Aralkyl bensyl ethers, methods of synthesis thereof, intermediate compounds and their use, methods for treatment and/or prevention, pharmaceutical composition and drug on basis of these compounds

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, specifically to bensyl aralkyl ether of formula or to its pharmaceutically acceptable salt, where: Ar represents imidazolil; R1, R2, R4 and R5 independently stand for hydrogen; R3 stands for a halogen; R6 stands for trifluoromethyl or trichloromethyl; n is an integer from 0 to 2; and m is 1. The invention also relates to the use of the compound of formula (1) for the treatment and/or prevention of diseases caused by fungi, or bacteria.

EFFECT: obtained new heterocyclic compounds with useful biological properties.

4 cl, 4 dwg, 9 tbl, 8 ex

 

AREA of TECHNOLOGY

The present invention relates to compounds, which are aralkylamines ethers described by Formula (I), their enantiomers, their diastereomers, their prodrugs, esters, pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, and/or mixtures thereof in any ratio of these compounds and/or derivatives, to methods for producing these compounds, intermediate compounds, pharmaceutical compositions containing such compounds, and/or derivatives, pharmaceutical preparations containing these compounds and/or derivatives. It also relates to the use of these compounds and/or derivatives for the treatment and/or prevention of pathological conditions and/or diseases caused by microorganisms such as fungi, bacteria and/or protozoa, for inhibiting the proliferation and/or survival of these microorganisms, to treat and/or prevent the formation of colonies of microorganisms in an individual, and for the manufacture of a medicinal product.

The present invention relates also to method of treatment and/or prevention of pathological States in mammals caused by fungi and/or other microorganisms, such as bacteria and protozoa, with the use of the compounds aralkylamines ethers described in Formulas� (I) and, in particular, the compounds 1-[2-(2,4-dichlorophenyl)-2-{[4-(trifluoromethyl)benzyl]oxy}ethyl]-1H-imidazole and 1-[2-(2,4-Dichlorophenyl)]-2-({4-[(2-phenyl)-2H-tetrazol]benzyl}oxy)-ethyl]-1H-imidazole.

The present invention encompasses compounds aralkylamines simple ether described in Formula (I), and mixtures thereof in any ratio, and their pharmaceutically acceptable salts and containing pharmaceutical compositions. In particular, the present invention relates to the use of compounds aralkylamines simple ether described in Formula (I) and, more specifically compounds 1-[2-(2,4-dichlorophenyl)-2-{[4-(trifluoromethyl)benzyl]oxy} ethyl]-1H-imidazole and 1-[2-(2,4-dichlorophenyl)]-2-({4-[(2-phenyl)-2H-tetrazol]benzyl}oxy)-ethyl]-1H-imidazole as a fungistatic and/or fungicidal antifungal drugs.

The LEVEL of TECHNOLOGY

Azoles are the main compounds used in clinical medicine for the treatment and/or prevention of pathological conditions and/or diseases associated with mushrooms.

The antifungal effect of azoles typically occurs through inhibition of ergosterol (ergosta-5,7,22-trien-3β-ol) by inhibiting proteins involved in its biosynthesis, such as: (a) the enzyme lanosterol 14-alpha-demethylase, which belongs to the family of cytochrome P-450 and is encoded by ERG11 gene, and (b) Delta 22 desaturase (coderamasino ERG5). Ergosterol is a Sterol precursor of vitamin D and a structural component of cell membranes of fungi, which can also be found in other microorganisms such as protozoa and bacteria.

The document U.S. 3,705,172 (Bayer), published 12/05/1972, relates to compounds of the N-trityl-imidazole, among which the connection clotrimazole, the structure of which is presented below, used in medical practice for local treatment of diseases caused by dermatophytes, yeasts and filamentous and dimorphic fungi.

The document U.S. 3,717,655 (Janssen), published 02/20/1973, refers to derivatives of amines or arylamidase simple esters, which are introduced in the clinical practice of antifungal drugs used to date, such as miconazole, econazole, and isoconazole, which is represented by the following structural fomulae:

Patent documents U.S. 4,144,346 (03/13/1979) and USA 4,267,179 (05/12/1981), both from Janssen, describe antifungal compounds derived from (dioxolan)imidazolov, among which are the drugs ketoconazole and Itraconazole, respectively, used in therapy currently, and whose chemical structure is shown below:

The document U.S. 4,062,966 (Pfizer), published 13/12/1977 relating to new derivatives of ethers of (ariatel)imidazole, describes antifungal drug Tioconazole.

Antifungal compounds bis-triazole and triazole described in patent document U.S. 4,400,219 (Pfizer), published 09/13/1983, and in patent document U.S. 5,278,175 (Pfizer), published 01/11/1994, which was used in the clinical setting as antifungal drugs. While fluconazole and voriconazole are disclosed, respectively, as:

Interestingly, prolonged and repeated exposure of fungal strains with antifungal drugs may cause resistance of these strains to the action of these drugs, reducing their effectiveness. This is expressed in the form of strain-specific genetic variant of a microorganism.

Such resistance may be the result of different mechanisms, such as but not limited to: (a) modification at the molecular level ERG11 gene, (b) an increased expression level efflux pumps for certain drugs, such as CDR (resistance, regardless of the degree of closure of the monolayer) and MDR (multidrug resistance), (c) modification of the degree�measuring biosynthesis, and (g) reduction of the intracellular concentration of the target enzymes.

The problem of resistance is becoming more relevant in the current epidemiological situation of diseases caused by fungi. It was noticed that in recent decades all over the world, there is a significant increase in the incidence of persons affected by fungal infections. Most of this increase is attributed to the prolonged survival of patients with weakened immune systems and frequent and/or chronic use of antimicrobials.

Thus, the majority of patients who are exposed to these infections, patients with a weakened immune system either as a direct result of immunosuppression caused by the use of cytotoxic drugs or HIV infection, or secondary, or because of other debilitating diseases such as cancer, acute leukemia, invasive surgical procedures or as a result of prolonged exposure to antimicrobial agents.

In particular, the prevalence of HIV infection contributes to an increase in opportunistic infections caused by fungi that are harmless to healthy people, but become pathogenic because of their weakened immune protection in HIV-infected patients.

Therefore, based on the current epidemiological situation of infection, �Swanney these microorganisms and the emergence of pathogenic strains resistant to currently used antifungal drugs, interest in the development of new compounds becomes apparent. It is desirable to develop compounds with a broad spectrum of antifungal activity, whereas the strains and/or species of fungi, resistant and/or resistant to known medicines.

Summary of the INVENTION

The aim of the present invention is to provide new compounds useful for the treatment of diseases and/or conditions associated with micro-organisms such as fungi, bacteria and/or protozoa, which are aralkylamines ethers, the chemical structure of which is shown in Formula (I):

in which:

Ar represents aryl, imidazolyl, 1,2,4-triazolyl and benzimidazolyl;

R1, R2, R4and R5independently represent hydrogen, halogen, C1-6alkyl;

R3is a substituent which is a halogen, (C1-6alkyl or O-R' in which R' represents hydrogen or lower alkyl;

R6is aryl or substituted aryl, trifluoromethyl, trichloromethyl or O-R' in which R' represents hydrogen or lower alkyl; Deputy aryl are halogen, or R�decal tetrazolyl;

n and m independently represent an integer from 0 to 5.

Provided that if Ar is imidazolyl, R3represents chlorine, R6is a u-phenyl and R1, R2, R4and R5represent hydrogen, n must be different from 2; and

when n and m is not equal to 0 and 1, R3or R6can be represented by alternates, which are not necessarily equal.

The present invention also includes salts, solvates, prodrugs and pharmaceutically acceptable esters of the compounds described by Formula (I) and their enantiomers and/or pharmaceutically acceptable salts, diastereomers and mixtures thereof in any ratio.

Another objective of the present invention is the provision of a method for producing compounds aralkylamines ethers described in Formula (I) and their intermediates used in the synthesis process.

In addition, the purpose of this invention is the description of the application aralkylamines ethers of the present invention or their salts, solvates, prodrug, esters, enantiomers and/or pharmaceutically acceptable diastereomers or mixtures thereof, for the treatment and/or prevention and/or for the manufacture of a medicinal product for the treatment and/or prevention of pathological conditions and/or diseases caused by microorganisms such as fungi, bacteria and/or protozoa, eukaryotic organisms. Furthermore, compounds of the present invention are used for inhibiting and/or deceleration and/or for the manufacture of a medicinal product for preventing and/or slowing the proliferation and/or survival of microorganisms, such as fungi, bacteria and/or protozoa, especially pathogenic microorganisms. In particular, the present invention is the use of aralkylamines ethers described in Formula (I), as a fungistatic and/or fungicidal antifungal drugs.

An additional objective of the present invention is to provide a method of treatment and/or prevention of pathological conditions and/or diseases associated with microorganisms, such as fungi, bacteria and/or protozoa, of a mammal needing such treatment. The method includes introducing an effective amount of at least one of the compounds aralkylamines simple ether described by Formula (I) according to the present invention, or its salts, solvates, prodrug, esters, enantiomers and/or pharmaceutically acceptable diastereomers, or mixtures thereof.

Another objective of this invention is to provide pharmaceutical compositions and dosage of the drug, soda�containing an effective amount, at least one of the compounds described by Formula (I), or salts, solvates, prodrug, esters, enantiomers and/or pharmaceutically acceptable diastereomers, or mixtures thereof, as active substances, and one or more pharmaceutically acceptable excipients.

