended in thionyl chloride (17 ml, 0.25 mol, 10 equiv) at room temperature, then boiled with reflux for two hours. Thionyl chloride was evaporated on a rotary evaporator and the residue was used for further syntheses without purification. Received a light yellow oil. Quantitative yield (4.64 g).

An example of the preparation of ethyl 2- (2,4-dioxothiazolidin-3-yl) propanoate (014).

Ethyl 2-bromopropanoate (6.12 g, 1.05 equiv) and the potassium salt of thiazolidinedione (5 g, 1 equiv) in 50 ml of acetonitrile are stirred overnight at room temperature. TLC control (eluent - dichloromethane). The precipitate is filtered off, washed with acetonitrile, and the solution is evaporated. The residue is triturated with hexane to form a solid, which is filtered and washed with hexane. Yield 4.95 g (70%). C ₈ H ₁₁ NO ₄ S. m / z 217.25. [M + H] + 218.25.

An example of obtaining 2- (2,4-dioxothiazolidin-3-yl) propanoic acid (015).

A mixture of ethyl 2- (2,4-dioxothiazolidin-3-yl) propanoic acid (2.7 g), acetic acid (32 ml) and concentrated hydrochloric acid (8 ml) was stirred overnight at the boil. After cooling to room temperature, the mixture was evaporated to dryness, after which it was evaporated twice with benzene. Yield 2.51 g (100%). C ₆ H ₇ NO ₄ S. m / z 189.19. [MH] ^- 188.19. ¹ H NMR: (500 MHz, DMSO-d ₆ ) δ = 12.59 (bs, 1H), 3.51 (q, J = 7.1 Hz, 1H), 3.38 (dd, J ₁ = 29.1 Hz, J ₂ = 15.4 Hz, 2H) 1.32 (d, J = 7.1 Hz, 3H).

An example of the preparation of ethyl 2- (5- (4-chlorobenzylidene) -2,4-dioxothiazolidin-3-yl) propanoate (016).

Ethyl 2-bromopropanoate (1.37 g, 1.05 equiv) and 5- (4-chlorobenzylidene) -2,4-dioxothiazolidin-3-id potassium (2 g, 1 equiv) in 10 ml of DMF are stirred overnight at room temperature. TLC control (eluent - dichloromethane). The solution is poured into 200 ml of water, the precipitated precipitate is filtered off, washed with water and dried. Yield 2.44 g (99%). C ₁₅ H ₁₄ ClNO ₄ S. m / z 339.80 [M + H] ⁺ 340.80. ¹ H NMR: (500 MHz, CDCl ₃ ) δ = 7.87 (s, 1H), 7.47 (m, 4H), 5.08 (q, J = 7.1Hz, 1H), 4.25 (q, J = 7.3 Hz, 2H) , 1.68 (d, J = 7.1 Hz, 3H), 1.28 (t, J = 7.3 Hz, 3H).

An example of obtaining 2- (5- (4-chlorobenzylidene) -2,4-dioxothiazolidin-3-yl) propanoic acid (017).

A mixture of ethyl 2- (5- (4-chlorobenzylidene) -2,4-dioxothiazolidin-3-yl) propanoate (2.44 g), acetic acid (32 ml) and concentrated hydrochloric acid (8 ml) was stirred overnight at the boil. After cooling to room temperature, the precipitate formed is filtered off, washed with water and dried. Yield 1.33 g (59%). C ₁₃ H ₁₀ ClNO ₄ S. m / z 311.75. [MH] ^- 310.75. ¹ H NMR: (500 MHz, DMSO-d ₆ ) δ = 13.25 (bs, 1H), 7.98 (s, 1H), 7.67 (d, J = 8.6Hz, 2H), 7.63 (d, J = 8.6 Hz, 2H), 5.02 (q, J = 7.1 Hz, 1H), 2.51 (d, J = 7.1 Hz, 3H).

An example of the production of 2- (5- (4-chlorobenzylidene) -2,4-dioxothiazalidin-3-yl) propanoic acid chloride (018).

2- (5- (4-Chlorobenzylidene) -2,4-dioxothiazalidin-3-yl) propanoic acid (200 mg, 0.64 mmol, 1 eq) is suspended in thionyl chloride (0.5 ml, 6.42 mmol, 10 eq) and boiled in within 2 hours. Then the reaction mass is cooled, thionyl chloride is evaporated on a rotary evaporator and the obtained substance is used further without purification. Quantitative yield (212 mg).

An example of obtaining methyl 2-bromo-2- (2,4-dichlorophenyl) acetate (019)

A solution of 2- (2,4-dichlorophenyl) acetic acid (10 g, 1 equiv.) In thionyl chloride (4.4 ml, 1.25 equiv.) Is boiled for two hours, after which bromine (7.8 g, 1 equiv.) Is added dropwise over a period of two hours. The mixture is boiled further overnight, after which it is cooled to room temperature and when cooled in a water bath, it is diluted dropwise with methanol (100 ml). The solvent is evaporated, the mixture is dissolved in benzene and washed with water, the benzene phase is stirred for 15 minutes with saturated NaHCO ₃ solution, dried with sodium sulfate and evaporated. Yield 14.24 g (98%). ¹ H NMR: (500 MHz, CDCl ₃ ) δ = 7.76 (d, J = 8.3 Hz, 1H), 7.43 (d, J = 2 Hz, 1H), 7.33 (m, 1H), 5.87 (s, 1H) 3.84 (s, 3H).

An example of obtaining methyl 2- (2,4-dichlorophenyl) -2- (2,4-dioxothiazolidin-3-yl) acetate (020)

Methyl 2-bromo-2- (2,4-dichlorophenyl) acetate (14.24 g, 1 equiv) and the potassium salt of 2,4-dioxothiazolidine (7.42 g, 1 equiv) in 50 ml of acetonitrile are stirred overnight at room temperature. TLC control (eluent - dichloromethane). The precipitate is filtered off, washed with acetonitrile, and the solution is evaporated. The residue is dissolved in methylene chloride and chromatographed on silica gel (eluent is methylene chloride). The fractions were evaporated to give a yellowish crystalline powder. Yield 6.8 g (43%). C ₁₂ H ₉ Cl ₂ NO ₄ S. m / z 334.18. [M + H] ⁺ 335.18 ¹ H NMR: (500 MHz, CDCl ₃ ) δ = 7.51 (d, J = 8.3 Hz, 1H), 7.43 (d, J = 2 Hz, 1H), 7.27 (m, 1H), 6.39 (s, 1H), 4.02 (s, 2H) 3.83 (s, 3H).