BRIEF description of the DRAWINGS AND TABLES

Fig.1: Characterization of compounds obtained by the method described in Examples 1 and 2, (1-[2-(2,4-dichlorophenyl)-2-{[4-(trifluoromethyl)benzyl]oxy}ethyl]-1H-imidazole (BL-123)), according to the method of NMR spectroscopy on nuclei of carbon (C13).

Fig.2: Characterization of compounds obtained by the method described in Examples 1 and 2, (1-[2-(2,4-dichlorophenyl)-2-{[4-(trifluoromethyl) benzyl]oxy}ethyl]-1H-imidazole (BL-123)), according to the method of NMR spectroscopy the 1H nuclei.

Fig.3: Characterization of compounds obtained by the method described in Example 3, (1-[2-(2,4-dichlorophenyl)]-2-({4-[(2-phenyl)-2H-tetrazol] benzyl}oxy)ethyl]-1H-imidazole (BL-137)), according to the method of NMR spectroscopy the 1H nuclei.

Fig.4: Characterization of compounds obtained by the method described in Example 3, (1-[2-(2,4-dichlorophenyl)]-2-({4-[(2-phenyl)-2H-tetrazol]benzyl} oxy)ethyl]-1H-imidazole (BL-137)), according to the method of NMR spectroscopy on nuclei of carbon (C13).

Formula (I): Structural Formula describing basic compounds included in the present invention, in which Ar repre�ulation of aryl, imidazolyl, 1,2,4-triazolyl, benzimidazolyl; R1, R2, R4and R5independently represent hydrogen, halogen, C1-6alkyl; R3is halogen, (C1-6alkyl or O-R' in which R' represents hydrogen or lower alkyl; lit independently represent an integer from 0 to 5; R6is aryl or substituted aryl, trifluoromethyl, trichloromethyl or O-R' in which R' represents hydrogen or lower alkyl; wherein substituents of aryl are halogen or a radical tetrazolyl. Provided that if Ar is imidazolyl, R3represents chlorine, R6is a u-phenyl and R1, R2, R4 and R5represent hydrogen, n must be different from 2, and when n and m is not equal to 0 and 1, R3or R6can be represented by alternates, which are not necessarily equal.

Of formula (Ia), (Ib) and (Ic): Basic structural formula, describing particularly preferred compounds of the present invention, where R3represents a halogen, and R6represents a phenyl radical, halogenfree, (tetrazolyl)phenyl, trifluoromethyl, trichloromethyl anywhere in the benzyl ring.

Method 1: General scheme of synthesis of compounds of the present invention, in which Ar, R1-R6n and m Formulas (II) and (III) are as described you�e, and in which X refers to the elements selected from the group consisting of Cl, Br, I, methanesulfonate and toluensulfonate.

Method 2: Separate diagram of the synthesis process of the present invention to produce compound BL-123.

Method 3: Separate diagram of the synthesis process of the present invention to produce compound BL-137.

Table 1: Examples of intermediate compounds described by Formulas II and III, which are used to obtain the compounds of the present invention, depending on the substituents, represented in positions of Ar, R1, R2, R4, R5, (R3)n, R6 and m, and in which the term "prot" represents a protective group of the present invention, and "X" represents an element selected from the group consisting of Cl, Br, I, MS (methanesulfonate) and TS (toluensulfonate).

Table 2: Identification of strains of filamentous fungi used in the tests on the sensitivity to antifungal agents of the present invention.

Table 3: Average value of minimum inhibitory concentration (MIC) obtained in four experiments testing the susceptibility of strains of filamentous fungi, which are described in Table 2, is made in a few days, with the readings of the results, performed on the fourth and seventh day.

Table 4: Average values MIC (minimum inhibitory concentration required for ing�of mirovaniya 50% of strains), MIC (minimum inhibitory concentration to inhibit 90% of strains) and CMC (minimum inhibitory concentration) for products used in testing the susceptibility of filamentous fungi to antifungal agents of the present invention.

Table 5: Identification of strains of bacteria and yeast, used to test for sensitivity to antifungal agents of the present invention.

Table 6: Minimum inhibitory concentration of the antifungal drugs tested against strains of yeast and bacteria, are described in Table 5.

Table 7: Example of a composition in cream form comprising compound BL-123 described in the present invention.

Table 8: Example of the powdery composition comprising compound BL-123 described in the present invention.

Table 9: Example of a composition in the form of a lotion comprising compound BL-123 described in the present invention.

DETAILED description of the INVENTION

The present invention discloses novel compounds which are useful for the treatment of pathological conditions that are caused by fungi and/or other microorganisms, such as bacteria and protozoa, which are aralkylamines ethers described by Formula (I) and their salts, solvates, prodrugs and pharmaceutical industry�ski acceptable esters:

in which:

Ar represents aryl, imidazolyl, 1,2,4-triazolyl and benzimidazolyl;

R1, R2, R4and R5independently represent hydrogen, halogen, C1-6alkyl;

R3is a substituent which is a halogen, (C1-6alkyl or O-R' in which R' represents hydrogen or lower alkyl;

R6is aryl or substituted aryl, trifluoromethyl, trichloromethyl or O-R' in which R' represents hydrogen or lower alkyl; Deputy aryl are halogen or a radical tetrazolyl;

n and m independently represent an integer from 0 to 5;

provided that if Ar is imidazolyl, R3represents chlorine, R6is a u-phenyl and R1, R2, R4and R5represent hydrogen, n must be different from 2; and

when n and m are different from 0 or 1, R3or R6can be represented by alternates, which are not necessarily equal; and

when the substituents R1, R2, R4and R5simultaneously represent hydrogen and R6represents a trifluoromethyl or trichloromethyl, 1,2,4-triazolyl radical must be associated with the main structure in a specific position 2, as follows

Compounds of Formula(I) have one or more asymmetric centers and, thus, can exist in enantiomeric and/or diastereoisomeric salt. In particular, the chiral center is indicated by an asterisk in the description of the structure of Formula (I). Thus, the present invention also encompasses enantiomers of compounds of Formula (I) in their individual separate modes of action and/or in the form of racemic mixtures or racemic mixtures of enantiomeric excess in any ratio.

Pharmaceutically acceptable salt of a compound of Formula (I) are formed by adding pharmaceutically acceptable acids. Examples of salts include, but are not limited to: nitrates, chlorides, bromhidrosis, sulfates, bisulfate, phosphates, hydrogen phosphates, acetates, benzoates, succinates, fumarate, maleate, lactates, citrates, tartrates, gluconate, methosulphate, benzolsulfonat and p-toluensulfonate.

In General, the description of the compounds of Formula (I), the term "aryl" described as Ar represents a phenyl group or a phenyl group substituted with 1 to 5 halogen atoms, from 1 to 5 (C1-6alkyl) and/or from 1 to 5 (C1-6alkoxy).

The term "alkyl" represents a primary alkyl chain, or, if available, a branched alkyl chain group she represented. Examples of "alkyl" groups of this invention include, but are not limited to: methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-p�ntil, s-pentyl, t-pentyl, i-pentyl, n-hexyl, s-hexyl or t-hexyl. The term "lower alkyl" refers to alkyl groups as defined above containing from 1 to 6 carbon atoms.

The term "halogen" represents fluorine, chlorine, bromine or iodine.

When R3or R6represent the group "0-R"' or "aryl" or "trifluoromethyl" or "trichloromethyl", these substituents may be attached at any suitable position of the phenyl group at one or more positions.

A certain group of compounds of the present invention is selected from compounds described by Formula (.), in which R1, R2, R4and R5represent hydrogen, R3is a halogen, n is an integer from 0 to 2, so that when n is 0, the aromatic ring, which is connected with R3is not substituted, m represents 1, R6represents phenyl, halogenhydrines, TetraSociology, triptoreline or trichlorethylene radical in any position of the benzyl ring, and Ar represents imidazolyl or 1,2,4-triazolyl in which, when n and m are different from 0 or 1, R3or R6can be represented by alternates, which are not necessarily equal, and/or when R6represents a trifluoromethyl or trichloromethyl, radical 1,2,4-triazolyl must be linked to the main article�usturoi in position, 2. This particular group of compounds of the present invention represented by Formulae (Ia), (Ib) and (Ic), which follow below, in which the substituents R3and R6are as specified in this paragraph:

More specifically, the preferred compounds of the present invention are compounds selected from the group including

1-[2-(2,4-dichlorophenyl)-2-{[3-(trifluoromethyl)benzyl]oxy}ethyl]-1H-imidazole

1-[2-(2,4-dichlorophenyl)-2-{[3-(trichloromethyl)benzyl]oxy}ethyl]-1H-imidazole

1-[2-(2,4-dichlorophenyl)-2-{[4-(trifluoromethyl)benzyl]oxy}ethyl]-1H-imidazole

1-[2-(2,4-dichlorophenyl)-2-{[4-(trichloromethyl)benzyl]oxy}ethyl]-1H-imidazole

1-[2-(2,4-dichlorophenyl)-2-{[3-(trifluoromethyl)benzyl]oxy}ethyl]-4H-1,2,4-triazole

1-[2-(2,4-dichlorophenyl)-2-{[3-(trichloromethyl)benzyl]oxy}ethyl]-4H-1,2,4-triazole

1-[2-(2,4-dichlorophenyl)-2-{[4-(trifluoromethyl)benzyl]oxy}ethyl]-4H-1,2,4-triazole

1-[2-(2,4-dichlorophenyl)-2-{[4-(trichloromethyl)benzyl]oxy}ethyl]-4H-1,2,4-triazole

1-[2-(2,4-dichlorophenyl)]-2-({4-[(2-phenyl)-2H-tetrazol]benzyl}oxy)ethyl]-1H-imidazole

1-{2-[(4'-chlorodiphenyl-4-yl)methoxy]-2-(2,4-dichlorophenyl)ethyl}-1H-imidazol-[2-(biphenyl-4-ylethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole

1-[2-(2,4-dichlorophenyl)]-2-({4-[(2-phenyl)-2H-tetrazol]benzyl}oxy) ethyl]-1H-1,2,4-triazole

1-{2-[(4'-chlorodiphenyl-4-ylethoxy]-2-(2,4-dichlorophenyl)ethyl}-1H-1,2,4-triazole

1-[2-(biphenyl-4-ylethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-1,2,4-triazole

1-[2-(2,4-dichlorophenyl)]-2-({4-[(2-phenyl)-2H-tetrazol]benzyl}oxy)ethyl]-4H-1,2,4-triazole

1-{2-[(4'-chlorodiphenyl-4-yl)methoxy]-2-(2,4-dichlorophenyl)ethyl}-4H-1,2,4-triazole

1-[2-(biphenyl-4-ilmetoxi-2-(2,4-dichlorophenyl)ethyl]-4H-1,2,4-triazole

1-[2-(4-chlorophenyl)-2-{[4-(trifluoromethyl)benzyl]oxy}ethyl]-1H-imidazole

1-[2-(4-chlorophenyl)-2-{[4-(trichloromethyl)benzyl]oxy}ethyl]-1H-imidazole

1-[2-(4-chlorophenyl)-2-{[4-(trifluoromethyl)benzyl]oxy}ethyl]-4H-1,2,4-triazole

1-[2-(4-chlorophenyl)-2-{[4-(trichloromethyl)benzyl]oxy}ethyl]-4H-1,2,4-triazole

1-[2-(2-chlorophenyl)-2-{[4-(trifluoromethyl)benzyl]oxy}ethyl]-1H-imidazole

1-[2-(2-chlorophenyl)-2-{[4-(trichloromethyl)benzyl]oxy}ethyl]-1H-imidazole

1-[2-(2-chlorophenyl)-2-{[4-(trifluoromethyl)benzyl]oxy}ethyl]-4H-1,2,4-triazole

1-[2-(2-chlorophenyl)-2-{[4-(trichloromethyl)benzyl]oxy}ethyl]-4H-1,2,4-triazole

1-[2-(4-fluorophenyl)-2-{[2-(trifluoromethyl)benzyl]oxy}ethyl]-1H-imidazole

1-[2-(4-fluorophenyl)-2-{[2-(trichloromethyl)benzyl]oxy}ethyl]-1H-imidazole

1-[2-(4-fluorophenyl)-2-{[2-(trifluoromethyl)benzyl]oxy}ethyl]-4H-1,2,4-triazole

1-[2-(4-fluorophenyl)-2-{[2-(trichloromethyl)benzyl]oxy}ethyl]-4H-1,2,4-triazole

1-[2-(2,4-differenl)-2-{[2-(trifluoromethyl)benzyl]oxy}ethyl]-1H-imidazole

1-[2-(2,4-differenl)-2-{[2-(trichloromethyl)benzyl]oxy}ethyl]-1H-imidazole

1-[2-(2,4-differenl)-2-{[2-(trifluoromethyl)benzyl]oxy}ethyl]-4H-1,2,4-triazole

1-[2-(2,4-differenl)-2-{[2-(trichloro�yl)benzyl]oxy}ethyl]-4H-1,2,4-triazole

or their salts, solvates, prodrugs, esters, enantiomers and/or pharmaceutically acceptable diastereomers.

Preferably, the compounds aralkylamines ethers of the Formula (I) according to the present invention can be obtained by reaction of O-alkylation of the alcohol corresponding to the connection, which must be obtained. Intermediate compound used to add an alkyl group, in accordance with the reaction of O-alkylation of the present invention may be, for example, obtained from benzylchloride, benzylmethyl or benzalconium substituted groups described below for R6that correspond to the connections that need to be obtained.

The reaction can be performed in a reaction medium containing a solvent tetrahydrofuran (THF) and sodium hydride, in the concentration range from 40% to 80%) (weight/volume) relative to the total volume of the reaction medium.

In another aspect, the reaction can be performed in a reaction medium containing a polar solvent, a solution of a strong base at concentrations from 20% to 70% (weight/volume) and basic organic salt at a concentration of 0.001 to 0.1 g/ml relative to the total volume of the reaction medium. Preferably, named polar organic solvent may be acetone or methyl ethyl ketone or their CME�ü; called a solution of a strong base can be a base containing alkali metal elements and alkaline earth metal, preferably selected from the group consisting of sodium hydroxide and potassium hydroxide; called basic organic salt, preferably, is triethylaluminium the ammonium benzylchloride.

The intermediate reaction products may, not necessarily, be provided with a protective group reactive fragments, such as, for example, associated with reactive nitrogen from tetrazole ring in the intermediate compounds containing it.

Examples of protective groups can be but not limited to: triticina group, N,N-dimethylsulfone, p-methoxyphenylalanine, benzenesulfonamide, 2,2,2-trichlorethylene, t-BUTYLCARBAMATE, N-2-chloroethylamine, N-triisopropylsilyl, N-2-nitrobenzylamine and/or N-2-tetrahydropyranyl.

Named method of obtaining, in General, can be represented by the following reaction 1:

in which Ar, R1-R6, n and m of the Formulas (II) and (III) shall be determined in accordance with the detailed description of Formula (I), in which X refers to the elements selected from the group consisting of Cl, Br, I, MS (methanesulfonate) and TS (toluensulfonate).

Preferably, the derivative 1-[2-(2,4-dichlorophenyl)-2-{[4-(trifluoromethyl)benzyl]oxy}ethyl]-1H-imidazole (BL-123)the present invention can be obtained from 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol and 1-(chloromethyl)-4-(trifluoromethyl)benzene according to the reaction below (Reaction 2).

The following examples illustrate but do not limit such, the methods of obtaining the compounds 1-[2-(2,4-dichlorophenyl)-2-{[4-(trifluoromethyl)benzyl]oxy}ethyl]-1H-imidazole(BL-123) in accordance with reactions 1 and 2 presented above.

EXAMPLE 1

10.30 g of compound 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol was suspended in 26 ml of acetone was then added 31 ml of 50% solution of sodium hydroxide in water, then more than 26 ml of acetone, maintaining the entire reaction mixture with vigorous stirring. Then added 45 g of trimetilammoniietilakrilata, maintaining the reaction mixture to reflux for thirty minutes. Continuing to stand the mixture to reflux, was added 8.2 g of compound 1-(chloromethyl)-4-(trifluoromethyl)benzene (dissolved in 13 ml of acetone, maintaining the stirring and reflux for 6 hours. In the end, the heterogeneous mixture was filtered and the phases were separated. The organic phase was evaporated by rotary evaporator at 45°C to dryness. The obtained residue was dissolved in 100 ml of cold ethyl ether. Was then added 2 ml of nitric acid (65%) at 0°C, maintaining the stirring for one hour. At the end

the product was filtered and washed with cold ethanol and dried at 65°C for 12 hours. Received product�t, in the form of white solids (compound BL-123) had the following characteristics: 1H NMR (300 MHz-DMSO (dimethyl sulfoxide)): 9.05 (1H, s), 7.72-7.74 (1H, m), 7.65-7.66 (4H, m), 7.53-7.54 (1H, m), 7.38-7.45 (3H, m), 5.51-5.20 (1H, m), 4.45-4.64 (4H, m). 13C NMR (75 MHz-DMSO): 142.1, 136.3, 134.1, 133.6, 133.3, 129.5, 129.2, 128.5, 128.1,127.9, 125, 2, 125.1, 123,, 119.8, 75.4, 69.7, 51.8; Elemental analysis calc. for SNS F3N3:=47.72%, N=3.37%, N=8.79%; obtained: C=48.06%, N=3.44%, N=8.76%. Melting point: 173-176°C.

EXAMPLE 2

More than 60% suspension of NaH (2.0 g) in dry tetrahydrofuran (THF) (18 ml) was added a solution of compound 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-retinol (5.14 g) in dry THF (52 ml) at room temperature. Then, to the reaction mixture was slowly added a solution containing the compound 1-(chloromethyl)-4-(trifluoromethyl)benzene (3.6 ml) in dry THF (10 ml), maintaining the resulting mixture to reflux for three hours. At the end of this time period was added 50 ml of water, and the product was extracted with ethyl acetate and dried with magnesium sulfate and the remaining solvent was evaporated by rotary evaporator. The residue obtained after the complete evaporation of the solvent, was dissolved in diethyl simple ether (20 ml) and cooled to 0°C. To a solution of the residue was carefully added 65% nitric acid (1.4 ml). The product is then filtered and dried at 65°C. the Pure product was obtained after recrystallization in methanol. Product rece�in the form of white solids (compound BL-123) had the following characteristics: 1H1H NMR (300 MHz-DMSO): 9.05 (1H, s), 7.72 to 7.74 (1H, m), 7.65-to-7.66 (4H, m), 7.53 to 7.54 (1H, m), 7.38 to 7.45 (3H, m), 5.51 to 5.20 (1H, m), 4.45 to 4.64 (4H, m). 13C NMR (75MT4-DMSO): 13C NMR (DMSO mg): 142.1, 136.3, 134.1, 133.6, 133.3, 129.5, 129.2, 128.5, 128.1, 127.9, 125, 2, 125.1, 123,, 119.8, 75.4, 69.7, 51.8. Melting point: 173 to 176°C.