An example of obtaining 2- (2,4-dichlorophenyl) -2- (2,4-dioxothiazolidin-3-yl) acetic acid (021).

A mixture of 2- (2,4-dichlorophenyl) -2- (2,4-dioxothiazolidin-3-yl) acetate (6.8 g), acetic acid (64 ml) and concentrated hydrochloric acid (16 ml) was stirred overnight at reflux. After cooling to room temperature, the mixture was evaporated to dryness, after which it was evaporated twice with benzene. Yield 6.51 g (100%). C ₁₁ H ₇ Cl ₂ NO ₄ S. m / z 320.15. [MH] ^- 319.15. ¹ H NMR: (500 MHz, DMSO-d ₆ ) δ = 12.25 (bs, 1H), 7.68 (d, J = 2 Hz, 1H), 7.49 (s, 1H), 7.48 (d, J = 2 Hz, 1H), 6.07 (s, 1H), 4.40 (dd, J1 = 27Hz, J2 = 17.8 Hz, 2H).

An example of the preparation of 2- (2,4-dichlorophenyl) -2- (2,4-dioxothiazolidin-3-yl) acetic acid chloride (022).

2- (2,4-Dichlorophenyl) -2- (2,4-dioxothiazolidin-3-yl) acetic acid (6.51 g) in excess of thionyl chloride is stirred at reflux for 1 hour. After cooling to room temperature, the mixture was evaporated to dryness, after which it was evaporated twice with benzene. Yield 6.88 g (100%).

An example of obtaining 3-carbomethoxypropyl thiazolidine-2,4-dione (023).

TZD potassium salt (1 g, 6.44 mmol, 1 equiv) is suspended in 15 ml of absolute DMF, then the calculated amount of an alkylating agent, bromobutyric acid methyl ester (1.17 g, 6.44 mmol, 1 equiv) is added and the reaction mass is stirred for 16 hours at 50 degrees . The reaction was monitored by TLC (methylene: hexane 3: 1), DMF was diluted with water (15 ml) and extracted twice with diethyl ether (20 ml each). The organic layer was separated, dried over sodium sulfate and the solvent was removed on a rotary evaporator. The resulting residue was dissolved in a minimum amount of methylene chloride, diluted with hexane until cloudy and purified by flash chromatography on silica gel (system: hexane - methylene chloride: 4: 1 hexane). Identity confirmed by chromatography. Received 816 mg of the substance in the form of a colorless liquid, yield 58%. C₈H_elevenNO_fourS. m / z 217.25. [M + H]⁺= 218.25.^oneH NMR (CDCl₃): δ = 3.93 (s, 2H), 3.67 (m, 5H), 2.34 (m, 2H), 1.94 (m, 2H).

An example of obtaining 3-carboxypropyl thiazolidine-2,4-dione (024).

3-Carboxypropyl thiazolidine-2,4-dione methyl ester (781 mg, 3.60 mmol, 1 equiv) was suspended in a mixture of acetic (15 ml) and hydrochloric acid (4 ml) and boiled for 16 hours. Then the reaction mass is cooled, the solvent is removed on a rotary evaporator, the residue is evaporated twice with toluene for drying. The resulting product is used further without purification. Colorless oil, 730 mg, quantitative yield. C ₇ H ₉ NO ₄ S. m / z 203.22. [MH] ^- = 202.22. ¹ H NMR (CDCl ₃ ): δ = 9.03 (bs, 1H), 3.95 (s, 2H), 3.71 (t, 2H, J ₁ = 6.85 Hz, J ₂ = 13.69 Hz), 2.40 (m, 2H ), 1.95 (qw, 2H, J ₁ = 6.85 Hz, J ₂ = 13.69 Hz).

An example of the production of 3-carboxypropyl thiazolidine-2,4-dione acid chloride (025).

3-Carboxypropyl thiazolidine-2,4-dione (730 mg, 3.59 mmol, 1 equiv) is dissolved in thionyl chloride (4.27 g, 35.92 mmol, 10 equiv) and boiled for 2 hours. Then thionyl chloride is evaporated on a rotary evaporator and the product is used further without purification. Brown oil, 800 mg, quantitative yield.

An example of obtaining 3-carbethoxybutyl thiazolidine-2,4-dione (026).

TZD potassium salt (1 g, 6.44 mmol, 1 equiv) is suspended in 15 ml of absolute DMF, then the calculated amount of an alkylating agent, valerianic acid ethyl ester (1.35 g, 6.44 mmol, 1 equiv) is added and the reaction mass is stirred for 16 hours at 50 degrees. The reaction was monitored by TLC (methylene: hexane 3: 1), DMF was diluted with water (15 ml) and extracted twice with diethyl ether (20 ml each). The organic layer was separated, dried over sodium sulfate and the solvent was removed on a rotary evaporator. The resulting residue was dissolved in a minimum amount of methylene chloride, diluted with hexane until cloudy and purified by flash chromatography on silica gel (elution system with pure hexane - methylene chloride: 4: 1 hexane). Received 886 mg of the substance as a colorless liquid, yield 56%. C ₁₀ H ₁₅ NO ₄ S. m / z 245.30. [M + H] ⁺ = 246.30. ¹ H NMR (CDCl ₃ ): δ = 4.12 (q, 2H, J ₁ = 6.84 Hz, J ₂ = 14.18 Hz), 3.94 (s, 2H), 3.64 (m, 2H), 2.32 (m, 2H), 1.64 (m, 4H), 1.25 (t, 3H, J ₁ = 6.84 Hz, J ₂ = 14.18 Hz).

An example of obtaining 3-carboxybutyl thiazolidine-2,4-dione (027).