Preferably, the derivative 1-[2-(2,4-dichlorophenyl)]-2-({4-[(2-phenyl)-2H-tetrazol]benzyl}oxy)ethyl]-1H-imidazole (BL-137), the present invention can be obtained from 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol [1] and 5-(4'-(methyl bromide)biphenyl-3-)-1-trityl-1H-tetrazole [2] in accordance with the reaction scheme below (Reaction 3).

The following example illustrates but does not limit, the receiving nitrate salt of compound 1-[2-(2,4-dichlorophenyl)]-2-({4-[(2-phenyl)-2H-tetrazol]benzyl}oxy)ethyl]-1H-imidazole (BL-137) according to the schemes of reactions 1 and 3 above.

EXAMPLE 3

3 is at a flask equipped with a mechanical stirrer and reflux condenser was loaded THF (120 ml) and NaH 60% (24 g). To this suspension was slowly added a solution of 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol [1] (0,233 mmol, 60 g in 600 ml THF) and the resulting solution was left under mechanical stirring for 30 min. After this time the reaction mixture was cooled in an ice bath and to it was slowly added a solution of 5-(4'-(methyl bromide)biphenyl-3-)-1-trityl-1H-tetrazole [2] (0,223 mmol; 129 g in 650 ml THF). When an additional process was completed,the ice bath was removed, and the reaction mixture was allowed to reflux and maintained for 4 hours. After this time the reaction mixture was cooled to room temperature and to it was slowly added 560 ml of water. This reaction mixture was extracted with 600 ml of ethyl acetate. The organic phase was separated and was extracted with 5% aqueous citric acid solution (2×420 ml). The aqueous phases were pooled and extracted with ethyl acetate (2×300 ml). Organic phases were combined, dried MgSO4. The solvent was evaporated by rotary evaporator and extracted oil of orange.

The crude reaction product obtained in stage A, was dissolved at 50°C in 1650 ml of acetonitrile. After reaching room temperature was added 1300 ml of 1.5 N aqueous solution of H2SO4. This mixture is kept under magnetic stirring for 2 hours. After this was added 2M aqueous solution of NaOH until a pH equal to 13. The reaction mixture was distilled at a temperature of 65/70°C with application of a vacuum to remove acetonitrile. The material left in the original flask, kept under stirring for 30 min at 30/35°C. the Resulting precipitate was filtered and washed with 600 ml of a mixture water/acetonitrile (80/20). The filtrate was extracted with hot toluene (4×450 ml). The aqueous phase was collected and, when heated, add sufficient acetic acid to get better� pH of about 7.0. Maintaining the temperature at about 55°C, was added ethyl acetate. This mixture was heated and stirred for 30 min. the Organic phase was collected and the aqueous phase was extracted with hot ethyl acetate (3×500 ml). Organic phases were combined and dried MgSO4. The solvent was removed by rotary evaporator until then, until the formation of dense solids. The crude reaction product was cooled in an ice bath with mechanical stirring for 2 hours. The precipitate was filtered and washed with 120 ml of acetonitrile. The resulting solid product is a yellowish-white color, the compound BL-137, had the following characteristics: 1H NMR (300 MHz CDCl 3): 3.78 (1H, dd, J=9 and 15 Hz), 3.91 (1H, d, J=15 Hz), 4.08 (1H, dd, J=3 and 15 Hz), 4.67 (1H, d, J=15 Hz), 4.92 (1H, dd, J=3:09 Hz), 6.78 to 6.86 (2H, m), 6.96 to 7.04 (4H, m), 7.39 to 7.67 (8H, m), 7.98 to 8, 01 (1H, m). 13C NMR data (125 MHz-COCl 3): 52.2, 72.4, 76.8, 119.9, 124.8, 126.4, 128.0, 128.2, 128.6, 128.9; 129.6, 130.6, 130.7, 131.4, 133.1, 134.4, 135.1, 136.1, 136.9, 139.9, 140.7, 155.8.HRMS (mass spectrometry high resolution) calc. for C25H20Cl2N 60 (MH+) m/z 491.1154 received 491.1134; melting point: 93-96°C.

Thus, the compounds described in the present invention, can be obtained from any of the schemes of reactions 1 to 3, and any of the described examples 1 to 3, using the corresponding intermediate compounds. For purposes of illustration, but not limitation, some intermediate compounds are presented in Table�TSE 1:

in which the term "prot" represents a protective group as defined in the present invention, and "X" represents an element selected from the group consisting of O, Br, I, MS (methanesulfonate) and TS (toluolsulfonic).

Compounds of the present invention, and also their salts, solvates, prodrugs, esters, enantiomers and/or pharmaceutically acceptable diastereomers, potentially possess antimicrobial activity, preferably anti-fungal activity.

In particular, the compounds described in the present invention, and their pharmaceutically acceptable salts, can be used as antifungal agents, while acting as a fungicide and/or fungistatic. Fungicides are antifungal drugs that destroy the integrity and/or function of fungal cells, stimulating her death, while the fungistatic antifungal drugs are a means capable of preventing the growth and/or division of fungal cells, making them static. Interestingly, fungicidal drugs are able to clear the fungal infection of the host and fungistatic drugs are usually not completely eliminate the infection.

In addition, the compounds described in the present invention, �EMERAUDE as inhibitors and/or inhibitors of proliferation and/or survival of microorganisms, such as fungi, bacteria and/or protozoa, especially pathogenic microorganisms.

Fungi can parasitize almost each group of eukaryotic organisms, from unicellular organisms, such as algae and protozoa to complex of plants, animals and human being. Microorganisms such as the fungi that cause diseases and/or disorders in plants and/or animals are called pathogenic, more specifically by pathogenic microorganisms. It is clear that when the disease, pathological condition and/or disorder, abnormal condition of the body, which decreases one or more bodily functions, associated with specific symptoms and signs that can be caused by external factors, such as invasive organisms, or internal factors of the body. The disease is clinically expressed as a pathological condition as a result of penetration into the body of pathogenic microorganisms, such as viruses, bacteria, fungi, protozoa, multicellular parasites, and proteins known as prions, infections are called.

Fungi that are pathogenic to mammals, can be divided into three morphological types: (a) yeasts, which are unicellular, reproduce asexually and grow in the form of colonies, (b) filamentous fungi that are multicellular, have p�regardto or aseptic hyphae, can reproduce sexually, asexual or parasexual way, and (iii) dimorphic fungi that can exist in yeast or mycelial form, depending on temperature and environmental conditions. Filamentous fungi can be divided into: (i), dermatophytes, and (ii) anemophily.

In particular, the compounds described in the present invention, and their salts and solvates, prodrugs, esters, enantiomers and/or pharmaceutically acceptable diastereomers can be used to treat and/or prevent disease caused by primary pathogenic fungi that can be represented but not limited to, dermatophytes and dimorphic fungi. Clearly, treating a set of tools, such as pharmacological, surgical or physical, the purpose of which is treatment or alleviation of diseases or symptoms, is carried out after diagnosis. At the same time, the warning consists in the use of means to prevent the onset or occurrence of symptoms and/or their distribution.

The main types of dermatophytes that are relevant to medicine, are Epidermophyton sp, Trycophyton Microsporum sp and sp, among which can be highlighted the following species: Trichophyton mentagrophytes, Trichophyton verrucosum, Trichophyton rubrum, Trichophyton shoenleinii, Trichophyton tonsurans, Trichophyton violaceum, Trichophyton concentricum, Microsporum gypseum, Microsporum canis, Micrsporum audouinii and Epidermophyton floccosum.

Among dimorphic fungi the main species that are important in medical terms, are: Paracoccidioides brasiliensis, Histoplasma capsulatum, Blastomyces dermatiditis development, Coccidioides immitis, Penicillium marneffei, and Sporothrix schenckii.

Antifungal activity of the compounds of the present invention was evaluated using analysis of in vitro minimum inhibitory concentration (MIC) of compound 1-[2-(2,4-chlorophenyl)-2-{[4-(trifluoromethyl) benzyl] oxy} ethyl]-1H-imidazole (BL-123).

Antifungal activity of compounds BL-123 was evaluated for several strains of filamentous fungi dermatophytes, taken from the clinical and laboratory strains, as shown in Example 4.

EXAMPLE 4

4.1 Cultivation of fungal strains.

For the experiments of the present invention used the type strains of fungi dermatophytes, which were obtained from clinical and laboratory strains from infected patients, as shown in Table 2.

Table 2.

Fungal strains were cultured on medium potato agar in the inclined chute at 30°C for 7 to 15 days.

4.2 Setup for training and testing.

For the experiments we used the compound 1-[2-(2,4-chlorophenyl)-2-{[4-(trifluoromethyl) benzyl] oxy} ethyl]-1H-imidazole (BL-123), in the form of its salts of nitric acid, and nitrate miconazole. Both compounds were dissolved in dimethylsulfoxide (DMSO), t�to, so that the final concentration of compounds was respectively equal to or less than 1%.

The methodology used to determine the sensitivity of the microorganism based on microradian broth culture according to the method described in Standard M38-A Reference method tetrazocine broth culture to determine the susceptibility of filamentous fungi to antifungal therapy; NCCLS, volume 22 No. 16, USA, 2008), consisted of the following:

the fungus was cultured in accordance with clause 4.1. In test tubes, which were grown mushrooms, add 5 ml of saline to remove the mushrooms from the surface of the agar. Then, this homogeneous suspension was transferred into a new tube, and was quantitatively evaluated by colony forming units (CFU) in accordance with the methods of calculation: (i) in Petri dishes with Sabouraud agar with dextrose and (ii) in the chamber Nejbauèra.

Then the strains of fungi are shown in Table 2, were inoculable in two parallel experiments in 96-well plates. Was used for the inoculum of 2 to 6×103CFU/ml of fungi in the hole, with a total volume of 0.2 ml of medium RPMI-1640 (nutrient medium for immunological diagnostics) (containing L-glutamine and without bicarbonate), buffered at pH 7.0 MOPS (3-(N-morpholine)froyanova acid). The procedure was performed in a laminar flow.

Be tested compounds, with�dilution series in two parallel experiments, at final concentrations of 16 ág/ml; 8 mg/ml, 4 μg/ml, 2 μg/ml, 1 μg/ml, 0.5 μg/ml; 0,25 µg/ml; 0,125 µg/ml; of 0.0625 μg/ml, or 0,03125 μg/ml was added to culture medium present in each well.

Incubation of fungi with these compounds was performed within 4, 5, 6 and 7 days at a temperature of from 30°to 35 ° C.

Quantitative assessment of growth of fungi was carried out for each hole, in comparison with the growth of fungi occurring in a negative control experiment, using a mirror device with inverted optics. A negative control experiment presented in mushrooms grown in a nutrient medium in the absence of test compounds. The methodology of this comparison is to quantify the growth of fungi, which produced a series of microdesmidae. In this method, a value of 4 means that there has been no reduction of growth. A value of 3 corresponds to a small decrease in growth of approximately 75% of the growth of fungi in a negative control experiment. A value of 2 corresponds to a significant reduction of fungal growth, or about 50% of their growth in a negative control experiment. A value of 1 means that there is a slight increase, which is about 25% of the growth in the negative control experiment, and a value of 0 corresponds to the optical prozrachnoi environment elitaste the growth of fungi.

In this experiment, the minimum inhibitory concentration (MIC) is considered as the lowest concentration of an agent capable of inhibiting at least 80% of the growth of colony-forming units (CFU).

The results obtained in a given experiment, presented in Table 3, which shows the average value of MIC obtained in four independent experiments pertaining to 4 and 7 days of incubation with compound BL-123 or miconazole.

The compound of the present invention, BL-123 showed that it has an inhibitory effect on the growth of 13 different strains of fungi, corresponding to the seven different species of dermatophytes.

Interestingly, the results presented in Table 3, show that some clinical strains resistant to the miconazole (strains I, VII and VIII), in this case, sensitive to the action of compounds BL-123.

Inhibitory effect of compound BL-123 was confirmed by the results obtained in the experiments conducted to obtain the value of minimum inhibitory concentration to inhibit 50% of the tested strains (MIC50), minimum inhibitory concentration to inhibit 90% of the tested strains (MIC90and versions of MICK (CMC), as described in Table 4.

In these experiments we found that the effect of ingibirovany� BL-123 remained the same, when we used low concentrations of compounds to inhibit the growth of 90% of the population of the tested strains. In contrast, a large part of the population of the same strains in the processing of miconazole was refractory to treatment in the case, applied the lowest concentration which inhibited the growth of 50% of the population.

Antimicrobial activity of the compounds of the present invention was measured using the in vitro assays the minimum inhibitory concentration (MIC) of compounds 1-[2-(2,4-chlorophenyl)-2-{[4-(trifluoromethyl)benzyl]oxy}ethyl]-1H-imidazole (BL-123) and 1-[2-(2,4-dichlorophenyl)]-2-({4-[(2-phenyl)-2H-tetrazol] benzyl} oxy) ethyl]-1H-imidazole (BL-137).

Antimicrobial activity of compounds BL-123 and BL-137 tested on several strains of yeasts and bacteria, as shown in Example 5.

EXAMPLE 5

5.1 Cultivation of yeast strains and bacteria.

For the experiments of the present invention was used (i) yeast strains obtained from clinical strains and laboratory strains, and (ii) bacterial strains were obtained from laboratory strains, as indicated in Table 5.

5.1.and the Cultivation of yeast strains - preparation of inoculum.

Yeast strains were grown in the culture medium Sabouraud agar with dextrose, support�Vaya a temperature of 35°C for 48 hours.

5.1.and Cultivation of bacterial strains preparation of inoculum.

Bacterial strains were grown in the culture medium Crypton-soy agar at 35°C for two to six hours (or until the turbidity of the solution corresponding to the standard turbidity of 0.5 on the Mcfarland).

5.2 the Procedure for preparation and testing.

For experiments that used the compound 1-[2-(2,4-chlorophenyl)-2-{[4-(trifluoromethyl) benzyl] oxy} ethyl]-1H-imidazole (BL-123) in the form of its nitrate salt, 1-[2-(2,4-dichlorophenyl)]-2-({4-[(2-phenyl)-2H-tetrazol]benzyl}oxy)ethyl]-1H-imidazole (BL-137), and miconazole nitrate. Compounds were dissolved in dimethylsulfoxide (DMSO), adjusting the final concentration of the compound equal to or less than 1%.

5.2.and Yeast strains.

The methodology used to test the sensitivity of the pathogen, was microrasbora in broth, in accordance with the method described in Standard M27-A2 Reference method tetrazocine broth culture to determine the susceptibility of yeasts to antifungal therapy - second edition, NCCLS, volume 22, number 15, USA, 2002), as follows:

yeast strains were grown in accordance with paragraph 5.1.and to obtain a culture containing 1×106up to 5×106CFU/ml. Then the suspension was diluted in culture medium RPMI-1640 (MOPS buffered 0,165 mol/l) �final concentration of about 50 to 2500 CFU/ml.

Diluted suspensions were inoculable in two parallel experiments in 96-well plates. The procedure was performed in a laminar flow.

Test compounds in the serial dilution in final concentrations of 16 ág/ml; 8 mg/ml; 4 mg/ml; 2 mg/ml; 1 μg/ml; 0.5 μg/ml; 0,25 µg/ml; 0,125 µg/ml; of 0.0625 μg/ml; or 0,03125 mg/ml was added to the culture medium in each well. Incubation of fungi with these compounds was performed for 48 hours at a temperature of from 30 to 35°C.

5.2.b Cultivation of bacterial strains.

The methodology used to test the sensitivity of the pathogen, was microrasbora in broth, according to the method described in Standard M7-A6 (Methodology of tests for sensitivity to antimicrobial agents by means of dilution for bacteria growing in an oxygen atmosphere 6th Edition: NCCLS, volume 23, No. 2, USA, 2003), as follows.

Bacterial strains were grown in accordance with clause 5.1.b to obtain a culture containing 1×107up to 5×107CFU/ml. Then the suspension was diluted in culture medium Mueller Hinton to final concentration of 5 x 104 CFU/ml.

Diluted suspensions were inoculable in 0.1 ml in 24-well plates in two parallel experiments. The procedure was performed in a laminar flow.

Be tested compounds in serial dilution, in two parallel�the intelligent experiments, with the final concentrations of 16 ág/ml; 8 mg/ml; 4 mg/ml; 2 mg/ml; 1 μg/ml; 0.5 μg/ml; 0,25 µg/ml; 0,125 µg/ml; of 0.0625 μg/ml; or 0,03125 mg/ml in 0.9 ml was added to the culture medium in each well.

Incubation of fungi with these compounds was performed within 24 hours at a temperature of from 30°to 35 ° C.

After incubation observed the growth of microorganisms with the naked eye by the presence of turbidity or the presence of sludge in the bottom of the trough. We have established in this experiment that turbid environment is a result of the growth of microorganisms, and the presence of sediment and transparent environment mean the absence of growth of microorganisms. Minimum inhibitory concentration (MIC) was defined as the lowest concentration of the test drug, which prevents any degree of bacterial growth.

It was shown that the compounds of the present invention BL-123 BL-137 have an inhibitory effect on the growth of three different species of yeast and two different types of bacteria as shown in Table 6 below.

Watching the results of this experiment, we concluded that the compounds of the present invention have an inhibitory effect on the growth of microorganisms, and therefore can be used as antimicrobials, preferably against fungi and bacteria. It is clear that to store�to be antimicrobial, any drug should be a chemical compound that destroys or inhibits the growth of microorganisms, such as fungi, bacteria and/or protozoa, or which is capable of destroying viruses.

Compounds of the present invention are intended for use against fungi, examples of which include, but are not limited to, birth: Aspergilus, Microsporum, Epidermophyton, Trichophyton, Candida, Phycomyces, Zygomyces, Rhizopus, Mucor, Absidia, Malassezia, Exophiala, Piedraia, Trichosporum, Sporothrix, Cladosporium, Phialophora, Fosecaea, Histoplasma, Coccidioides, Fusarium, Penicillium, Blastomyces, Cryptococcus, Paracoccidioides, Scedosporium, Sacharomyces, Piedraia, Actinomyces, Keratinomyces, Nannizia, Arthroderma, Ctenomyces, Olpidium, Physodema, Synchytrium, Phytophora, Verticillium, Gliocladium, Rhytisma, Sclerotinia, Ophiostoma, Lophiodermium, Elsinoe, Capnodium, Mycosphaerella, Venturia, Gaeumannomyces, Alternaria, Bipolaris, Botrytis, Cercospora, Diplodia, Dreschlera, Exerohilum, Phoma, Phomopsis, Rhisoctonia, Puccinia, Erysphe, Phyllactinia, Uncinula, Phragmidium, Melampsora, Eutypha, Neroccio, Xylaria, Ceratobasidium, Heterobasidium, Thanatephorus, Armillaria, and others.