3-Carboxybutylthiazolidine-2,4-dione ethyl ester (866 mg, 3.53 mmol, 1 equiv) was suspended in a mixture of acetic (16.5 ml) and hydrochloric acid (4.4 ml) and boiled for 16 hours. Then the reaction mass is cooled, the solvent is removed on a rotary evaporator, the residue is evaporated twice with toluene for drying. The resulting product is used further without purification. Colorless oil, 770 mg, quantitative yield. C ₈ H ₁₁ NO ₄ S. m / z 217.25. [MH] ^- 218.25. ¹ H NMR (CDCl ₃ ): δ = 8.72 (bs, 1H), 3.96 (s, 2H), 3.66 (m, 2H), 2.40 (m, 2H), 1.67 (m, 4H).

An example of the production of 3-carboxybutyl thiazolidine-2,4-dione acid chloride (028).

3-Carboxybutyl thiazolidine-2,4-dione (750 mg, 3.45 mmol, 1 equiv) was dissolved in thionyl chloride (4.11 g, 34.52 mmol, 10 equiv) and boiled for 2 hours. Then thionyl chloride is evaporated on a rotary evaporator and the product is used further without purification. Brown oil, 815 mg, quantitative yield.

An example of obtaining 2- (2,4-difluorophenyl) -4- (tert-butoxycarbonylpiperazin-1-yl) -, 3- ( 1H -1,2,4 triazolyl-1-yl) propan-2-ol (029).

A mixture of oxirane -1 - ((2- (2,4-difluorophenyl) -2-oxiranyl) methyl) - 1H -1,2,4-triazole, methanesulfonate (17.2 g, 1 equiv.), Boc-piperazine ( 9.6 g, 1 equiv.) And triethylamine (10.4 ml, 1.5 equiv.) Are boiled in ethanol for 3 hours. Ethanol is evaporated, the residue is dissolved in methylene chloride and washed with an aqueous solution of citric acid until acidic, then with water. The organic phase is dried over Na ₂ SO ₄ and evaporated. The product in the form of foamed oil crystallized upon standing. Yield 13.02 g (59%). C ₂₀ H ₂₇ F ₂ N ₅ O _3. m / z 423.77. LCMS [M + H] ⁺ 424.77. ¹ H NMR: (500 MHz, CDCl ₃ ) δ = 8.13 (s, 1H), 7.79 (s, 1H), 7.56 (m, 1H), 6.83 (m, 2H), 4.54 (dd, J ₁ = 25.2 Hz , J ₂ = 14.2 Hz, 2H), 3.33 (m, 5H), 3.10 (m, 1H), 2.77 (m, 1H), 2.36 (m, 4H), 1.43 (s, 9H).

An example of the preparation of 2- (2,4-difluorophenyl) -4- (piperazin-1-yl) -3- (1H-1,2,4-triazolyl-1-yl) propan-2-ol hydrochloride (030).

A solution of Boc amide (10.0 g) in a saturated solution of hydrogen chloride in ethyl acetate (60 ml) was stirred overnight at room temperature, and a precipitate formed gradually. The next day, the precipitate formed is filtered off and washed with ethyl acetate. Yield 8.44 g (98.0%). C_fifteenH₁₉F₂N₅O. m / z 323.35 on a free base. [M + H]⁺ 324.35.

¹ H NMR: (500 MHz, DMSOd6) δ = 9.63 (bs, 2H), 8.56 (s, 1H), 7.88 (s, 1H), 7.42 (m, 1H), 7.24 (m, 1H), 7.02 (m , 1H), 4.79 (d, J = 14 Hz, 1H), 4.70 (d, J = 14 Hz, 1H), 4.56 (bs, 1H), 4.02 (dd, J ₁ = 14.2 Hz, J ₂ = 7.1 Hz , 2H), 3.71-3.19 (m, 8H).

An example of obtaining 2- (2,4-difluorophenyl) -4- (3-chloroethylcarbonylpiperazin-1-yl) -3- (1H-1,2,4-triazolyl-1-yl) propan-2-ol (031).

2- (2,4-Difluorophenyl) -4- (piperazin-1-yl) -3- (1H-1,2,4-triazolyl-1-yl) propan-2-ol hydrochloride (700 mg, 1.95 mmol, 1 equiv) was suspended in methylene chloride (20 ml), then triethylamine (591 mg, 5.84 mmol, 3 equiv) was added. The reaction mass was cooled in an ice bath, then chlorpropionyl chloride (296 mg, 2.33 mmol, 1.2 equiv) was added dropwise. Upon completion of the addition of the acid chloride, the pH of the mixture was controlled; it should be at least 8. The reaction mass was gradually heated to room temperature and stirred overnight at room temperature. Then it was washed with a saturated solution of citric acid until acidic, the organic layer was separated, dried over sodium sulfate and methylene chloride was distilled off on a rotary evaporator. The resulting residue was dissolved in methylene chloride and the substance was purified by silica gel chromatography; the methylene chloride system was a 4% solution of methanol in methylene. Yield 80% (647 mg), dark yellow oil. C ₁₈ H ₂₂ ClF ₂ N ₅ O _2. m / z 413.86

An example of obtaining derivatives of triazole (2,4-dichlorophenyl)

An example of obtaining 2,4-dichloro- (1 N -1,2,4-triazolyl) acetophenone (032).

2,2 ', 4' - Trichloroacetophenone (4 g, 18 mmol, 1 equiv), triazole (1.48 g, 21 mmol, 1.2 equiv) and sodium bicarbonate (2.26 g, 27 mmol, 1.5 equiv) were suspended in absolute toluene (120 ml) and boiled overnight under reflux equipped with a calcium chloride tube. Then the reaction mass was cooled, toluene was distilled off on a rotary evaporator, the residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with saturated sodium chloride solution, dried over sodium sulfate, and ethyl acetate was distilled off on a rotary evaporator. The resulting residue was dissolved in methylene chloride, and the substance was purified by silica gel chromatography (methylene chloride system - 3% methanol in methylene solution). 2.56 g of 2,4-dichloro-alpha (1H-1,2,4-triazolyl) acetophenone are obtained in the form of a light brown powder. The yield is 56%. C ₁₀ H ₇ Cl ₂ N ₃ O _.. m / z 256.09. [M + H] ⁺ 257.09. ¹ H (CDCl ₃ ): 8.28 (s, 1H), 7.97 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.36 (dd, J ₁ = 8.4 Hz, J ₂ = 2.0 Hz, 1H), 5.62 (s, 2H).