Examples of bacteria against which are compounds of the present invention, may represent genera: Actinomyces, Corynebacterium, Mycobacterium, Nocardia, Bacillus, Bifidobacterium, Clostridium, Erysipelothrix, Listeria, Staphylococcus, Streptococcus, Pneumococcus, Anaplasma, Ehrlichia, Neorickettsia, Wolbachia, Bacterioides, Bartonella, Bordetella, Borrelia, Brucella, Burkholderia, Campylobacter, Chlamydia, Chlamydophila, Escherichia, Klebsiella, Proteus, Salmonella, Serratia, Yersinia, Fusobacterium, Helicobacter, Acinetobacter, Mycoplasma, Neisseria, Neisseria, Meningococcus, Actinobacillus, Haemophilus, Pasteurella, Pseudomonas, Rickettsia, Treponema, and others.

The simplest examples against which intended�hree compounds of the present invention, may represent genera: Plasmodium, Toxoplasma, Balantidium, Coccidia, Cryptosporidium, Cylospora, Isospora, Sarcocystis, Babesia, Active, Fragilis, Gidrdia, Leishmania, Acanthamoeba spp., Blastocystis, Anaplasma, Ehrlichia, Trychomonas, Trypanosoma, Giardia, Entamoeba, and others.

Compounds described in this invention and their salts, solvates, prodrugs, esters, enantiomers and/or their pharmaceutically acceptable diastereomers, can be used for the manufacture of a medicinal product for the treatment and/or prevention of pathological conditions and/or diseases associated with microorganisms, such as fungi, bacteria and/or protozoa. In addition, the compounds described in this invention and their salts, solvates, prodrugs, esters, enantiomers and/or their pharmaceutically acceptable diastereomers can be used for the manufacture of a drug for inhibiting the proliferation and/or survival of microorganisms, such as fungi, bacteria and/or protozoa, especially pathogenic microorganisms.

Thus, the present invention provides a method for the treatment and/or prevention of pathological conditions and/or diseases associated with microorganisms, such as fungi, bacteria and/or protozoa, for example, dermatophytes, yeasts, filamentous fungi, the dermatophytes, gram-negative and gram-positive bacteria � protozoa, in mammals by introduction of at least one compound described by Formula (I) according to the present invention, and salts, solvates, prodrug, esters, enantiomers and/or pharmaceutically acceptable diastereomers.

The present invention also provides a method of inhibiting the proliferation and/or survival of microorganisms, such as fungi, bacteria and/or protozoa, especially pathogenic microorganisms.

Thus, we believe that provided proven efficacy, the compounds of Formula (I) and their pharmaceutically acceptable salts are of interest for therapy, especially for treatment and/or prevention in an individual of pathological conditions and/or diseases associated with microorganisms, such as fungi, bacteria and/or protozoa. Under the means an individual organism, which is as absolutely independent physiological unit and individual genotype.

Diseases that affect people caused by pathogenic fungi are called mycoses. Mycoses can be divided into three groups, depending on the location and the depth at which they lie in the body, namely: (i) superficial mycoses: infections on the surface of the skin, nails, hair, mucous membranes and/or hair, (ii), subcutaneous mycosis caused by fungi that are able�and to penetrate into the deeper layers of the skin, such as the subcutaneous tissue, connective tissue and bone tissue, and (iii), systemic mycosis (or deep): the most severe invasive fungal infection that can be contracted by inhalation of spores of pathogenic fungi that remain and grow in the lungs and reach the bloodstream and can infect other organs of the body.

The main superficial mycoses caused by dermatophytes (fungi affecting the skin) and are called ringworm (tinea). Examples of the most common ringworm can be: (i) a fungal infection of scalp (head skin), caused by various dermatophytes such as M. Canis, (microsporia scalp), T. tonsurans (shingles), T. mentagrophytes, E. floccosum, M. gypseum (keríon), T. violaceum, T. schoenleinii (fungal infection of the feet, T. verrucosum and T. schonleinii, (ii) ringworm of the beard and mustache, caused by T. rubrum and T. Mentagrophytes, (iii) trichophytosis smooth skin of the body, most commonly caused by T. rubrum, T. mentagrohytes and M. kennels, (iv) dermovate stop (legs and arms), often caused by T. rubrum, T. mentagrohytes and E. Floccosum, (v) ringworm of the crotch (crotch), caused by T. rubrum, T. mentagrohytes and E. Floccosum, (vi) a fungal infection of the ear caused by M. kennels, (vii) cherepanovskiy ringworm caused by T. Concentricum, (viii) tinea of the nails, fungal onychia), mainly due to the different dermatophyte genera Trichophyton, Epidermophyton, rarely Microsporum.

To�ome, mushrooms, which, of course, are not pathogenic for humans, can develop opportunistic infections, secondary to other, pre-existing pathological conditions and weakened immune system of the host. The main examples of fungi that cause opportunistic infections are: (i) filamentous fungi, mostly belonging to the genus Aspergillus sp, Fusarium sp, Scedosporium sp, sewage and dark-colored pigmented) fungi and (ii) yeast, mostly belonging to the genera Candida sp, Cryptococcus sp, Trichosporon sp, Rhodotorula SP, Malassezia sp and Saccharomyces sp.

Examples of clinically significant dermatoses caused by other opportunistic filamentous fungi, can serve as (i), colorful (pityriasis) versicolor (skin), caused by Malassezia furfur; (ii) Pityrosporum folliculitis, caused by the fungi Malassezia furfur infection of the hair follicle and sebaceous glands; (iii) black versicolor (hands and arms or sides of the toes) caused by Cladosporium werneckii; (iv) black Piedra (hair), caused by the fungus Piedraia hortai.

In addition, you can also refer to examples of diseases caused by opportunistic fungal yeast such as (i) trichosporonosis caused by a yeast Trichosporon beigelii, which is divided into white Piedra (hair) and trichosporon genitals and groin (rash on the genitals and groin area), (ii) candidiasis, caused by Candida sp, n�the most often represented by C. albicans, but, as has been found, also found the species C. tropicalis, C. parapsilosis, C. Guilliermondii, and Candida can be subdivided into oral candidiasis, vulvovaginal candidiasis, candidiasis of the glans penis, intertriginous candidiasis, mucocutaneous candidiasis and follicular candidiasis.

Among deep mycosis exist: (i) paracoccidioidomycosis caused Paracoccicioides brasiliensis, which is manifested through the forms of integument of skin, shape of the mucous membranes, forms the lymph nodes, Vicere form in other organs and mixed forms, (ii) lobatos caused by Paracoccidioides loboi, (iii) chromoblastomycosis or hromomikoza, called pigmented fungi, such as Fosecaea pedrosoi, Fosecaea compacta, Cladosporium cartionii, Phialophora verrucosa and Rhinocladiella aquaspersa; (iv) sporotrichosis caused by Sporothrix schenckii, and is manifested in the external cutaneous and extra-cutaneous forms, (v) madorsky foot, caused by certain fungi that include Pietriellidium boydii, Cephalosporium sp, Madurella sp, Pyrenochaeta sp, Exophiala sp; (vi) histoplasmosis, caused by Histoplasma capsulatum, (vii) paulitics caused by fungi Exophiala jeanselmei, Wangiella dermatitis, Cladosporium bantiasenum, Alternaria alternada, Exophiala moniliae, Exophiala spinifera, Phialophora verrucosa, Phloma sp, Curvularia geniculata, Mycelia sterilia; (viii) entomophthoramycosis caused by fungi in the Female haptosporus, Conidiobolus coranatus or Conidiobolus incongrus; (ix) mucormycosis, caused by the fungus Absidia corymbifera, Rhizomucmu pussilus, ramossimus Mucor, Rhizopus microsporus, Rhizopus oryzae, Rhizopus rhizopodiformis, Cunninghamella Berthollet, Saksenae vasiforis; (x) cryptococcosis, caused by Cryptococcus neoformans; (xi) Coccidioidomycosis, caused Coccidoides immitis (xii) North American blastomycosis, caused Bastomyces dermatitis, (xiii) rhinosporidiosis caused by Rhinosporidium seeberi.

In particular, the compounds of Formula (I) according to the present invention can be applied, not limited to the following: for the treatment or prevention of pathological conditions and/or diseases such as microsporidia the scalp, tinea, deep trichophytosis (keríon), a fungal disease of the feet, alimentary toxic aleukia, ringworm of the beard and mustache, trichophytosis smooth skin of his torso, dermovate foot, crotch ringworm, a fungal infection of the ear, cherepanovskiy versicolor, tinea of the nails, colorful pityriasis, Pityrosporum folliculitis, black shingles, black Piedra, trichosporon, oral candidiasis, vulvovaginal candidiasis, candidiasis of the glans penis, intertriginous candidiasis, candidiasis of the tonsils and/or candidiasis of the mucous membranes.

Diseases caused by fungi affecting plants, are of great importance, because the parasites are destructive for them. They are found mainly on cultivated plants, which causes a significant damage to agriculture. These diseases can be rust, mold, soot or mold fungus, depending�and from the pathogen, while some fungi can also produce toxins - mycotoxins. Mycotoxins can cause disease in humans, in particular, such a toxin, aflatoxin, produced by Aspergillus flavus, which is a potential human carcinogen.