Production Example 1 - ((2- (2,4-Dichlorophenyl) oxiran-2-yl) methyl) -1 H -1,2,4-triazole (033).

To a mixture of 2,4-dichloro-alpha (1H-1,2,4-triazolyl) acetophenone (2.0 g, 7.81 mmol, 1 equiv.), Trimethylsulfoxonium iodide (1.72 g, 7.81 mmol, 1 equiv) and hexadecyltrimethylammonium bromide (71 mg, 0.20 mmol, 0.025 equiv.) In 20 ml of toluene is added 1.28 ml of a 20% sodium hydroxide solution (312 mg, 7.81 mmol, 1 equiv). The mixture is stirred at 60 ° C for 2 hours. The emulsion is filtered, the toluene phase is separated and evaporated. The resulting substance is used further without purification. Quantitative yield (2.1 g), brown oil. C ₁₁ H ₉ Cl ₂ N _{3 O.} m / z 270.12. [M + H] + = 271.12. ¹ H (CDCl ₃ ): 8.10 (s, 1H), 7.88 (s, 1H), 7.38 (d, J = 1.8 Hz, 1H), 7.16 (dd, J ₁ = 8.2 Hz, J ₂ = 1.8 Hz, 1H ), 7.10 (d, J = 8.2 Hz,, 1H), 4.86 (d, J = 14.9 Hz, 1H) 4.48 (d, J = 14.9 Hz, 1H), 2.96 (d, J = 4.3 Hz, 1H), 2.88 (d, J = 4.3 Hz, 1H). Identity confirmed by chromatography.

Production Example 2- (2,4-Dichlorophenyl) -4- (tert-butoxycarbonylpiperazin-1-yl) -3- (1 N -1,2,4 triazolyl-1-yl) propan-2-ol (034).

A mixture of oxiran - 1 - ((2- (2,4-dichlorophenyl) oxiran-2-yl) methyl) -1 H -1,2,4-triazole (2.1 g, 7.77 mmol, 1 equiv), Boc-piperazine ( 1.45 g, 7.77 mol, 1 equiv.) And triethylamine (944 mg, 9.33 mmol, 1.2 equiv.) Are boiled in ethanol overnight. Ethanol is evaporated, the residue is dissolved in methylene chloride and washed with aqueous citric acid until acidic, then with water. The organic phase is dried over Na ₂ SO ₄ and evaporated. The residue is dissolved in methylene chloride and the substance is purified by chromatography on silica gel (methylene chloride system - 3% methanol in methylene chloride. Yield 13% (465 mg), brown oil. C ₂₀ H ₂₇ Cl ₂ N ₅ O _3. m / z 456.37. [M + H] ⁺ = 457.37.

An example of obtaining 2- (2,4-dichlorophenyl) -4- (piperazin-1-yl) -3- (1 N -1,2,4 triazolyl-1-yl) propan-2-ol hydrochloride (035).

A solution of 2- (2,4-dichlorophenyl) -4- (tert-butoxycarbonylpiperazin-1-yl) -3- (1 H -1,2,4 triazolyl-1-yl) propan-2-ol (456 mg) in a saturated solution of hydrogen chloride in ethyl acetate (5 ml) is stirred overnight at room temperature, while a precipitate gradually forms. The next day, the precipitate formed is filtered off and washed with ethyl acetate. Yield of 2- (2,4-dichlorophenyl) -4- (piperazin-1-yl) -3- (1H-1,2,4 triazolyl-1-yl) propan-2-ol hydrochloride 381 mg (97%). C ₁₅ H ₁₉ Cl ₂ N ₅ O. m / z 356.25 (free base). [M + H] + = 357.25.

Production Example 1- (1 N -1,2,4-triazol-1-yl) -2- (2,4-difluorophenyl) -3-cyclopropylamino-2-propanol (036)

A mixture of oxirane in the form of a free base (obtained from salt with stirring in a mixture of an aqueous solution of Na ₂ CO ₃ and methylene chloride, 1 g, 1 equiv.) And cyclopropylamine (241 mg, 1 equiv.) Is boiled in ethanol overnight. Ethanol is evaporated, the residue is dissolved in methylene chloride and washed with an aqueous solution of citric acid until acidic, then with water. The organic phase is dried over Na ₂ SO ₄ and evaporated. The residue is purified by chromatography on silica gel (eluent - 5% ethyl acetate in methylene chloride). The fractions were evaporated to give the product as an oil. Yield 930 mg (75%). ¹ H NMR: (500 MHz, CDCl ₃ ) δ = 8.09 (s, 1H), 7.82 (s, 1H), 7.53 (m, 1H), 6.82 (m, 2H), 4.58 (dd, J ₁ = 36 Hz , J ₂ = 14.3 Hz, 2H), 3.32 (d, J = 12.5 Hz, 1H), 3.00 (d, J = 12.5 Hz, 1H), 2.12 (m, 1H), 1.76 (bs, 2H), 0.41 ( m, 2H); 0.26 (m, 2H).

Production Example 1- (1 N -1,2,4-triazol-1-yl) -2- (2,4-difluorophenyl) -3-propylamino-2-propanol (037)

A mixture of oxirane in the form of a free base (obtained from salt with stirring in a mixture of an aqueous solution of Na ₂ CO ₃ and methylene chloride, 1 g, 1 equiv.) And propylamine (249 mg, 1 equiv.) Is boiled in ethanol overnight. Ethanol is evaporated, the residue is dissolved in methylene chloride and washed with an aqueous solution of citric acid until acidic, then with water. The organic phase is dried over Na ₂ SO ₄ and evaporated. The residue is purified by chromatography on silica gel (eluent - 5% ethyl acetate in methylene chloride). The fractions were evaporated to give the product as an oil. Yield 969 mg (78%). ¹ H NMR: (500 MHz, CDCl ₃ ) δ = 8.12 (s, 1H), 7.82 (s, 1H), 7.57 (m, 1H), 6.82 (m, 2H), 4.57 (dd, J ₁ = 52.1 Hz , J ₂ = 14.2 Hz, 2H), 3.98 (bs, 2H), 3.16 (d, J = 12.6 Hz, 1H), 2.90 (d, J = 12.6 Hz, 1H), 2.47 (m, 2H), 1.39 ( m, 2H), 0.84 (t, J = 7.3 Hz, 3H).

An example of obtaining 1-azido-2- (2,4-difluorophenyl) -3- (1H-1,2,4-triazol-1-yl) propan-2-ol (038).

Oxyran methanesulfonate (2 g, 6.30 mmol, 1 equiv), ammonium chloride (341 mg, 6.37 mmol, 1.01 equiv) and sodium azide (1.23 g, 18.91 mmol, 3 equiv) were suspended in methanol and refluxed for 16 hours. Then methanol was evaporated, the residue was partitioned between ethyl acetate (30 ml) and water (20 ml). The organic layer was separated, washed with saturated sodium chloride solution (15 ml), dried over sodium sulfate and the ethyl acetate was removed on a rotary evaporator. The resulting product was used further without purification. The output is quantitative. C ₁₁ H ₁₀ F ₂ N ₆ O. [M + H] ⁺ 281.24.

¹ H (CDCl ₃ ): 8.13 (s, 1H), 7.90 (s, 1H), 7.52 (m, 1H), 6.80 (m, 2H), 4.76 (m, 3H), 3.68 (d, 1H, J = 12.72 Hz), 3.54 (d, 1H, J = 12.72 Hz).

An example of obtaining 1- (4- (aminomethyl) -1H-1,2,3-triazol-1-yl) -2- (2,4-difluorophenyl) -3- (1H-1,2,4-triazol-1 -yl) propan-2-ol (039).

1-Azido-2- (2,4-difluorophenyl) -3- (1H-1,2,4-triazol-1-yl) propan-2-ol (500 mg, 1.78 mmol, 1 eq.) Was dissolved in tert- butanol (20 ml), then an excess of propargylamine (295 mg, 5.35 mmol, 3 eq.) was added. While stirring, a solution of copper sulfate pentahydrate of copper sulfate (44 mg, 0.18 mmol, 0.1 equiv) in water (10 ml) and sodium ascorbate (71 mg, 0.36 mmol, 0.2 equiv) in water (10 ml) was added to the resulting mixture. The reaction mass was stirred for 16 hours at room temperature. Then the solvent mixture was evaporated on a rotary evaporator and the resulting product was used further without purification. C ₁₄ H ₁₅ F ₂ N ₇ O. [M + H] ⁺ 336.32.

An example of obtaining tert-butyl 4 - ((2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) (methyl) amino) piperidin-1 -carboxylate (040).

To a solution of Boc-amide (570 mg, 1.30 mmol, 1 equiv) in methanol (20 ml) was added an aqueous solution of formalin (88 μl of a 40% solution, 39 mg in terms of pure formalin, 1.30 mmol, 1 equiv), acetic acid (8 μl) and sodium cyanoborohydride (98 mg, 1.56 mmol, 1.2 equiv). The reaction mass was stirred for 16 hours at room temperature, then the methanol was evaporated, the residue was partitioned between ethyl acetate and water, and ethyl acetate was separated. The organic phase is dried over sodium sulfate, the solvent is evaporated on a rotary evaporator and the substance is isolated, purified by flash chromatography on silica gel (elution system with ethyl acetate - methanol: ethyl acetate 1: 4). The yield of the target compound is 98% (577 mg). C ₂₂ H ₃₁ F ₂ N ₅ O ₃ . [M + H] ⁺ 452.52.

¹ H (CDCl ₃ ): 8.23 (s, 1H), 7.81 (s, 1H), 7.60 (m, 1H), 6.84 (m, 2H), 4.62 (m, 2H), 4.15 (m, 2H), 3.85 (m, 1H), 3.04 (m, 1H), 2.67 (m, 4H), 2.09 (m, 4H), 1.85 (m, 1H), 1.69 (m, 2H), 1.47 (s, 9H).

An example of obtaining 2- (2,4-difluorophenyl) -1- (methyl (piperidin-4-yl) amino) -3- (1H-1,2,4-triazol-1-yl) propan-2-ol dihydrochloride ( 041).

A solution of Boc amide (550 mg) in a saturated solution of hydrogen chloride in ethyl acetate (10 ml) was stirred overnight at room temperature, and a precipitate formed gradually. The precipitate formed is filtered off and washed with ethyl acetate. Yield 77% (400 mg). C ₁₇ H ₂₅ Cl ₂ F ₂ N ₅ O. [M + H] + 425.32.

¹ H (DMSO-d6): 9.48 (bs, 1H), 9.25 (bs, 1H), 9.10 (bs, 1H), 8.61 (s, 1H), 7.86 (s, 1H), 7.49 (m, 1H), 7.31 (m, 1H), 7.07 (m, 1H), 4.83 (m, 1H), 4.73 (m, 1H), 3.38 (m, 4H), 3.14 (m, 2H), 2.88 (m, 2H), 2.71 (m, 1H), 2.42 (m, 1H), 2.18 (m, 2H), 1.90 (s, 3H).

Characterization of the biological activity of the compounds

A comparative study of the spectrum of the antifungal action of the compounds of the invention in an in vitro experiment by the method of double micro-dilutions in broth.

The experiment was carried out using standard strains and clinical isolates. The sensitivity to reference strains and standard drugs used in the study is normalized according to GOST R ISO 16256-2015 and serves as a criterion for the accuracy of the experiment.

To monitor the studies and the comparative activity of the synthesized compounds, standard preparations of ketoconazole (Ketoconazole, Sigma-Aldrich), fluconazole (Fluconazole, Sigma-Aldrich), Amphotericin B and the control strain of Candida parapsilosis (ATCC 22019 ) were used.

The analysis was carried out by the method of serial microdilutions in accordance with GOST R ISO 16256-2015 “Clinical laboratory studies and diagnostic test systems in vitro . Reference method for testing the in vitro antimicrobial activity against yeast causing infectious diseases ”and the recommendations of the World Non-Profit Organization for the Development of Standards and Recommendations in 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 the compounds were dissolved in dimethyl sulfoxide (DMSO), the concentration of the main 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 double dilutions of the test samples was prepared in 96-well immunological plates in a volume of 100 μl of RPMI-1640 medium with L-glutamine (FSUE PIPVE named after Chumakov, Russia) containing 0.2% glucose.