Examples of pathological conditions and/or diseases associated with bacteria, which can be treated and/or prevented by administration of the compounds of the present invention may be but not limited to: actinomycosis, Whipple's disease, diphtheria, eritrazma, leprosy, Buruli ulcer, paratuberculosis, tuberculosis, tuberculoma, pericarditis, erythema, mycetoma, anthrax, botulism, enterocolitis, enterotoxemia, gas gangrene, tetanus, erysipelas, meningitis, pneumonia, furunculosis, impetigo, endocarditis, rheumatic fever, anaplasmosis, arlais, angiomatosis, brucellosis, melioidosis, conjunctivitis, lymphogranuloma venereum, trachoma, psittacosis, infection, granuloma, typhoid fever, paratyphoid fever, gingivitis, legionellosis, leptospirosis, pleuropneumonia, gonorrhea, typhoid fever, spots on the skin, syphilis, cancer, neurosyphilis, tularemia, cholera, and others.

Examples of pathological conditions and/or diseases associated with protozoa, which can be treated and/or prevented by administration of the compounds of the present invention, can� to be not limited to: malaria, toxoplasmosis, balantidiasis, coccidioidomycosis, cryptosporidiosis, cyclospora, isospora, sarcosporidiosis, babesiosis, durin, theileriosis, trypanosomiasis, dientamoeba, amoebiasis, giardiasis, leishmaniasis, trichomoniasis, Chagas disease, amoebiasis, amoebic dysentery, and others.

Compounds described by Formula (I) according to the present invention, and their salts, solvates, Pro drugs, esters, enantiomers and/or pharmaceutically acceptable diastereomers can be entered via any suitable means, such as topically, orally, parenterally, intraperitoneally and/or vaginally.

Pharmaceutical compositions containing as active substance an effective amount of derivatives of Formula (I) or their salts, solvates, prodrug, esters, enantiomers and/or pharmaceutically acceptable diastereomers, separately or in mixture of at least two compounds of Formula (I) according to the present invention, can be presented in the form of liquid, semi-solid or solid substance, such as but not limited to, (i), creams, gels, gel-creams, hydrogels, powders, ointments, lotions or emulsions, (ii) capsules, not necessarily, coated, chewable, effervescent, multi-layer or soluble as (iii) capsules of any kind, such as hard capsule, soft gel capsule, and starch; (iv) cap�uly, (v) postdispersal or effervescent, (vi) tablets, (vii), granules, not necessarily in the form of microparticles or microcapsules, or in the form of vectorized drugs, such as liposomes, (viii) not necessarily, local, oral, nasal, or ophthalmic solutions; (ix) candles, (x) syrups, (xi) suspension; (xii) injection, including subcutaneous, intradermal, intramuscular and intravenous administration, and others.

In addition, the present invention presents a pharmaceutical composition, controlled action, fast action, prolonged action and delayed action.

Pharmaceutical compositions and medicaments containing the compounds described in this izobreteniya, and also their salts, solvates, prodrugs, esters, enantiomers and/or pharmaceutically acceptable diastereomers, are used for the treatment of pathological conditions caused by fungi and/or other microorganisms, such as bacteria and/or protozoa, in mammals.

Pharmaceutical compositions containing as active ingredients compounds described in this invention and their salts, solvates, prodrugs, esters, enantiomers and/or pharmaceutically acceptable diastereomers, can contain these compounds individually or as mixtures or in combination with drummachines substance.

For the introduction of mammals during the prevention or treatment of pathological conditions caused by fungi and/or other microorganisms, such as bacteria and/or protozoa, the dosage of the compounds described in Formula (I) is in the range of 0.001 to 1000 mg per day for patients in need. In practice, the physician should determine the most appropriate system standard doses for each patient, which varies depending on age, weight and individual patient response.

The examples illustrate a few pharmaceutical compositions for topical application containing a compound of Formula (I) according to the present invention, can be, not limited to, those described below.

EXAMPLE 6

Method of obtaining:

In the first tank heats the water at a temperature of 75°C±5°C, and then dissolve the methylparaben and propylparaben. In the second vessel at a temperature of 75°C±5°C was heated with anhydrous lanolin, Polysorbate 60, servicemonitor, cetyl alcohol, propilenglikolmonostearata and isopropyl myristate until completely melted. The contents of the first container is added to the contents of the second vessel with stirring, and then cooled to a temperature of 45°C±5°C. To this mixture was slowly added active substance BL-123, propylene glycol, and, optionally, DMSO. Get�nnow the mixture was cooled to a temperature of 30°C (25-35°C), and it is not necessary to add flavor. To the total mass of water was added, and the mixture homogenized.

EXAMPLE 7

Silicon dioxide was mixed with flavoring and then passed through a sieve of 60 mesh. In a separate container mixed active substance BL-123, zinc oxide and pharmaceutically acceptable talcum powder and passed through a sieve of 40 mesh. After this process, the powders were mixed.

EXAMPLE 8

In a container of sufficient capacity were added Macrogol 300 and propylene glycol and heated at a temperature of from 60° to 70°C. is Then added with stirring to the active substance BL-123 and, not necessarily, at a temperature of 60°C-70°C and stirred until complete dissolution. The mixture was cooled to a temperature of 30°C and, optionally, can add flavor. The final volume was supplemented with propylene glycol and stirred to obtain a lotion.

Compounds that are considered to be anti-fungal, can be associated with targets, as described, but are not limited to the followings: [Amaral, AC et al "Therapeutic targets in Paracoccdioides brasiliensis: post-transcriptome perspectives" Gent Res Mol 4 (2):430-449. 2005]

(i) synthase, such as (a) 1,3-glucan synthase, relevant to the virulence of fungi, and (b) chitin-synthase involved in the synthesis of chitin, which is found exclusively in fungi; and

(ii) reenact�their enzymes such as (a) mannosyltransferase, which plays an important role in shaping the structure of the cell wall, adhesion, and virulence; (b) transglucosidase involved in the final architecture of the fungus, and (C) hydrolases, which have multiple roles in morphogenetic events.

(iii) plasma membrane components, such as: (a) the Sterol-ergosterol that is essential component in the plasma membrane, and thus a unique phenomenon in fungi; (b) the components of the metabolic pathway of sphingolipids, such as inositolphosphorylceramide that represent various fungi; and (C) proton ATPase, which are necessary to maintain cellular homeostasis through regulation of ion exchange in the cell.

(iv) molecular components, such as (a) topoisomerases, which are enzymes that interfere with replication, transcription, recombination and segregation of chromosomes, and whose differences between human cells and the yeast cells can be used in the molecular modelling; (b) the elongation factors required for protein synthesis, as, for example, elongation factor 3, is present in fungi, and the missing and other organisms, including humans, (c) Hsp90 is a protein highly conservative among different organisms and apparently associated with the pathogenicity of fungi; (d) N-myristoyltransferase responsible for the transfer of myristate on aminoterminal glycine residue of several proteins of eukaryotic cells, necessary for the survival of fungi, and whose difference between the way humans and fungi have been discovered; and (e) prenyltransferase responsible for prenisolone proteins that participate in various cellular functions such as cell growth, differentiation, signal transduction, among others, has weak similarity to human forms.

(v) proteins involved in the transmission of cellular signals, such as (a) calcineurin specific serine-treoninove phosphatase saved in eukaryotes that plays a crucial role in maintaining cellular homeostasis through the control of intracellular calcium under stress, and is associated with the virulence of the fungus; and (b) TOR, which are proteins associated with phosphatidylinositol kinase, known for its involvement in cell growth in response to mitogenic signals.

(vi) components of cellular metabolism, such as (a) the purpose glioksilatnyj cycle, which is an alternative way in which the fungus gets energy in the process involves the enzymes isocitrate-lyase and malate-synthase; (b) urease, which is metallothermic responsible for the hydrolysis of urea �about carbamate, increasing the pH. The same is fungal pathogenic factor, which is absent in humans; and (c) protoxides, an enzyme of the purine path of disintegration, is involved in the kidnapping of fungal free radicals, playing a vital role in their survival, and characterized by the fact that this pathway is absent in humans.

(vii) significant genes, such as (a) CDC28 and (b) Civl who are involved in basic cell cycle of fungi.

1. Ensilability ether characterized by the Formula (I):

or its pharmaceutical acceptable salts, where:
Ar represents imidazolyl;
R1, R2, R4and R5independently represent hydrogen;
R3is a halogen;
R6represents trifluoromethyl or trichloromethyl;
n represent an integer from 0 to 2; and
m represents 1.

2. The compound according to claim 1, wherein the pharmaceutically acceptable salt is selected from the group consisting of nitrates, chlorides, bromhidrato, sulfates, bisulfates, phosphates, hydrogen phosphates, acetates, benzoate, succinates, fumarates, malatov, lactates, citrates, tartrates, gluconates, methosulphate, benzolsulfonat and p-toluensulfonate.

3. The compound according to claim 1, where the compound is a 1-[2-(2,4-dichlorophenyl)-2-{[4-(trifluoromethyl)benzyl]oxy}ethyl]-1H-imidazole or its headlights�asepticheskie acceptable salt.