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

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

The research results are presented in table 3.

Table 3. Results of an in vitro study of the spectrum of the antifungal action of the compounds of the invention by the method of double micro-dilutions in broth.

No. of compound according to the invention Minimum Inhibitory Concentration (MIC) μg / ml In relation to the strain C.parapsilosis ATCC 22019 24 h 48 h 8 0.06 0.125 9 0,03 0.06 10 0,03 0.125 eleven 0,03 0.5 12 0.125 0.25 13 1,0 2 fourteen 0.125 2 fifteen 0.125 0.25-0.5 16 0.5 0.5-1.0 17 0.125 0.5 twenty one one 21 0.5 0.5-1 22 0.125 0.25 24 0.015 0.5-1 26 one 1-2 29th 2 2-4 41 0.25 one Amphotericin B one 2 Fluconazole 2 four Ketoconazole 0.06 0.125 In relation to the strain C.albicans ATCC 24433 24 h 48 h fourteen 2 4-8 24 one one 29th 2 four 41 0.125 0.125 Fluconazole 2 four Ketoconazole 8 > 32 In relation to the strain A. niger 137a 9 1-2 fourteen 1-2 41 1-2 Fluconazole > 32 Ketoconazole 4-8 Amphotericin B one In relation to the strain T.rubrum 2002 8 0.06 9 0,03 10 1,0 eleven 0.5 12 0.5-1 13 0.5 fourteen 0.125 fifteen 0.5 16 0.5 17 one twenty 2 21 0.125 22 0.125 24 0.25 25 0.25 29th 0.25 thirty 0.25 32 0.25 Fluconazole > 32 Ketoconazole 0.125 In relation to the strain M.canis B-200 8 0.06 9 0,03 10 0.125 eleven one 12 2 13 2 fourteen 0.25 fifteen 0.5-1 16 2-4 17 0.5 twenty four 21 0.25 22 0.25 24 0.5-1 25 0.5 29th 0.5 thirty one 32 0.5 Fluconazole > 32 Ketoconazole 0.125

A comparative evaluation of the activity of the claimed compounds of the invention in vitro against fungal strains of dermatophytes and comparison preparations (fluconazole and Amphotericin B, as well as ketoconazole) showed that the compounds of the invention are not inferior to widely used commercial preparations. The compounds of the invention have a wide spectrum of antifungal activity, which confirms their promise for use in clinical practice for the treatment of infectious diseases caused by fungal infections, in particular in dermatology. In addition, the activity of most of the claimed compounds of the invention in relation to Candida parapsilosis is not inferior to or superior to the activity of Fluconazole and approaches Ketoconazole. In addition, the compounds of the invention, unlike Fluconazole, inhibit the growth of filamentous fungi M.canis B-200 and T.rubrum 2002. In addition, the compounds of the invention, in particular compounds 8, 17, 20, 21-25, 29, 30 and 32, unlike Fluconazole, affect both yeast (Candida spp.) and filamentous ( Microsporum canis, Trichophyton spp .) fungi.

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

The antifungal activity of the compounds of the invention and the microbiological standards of ketoconazole, fluconazole and itraconazole was studied by the spectrum of antifungal activity against clinical isolates of Candida spr . micromethod of double serial dilutions in RPMI 1640 nutrient broth in respect of 10 clinical isolates and standard Candida spr .

Assessment of activity was carried out in accordance with the recommendations of the World Non-Profit Organization for the Development of Standards and Recommendations in Medicine - Clinical and Laboratory Standards Institute (CLSI). Used the M27-A3 methods ( Clinical and Laboratory Standards Institute. Approved standard third edition M27-A3, Wayne, PA, USA, 2008 ) and ISO 16256: 2012 Clinical laboratory testing and in vitro diagnostic test systems - Reference method for testing the in vitro activity of antimicrobial agents against yeast fungi involved in infectious diseases (IDT) to determine the minimum inhibitory concentration (MIC) using a serial dilution micrometer in RPMI 1640 medium with glucose added to a concentration of 0.2%.

To obtain seed, the strains were grown on GRM 2 agar (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 the 0.5 McFarland turbidity standard (~ 5 × 10 ⁶ CFU / ml for yeast cultures), the microbial titer of the prepared suspension was evaluated densitometrically (Densimat, Biomerieux). The resulting suspension was diluted from 1: 1000 to ~ 2.5 x 10 ³ colonies of the forming units (CFU / ml) in RPMIc medium with 0.2% glucose.

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

We used 96 well plates for immunological studies (Medpolymer, St. Petersburg). 100 μl of a suspension of yeast cultures in culture medium were added to the plate wells, samples and control preparations in the concentration range 32 - 0.125 μg / ml, a standard sample of ketoconazole in the range 64-0.015 μg / ml. After making the test samples, the suspension density 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 in the nutrient broth.

To comply with the accuracy of the procedure for determining the MIC values of the studied strains, the reference Candida parapsilosis ATCC 22019 strain was included in the experiment, for which the growth inhibitory concentration of ketoconazole (MIC) should not go beyond the confidence limits specified in the document ( Clinical and Laboratory Standards Institute: References; informational supplement (M27-S3). Wayne, PA: Clinical and Laboratory Standards Institute; 2007 ; ISO 16256: 2012 Clinical laboratory testing and in vitro diagnostic test systems - Reference method for testing the in vitro activity of antimicrobial agents against yeast fungi involved in infectious diseases (IDT) :

Sensitivity assessment was carried out visually after incubation at 35 ° C for 24 and 48 hours.

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

Table 4: Comparative results of the compounds of the invention against clinical isolates of Candida spp, including resistant. * - C. albicans and 8R C.albicans 604M.

Sample No. Minimum Inhibitory Concentration (μg / ml) 24 h 48 h C. tropicalis  3019 8 2 2-4 9 0.5 0.5 10 0.25 one eleven 0.25 0.5 12 one 2 fourteen one four 24 2 four 41 one 2 Ketoconazole 0.25 0.5 Itraconazole 2 four Fluconazole 16 16 C.glabrata  61L 8 0.5 2 9 0.25 1-2 eleven one 2 fourteen one one 41 0.25 2 Ketoconazole 0,03 2 Itraconazole 0.25 0.5-1 Fluconazole 0.25 one C. krusei 432M 8 0.5 0.5-1 9 2 2-4 eleven one 2 12 one 2 13 one 2 fourteen one 2 41 2 four Ketoconazole 0.5-1 one Itraconazole 0.5 0.5 Fluconazole 32 > 32 C.  albicans 8R 8 8 8 9 four 32 40 2 8 Ketoconazole 16 16 Itraconazole 16 32 Fluconazole > 32 > 32 C. albicans 604 M 8 8 8 9 32 32 fourteen one one fifteen 16 32 17 2 8 24 8 16 29th 16 16 37 0.25 four Ketoconazole 8 16 Itraconazole 16-32 16-32 Fluconazole > 32 > 32 C. utilis 84 8 0.5 one 9 0.125 0.25 fourteen 0.5 2 Ketoconazole 0,03 0,03 Itraconazole 0.125 0.25-0.5 Fluconazole 8 16 Cryptococcus neoformans 8 0.06 9 0,03 17 0.25 37 0.25 41 four Ketoconazole 16 Itraconazole 0.5 Fluconazole 8

A comparative analysis of the compounds of the invention and comparative preparations (ketoconazole, itraconazole and fluconazole) revealed the advantages of the claimed compounds in relation to various strains of Candida spp. including resistant ones ( C.albicans 604M (R), C.albicans 80 (R) or not sensitive to modern commercial preparations of itraconazole, ketoconazole and fluconazole ( C. tropicalis 3019, C.glabrata 61L, C. krusei 432M) . according to the activity against C. spp,) a compound of the invention, particularly compounds 8-12, 14, 24 showed MIC values sopostavimye ketoconazole and itraconazole, and against resistant strains of C.albicans 604M (R) and C. albicans 8 (R) is even better than ketoconazole and itraconazole. Given the fact that ketoconazole has significant toxicity, the claimed compounds can be in serious competition, because the compounds of the invention are characterized by reduced toxicity.

On the other hand, the claimed compounds constitute a serious competition to fluconazole, to which a constant growing resistance is recorded. And since the compounds of the invention are hybrids and have an additional mechanism of action on a 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. 9) in relation Candida albicans on the model of intraperitoneal infection of mice (express method) with the commercial drug Voriconazole.

Comparison drug

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

Solvent

Due to the water insolubility of compound No. 9 and voriconazole, dimethyl sulfoxide (DMSO) (LenReactive) was used as a solvent.

Test culture

The strain Candida albicans RCPH Y 1274 was obtained from the "Russian collection of pathogenic mushrooms" Research Institute of Medical Mycology named after P.N. Kashkina SZGMU them. I.I. Mechnikov. The strain is characterized by resistance to fluconazole and sensitivity to voriconazole.

Culture medium

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

Laboratory animals

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

Animals were adapted within 7 days of 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 deviations detected during the examination 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 introduction of voriconozole (B), and the control group (D - intraperitoneal injection of 0.5 ml 20% DMSO). Animals were divided into groups by random selection.

To compare the efficiency of suppressing the germination of yeast cells of C. albicans in the glands of mice with different doses of compound No. 9 and voriconazole, the percentage of germination of yeast cells in each of these groups of animals was calculated in relation to control group D (20% DMSO). Then, the percentage of inhibition of germination of C. albicans cells was calculated: 100% -% germination (Table 5).

Table 5. Suppression of the process of formation of growth tubes of C. albicans ( strain RCPG Y 1274) in the glands of mice with various doses of compound No. 9 and voriconazole.

Animal Group Number Input Connection The dose of the administered compound % suppression * p ** one compound number 9 5 mg / kg 22.33 0.00001 2 compound number 9 12 mg / kg 30.86 0.00001 3 compound number 9 25 mg / kg 41.04 0.00001 AT voriconazole 12 mg / kg 17.00 *% inhibition - the proportion of cells that did not form growth tubes;
** p - comparison with voriconazole.

As follows from the results presented in table 11, compound No. 9, when administered at a dose 2.4 times lower (5 mg / kg) than voriconazole (12 mg / kg), more effectively suppressed the formation of growth tubes by C. albicans yeast cells in (22.33 against 17.00%). When administered in equal doses (12 mg / kg), compound No. 9 was also more effective than voriconazole (30.86 versus 17.00%). With an increase in dose, compound No. 9 to 25 mg / kg, which was 2.1 times higher than the dose of voriconazole (12 μg / kg), an inhibitory effect on the germination of C. albicans yeast cells was also noted (41.04 versus 17.00%) .

As a result of a study on the model of intraperitoneal infection of mice (express method), it was found that the compounds of the invention, in particular compound No. 9, when administered at doses of 5 mg / kg and 12 mg / kg, 25 mg / kg more actively inhibits the formation of growth tubes by yeast Candida albicans cells than voriconazole at a dose of 12 mcg / 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, for example, diseases such as dermatophytosis, superficial mycosis, candidiasis of the skin and nails, vaginal candidiasis, candidal stomatitis, endocarditis and other diseases of humans and animals.

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

Claims (61)

1. The compound of General formula (I):

or its pharmaceutically acceptable salt, where: Z is independently selected and represents a fragment selected from:

moreover, the asterisk indicates the point of accession; X is independently selected and is O or S; R ¹ is independently selected and is a moiety, representing:

optionally having 1-3 substituents R ′, which is independently selected and is —C _1-7 -alkyl, —OC _1-7 -alkyl, halogen, —OH, —C _5-7 -cycloalkyl, piperazinyl, optionally containing a substituent selected from -C _1-7 -alkyl; moreover, the asterisk indicates the place of attachment of the substituent; R ² is independently selected and is H, —C _1-7 alkyl, phenyl; said phenyl in the R ² moiety is optionally substituted with at least two halogen substituents; R ³ is independently selected and is halogen; R ⁴ is independently selected and is halogen; n take values from 0 to 3. 2. The compound according to claim 1, in which: R ³ is independently selected and is chloro, fluoro; R ⁴ is independently selected and is chloro, fluoro. 3. The compound according to claim 1, selected from the group: 5- (2,4-dichlorobenzylidene) -3- (2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -2-oxoethyl) thiazolidine-2,4-dione; 5- (4-chlorobenzylidene) -3- (2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -2-oxoethyl) thiazolidine-2,4-dione; 5- (4-methoxybenzylidene) -3- (2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -2-oxoethyl) thiazolidine-2,4-dione; 5- (4-ethylbenzylidene) -3- (2- (4- (2- (2,4-difluorophenyl1) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -2-oxoethyl) thiazolidine-2,4-dione; 5- (4-isopropyl-benzylidene) -3- (2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -2-oxoethyl) thiazolidine-2,4-dione; 5- (4-tert-butylbenzylidene) -3- (2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -2-oxoethyl) thiazolidine-2,4-dione; 5- (4-chlorobenzylidene) -3- (2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -2-oxoethyl) -2-thio-1,3-thiazolidin-4-one; 5- (4-chlorobenzylidene) -3- (2- (4- (2- (2,4-dichlorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -2-oxoethyl) -2-thio-1,3-thiazolidin-4-one; 3- (2- (4- (2- (2,4-dichlorophenyl) -2-hydroxy-3- (1H-1,2,4-tyrazol-1-yl) propyl) piperazin-1-yl) -2 -oxoethyl) -5- (4-methoxybenzylidene) -2-thio-1,3-thiazolidin-4-one; 5- (4-chlorobenzylidene) -3- (1- (4- (2- (2,4-difluorophenyl-2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazine -1-yl) -1-oxopropan-2-yl) thiazolidin-2,4-dione; 5- (2-hydroxy-3,5-dichlorobenzylidene) -3- (2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazole- 1-yl) propyl) piperazin-1-yl) -2-oxoethyl) thiazolidin-2,4-dione; 3- (1- (2,4-dichlorophenyl) -2- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -2-oxoethyl) -5- (4-fluorobenzylidene) thiazolidine-2,4-dione; 3- (3- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -3 -oxopropyl) -5- (4-methoxybenzylidene) thiazolidine-2,4-dione; 5- (2,4-dichlorobenzylidene) -3- (3- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -3-oxopropyl) thiazolidin-2,4-dione; 5- (4-chlorobenzylidene) -3- (3- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -3-oxopropyl) thiazolidin-2,4-dione; 5- (2-chloro-6- (4-methylpiperazin-1-yl) benzylidene) -3- (4- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1 2,4-triazol-1-yl) propyl) piperazin-1-yl) -4-oxobutyl) thiazolidin-2,4-dione; 5- (4-chlorobenzylidene) -3- (4- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -4-oxobutyl) thiazolidin-2,4-dione; 3- (4- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -4 -oxobutyl) -5- (4-fluorobenzylidene) thiazolidine-2,4-dione; 5- (2,4-dichlorobenzylidene) -3- (4- (4- (2- (2,4-difluorenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -4-oxobutyl) thiazolidin-2,4-dione; 5- (3,5-dichloro-2-hydroxybenzylidene) -3- (4- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazole- 1-yl) propyl) piperazin-1-yl) -4-oxobutyl) thiazolidin-2,4-dione; 5- (3,5-dichloro-2-hydroxybenzylidene) -3- (5- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazole- 1-yl) propyl) piperazin-1-yl) -5-oxopentyl) thiazolidin-2,4-dione; 5- (4-chlorobenzylidene) -3- (5- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -5-oxopentyl) thiazolidin-2,4-dione; 5- (2,4-dichlorobenzylidene) -3- (5- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -5-oxopentyl) thiazolidin-2,4-dione; 5- (2-chloro-6- (4-methylpiperazin-1-yl) benzylidene) -3- (5- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1 2,4-triazol-1-yl) propyl) piperazin-1-yl) -5-oxopentyl) thiazolidin-2,4-dione; 3- (5- (4- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) piperazin-1-yl) -5 -oxopentyl) -5- (4-fluorobenzylidene) thiazolidine-2,4-dione; N-cyclopropyl-2- (5- (2,4-dichlorobenzylidene) -2,4-dioxothiazolidin-3-yl) -N- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H- 1,2,4-triazol-1-yl) propyl) acetamide; N-cyclopropyl-2- (5- (4-chlorobenzylidene) -2,4-dioxothiazolidin-3-yl) -N- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1, 2,4-triazol-1-yl) propyl) acetamide; N-cyclopropyl-2- (5- (4-fluorobenzylidene) -2,4-dioxothiazolidin-3-yl) -N- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1, 2,4-triazol-1-yl) propyl) acetamide; 2- (5- (2,4-dichlorobenzylidene) -2,4-dioxothiazolidin-3-yl) -N- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2, 4-triazol-1-yl) propyl) -N-propylacetamide; 2- (5- (4-chlorobenzylidene) -2,4-dioxothiazolidin-3-yl) -N- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4- triazol-1-yl) propyl) -N-propylacetamide; 2- (5- (4-fluorobenzylidene) -2,4-dioxothiazolidin-3-yl) -N- (2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4- triazol-1-yl) propyl) -N-propylacetamide. 4. The use of compounds according to claim 1 as an antifungal agent. 5. The use of a compound according to claim 1 for preparing a pharmaceutical composition for treating and / or preventing an infectious disease of microbial etiology in a subject caused by a fungal infection. 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 the microbial etiology is caused by a fungus of the species Aspergillus fumigatus. Aspergillus niger, Microsporum canis or Trichophyton rubrum. 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 of claim 8, wherein the disease is dermatophytosis, superficial mycosis, candidiasis of the skin and / or nails, vaginal candidiasis, candidal stomatitis or endocarditis. 10. A pharmaceutical composition for treating and / or preventing an infectious disease of microbial etiology in a subject caused by a fungal infection, comprising an effective amount of a compound according to claim 1 and at least one pharmaceutically acceptable excipient. 11. The pharmaceutical composition according to p. 10, characterized in that the pharmaceutically acceptable excipient is a carrier, excipient and / or solvent. 12. The pharmaceutical composition according to p. 10, characterized in that the disease is a disease of the skin, nails and / or internal organs. 13. The pharmaceutical composition according to p. 12, characterized in that the disease is dermatophytosis, superficial mycosis, candidiasis of the skin and / or nails, vaginal candidiasis, candidal stomatitis or endocarditis.