4. Use of a compound according to any one of claims.1-3 for the treatment and/or prevention of conditions and/or diseases associated with fungi or bacteria.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to new quinolin-4-one derivatives of formula (1) or to its pharmaceutically acceptable salt, wherein R1 represents: (1) hydrogen, (2) C1-C6 alkyl, (35) carbamoyl-C1-C6 alkyl optionally containing morpholinyl-C1-C6 alkyl, or (36) phosphonoxy-C1-C6 alkyl optionally containing one or two C1-C6 alkyl groups on a phosphonoxy group; R2 represents: (1) hydrogen or (2) C1-C6 alkyl; R3 represents phenyl, thienyl or furyl, wherein a phenyl ring presented by R3, can be substituted by one C1-C6 alkoxy group; R4 and R5 are bound to form a group presented by any of the following formulas: , , , , , , or a group presented by the following formula: a group optionally containing one or more substitutes specified in a group consisting of C1-C6 alkyl groups and oxogroups; R6 represents hydrogen; and R7 represents C1-C6 alkoxy group. The invention also refers to a pharmaceutical composition based on the compound of formula , to a preventive and/or therapeutic agent based on the compound of formula (1), using the compound of formula (1), a method for preparing the compound of formula , as well as to specific compounds.

EFFECT: there are prepared new quinolin-4-one derivatives effective in treating neurodegenerative diseases, diseases caused by neurological dysfunction, or diseases caused by mitochondrial dysfunction.

18 cl, 1 tbl, 257 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 1-(2-{[4-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenylcarbamoyl)butyl]methylcarbamoyl}ethyl)piperidin-4-yl ester of biphenyl-2-ylcarbamic acid or to its pharmaceutically acceptable salt. The invention also refers to a pharmaceutical composition based on the above compound, a method and an intermediate compound for producing the above compound.

EFFECT: produced is the new heterocyclic compound effective in treating pulmonary disorders, including in chronic obstructive pulmonary disease or asthma.

9 cl, 3 tbl, 170 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to specific compounds or to their therapeutically acceptable salt presented in the patent claim and representing sulphonyl benzamide derivatives. The invention also refers to a pharmaceutical composition inhibiting the activity of anti-apoptotic proteins of the family Bcl-2, containing an excipient and an effective amount of a specific sulphonyl benzamide derivative.

EFFECT: sulphonyl benzamide derivatives inhibiting the activity of anti-apoptotic Bcl-2 proteins.

2 cl, 3 tbl, 558 ex

Antiviral compounds // 2541571

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I, such as below, or its pharmaceutically acceptable salts. What is described is a method for preparing them.

,

wherein: A independently from B means phenyl,

, or ,

and B independently from A means phenyl,

, or ,

and the values Z, Y, D, L1, L2, L3, Z1, Z2 are presented in the patent claim.

EFFECT: compounds are effective for hepatitis C virus (HCV) replication inhibition.

17 cl, 3 tbl, 8 dwg, 177 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compounds of formula I

and to their pharmaceutically acceptable salts, where A is selected from CH or N; R1 is selected from the group, consisting of C3-6-cycloalkyl, C3-6-cycloalkyl-C1-7-alkyl, C1-7-alkoxy-C1-7-alkyl, halogen-C1-7-alkyl; R2 and R6 independently on each other represent hydrogen of halogen; R3 and R5 independently on each other are selected from the group, consisting of hydrogen, C1-7-alkyl and halogen; R4 is selected from the group, consisting of hydrogen, C1-7-alkyl, halogen and amino; R7 is selected from the group, consisting of C1-7-alkyl, C1-7alkoxy-C1-7-alkyl, C1-7-alkoxyimino-C1-7-alkyl, 4-6-membered heterocyclyl, containing one heteroatom O, phenyl, with said phenyl being non-substituted or substituted with one hydroxy group, and 5-10-membered heteroaryl, containing 1-3 heteroatoms, selected from N, S and O, said heteroaryl is not substituted or is substituted with one or two groups, selected from the group, consisting of C1-7-alkyl, hydroxy, C1-7-alkoxy, cyano, C1-7-alkylaminocarbonyl and halogen. Invention also relates to pharmaceutical composition based on formula I compound and to method of obtaining formula I compound.

EFFECT: obtained are novel heterocyclic compounds, which are agents, increasing level of LDLP.

17 cl, 2 tbl, 89 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I , II or IV , wherein the radical values W, V, Ra, Rb, X, L, Rt, A are presented in the patent claim.

EFFECT: declared compounds identify and bind the CA-IX protein; they can contain a radioactive element for radionuclide imaging or therapeutic application.

27 cl, 1 tbl, 5 dwg, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to substituted isoquinolines and isoquinolinones of formula (I) and to their stereoisomer and/or tautomer forms and/or pharmaceutically acceptable salts, wherein R1 is H, OH or NH2; R3 is H; R4 is H, halogen or (C1-C6)alkylene-R'; R5 is H, halogen, (C1-C6)alkyl; R7 is H, halogen, (C1-C6)alkyl, O-(C1-C6)alkyl; R8 is H; R6 is absent; or is one of (C1-C4)alkylene related to a cycloalkyl ring related to a cycloalkyl ring, wherein (C1-C4)alkylene forms a second bond to another carbon atom of the cycloalkyl ring to form a bicyclic ring system, R10 is H, phenyl, or pyridine, wherein phenyl is unsubstituted or substituted; R11 is H, (C1-C6)alkyl; or R11 and R12 together with the carbon atom to which they are attached form (C3)cycloalkyl; R12 is (C1-C6)alkyl, (C3-C8)cycloalkyl or phenyl; or R12 is H, provided r=2 and another R12 is other than H; or R11 and R12 together with the carbon atom to which they are attached form (C3)cycloalkyl; R13 and R14 are independently H, (C1-C6)alkyl, (C1-C6)alkylene-R', C(O)O-(C1-C6)alkyl, n is equal to 0; m is equal to 1 or 2; s is equal to 1 or 2; r is equal to 1 or 2; L is O, NH; R' is (C3-C8)cycloalkyl, (C6-C10)aryl; wherein in R11 and R12 residues, alkyl is unsubstituted or optionally substituted by one OCH3; wherein in R11 and R12 residues, alkyl is unsubstituted or optionally substituted by one or more halogens; wherein in R10 and R12 residues, (C6-C10)aryl is unsubstituted or optionally substituted by one or two groups optionally specified in halogen, CN, (C1-C6)alkyl, O-(C1-C6)alkyl, SO2-(C1-C6)alkyl, CF3 and OCF3. Also, the invention refers to using a compound of formula (I).

EFFECT: there are prepared new isoquinoline and isoquinolinone derivatives effective in treating and preventing the diseases related to Rho-kinase inhibition.

38 cl, 132 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to fumarate salts of 2-(cyclohexylmethyl)- N-{2-[(2S)-1-methylpyrrolidin-2yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulphonamide, to based on them pharmaceutical compositions, method of their obtaining and methods of their application.

EFFECT: obtained are novel salts of 2-(cyclohexylmethyl)- N-{2-[(2S)-1-methylpyrrolidin-2yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulphonamide, possessing properties of H3 histamine receptor antagonists.

16 cl, 9 dwg, 8 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula

possessing inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases. In formula (I-b), ring A and ring B represents phenyl; Ry represents -CN, -CF3, C1-4 aliphatic group, C1-4 halogenaliphatic group, -OR, -C(O)R or -C(O)N(R)2; each group R independently represents hydrogen or a group specified in C1-6 aliphatic group optionally containing a substitute presented by halogen, -(CH2)0-4R°, -(CH2)0-4OR°, -(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)OR°, -(CH2)0-4C(O)R°, -(CH2)0-4S(O)2R°, or 5-6-merous substituted or aryl ring containing 1-2 heteroatoms independently specified in nitrogen or oxygen optionally substituted by group =O, -(CH2)0-4R°, -(CH2)0-4N(R°)2 or -(CH2)0-4OR°; phenyl; 5-6-merous heterocyclic ring containing 1-2 heteroatoms independently specified in nitrogen, oxygen or sulphur optionally substituted by group -(CH2)0-4R°, -(CH2)0-4OR° or =O; or 6-merous monocyclic heteroaryl ring containing 1 nitrogen atom; W1 and W2 represent -NR2-; R2 represents hydrogen, C1-6aliphatic group or -C(O)R; m and p are independently equal to 0, 1, 2, 3 or 4; Rx is independently specified in -R, -OR, -O(CH2)qOR or halogen, wherein q=2; Rv is independently specified in -R or halogen; R1 and R° radical values are presented in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds.

EFFECT: preparing the compounds possessing the inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases.

17 cl, 25 dwg, 20 tbl, 286 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compound of formula (I) or its racemate, enantiomer, diastereoisomer and their mixture, as well as to their pharmaceutically acceptable salt, where A is selected from the group, consisting of carbon atom or nitrogen atom; when A represents carbon atom, R1 represents C1-C6-alkoxyl; R2 represents cyano; when A represents nitrogen atom, R1 hydrogen atom or C1-C6-alkoxyl; where said C1-C6-alkoxyl is optionally additionally substituted with one C1-C6-alkoxyl group; R2 is absent; R3 represents radical, which has the formula given below: or , where D represents phenyl, where phenyl is optionally additionally substituted with one or two halogen atoms; T represents -O(CH2)r-; L represents pyridyl; R4 and R5 each represents hydrogen atom; R6 and R7 each is independently selected from hydrogen atom or hydroxyl; R8 represents hydrogen atom; R9 represents hydrogen atom or C1-C6-alkyl; r equals 1 and n equals 2 or 3. Invention also relates to intermediate compound of formula (IA), method of obtaining compound of formulae (I) and (IA), pharmaceutical composition based on formula (I) compound and method of its obtaining and to application of formula (I) compound.

EFFECT: novel heterocyclic compounds, inhibiting activity with respect to receptor tyrosine kinases EGFR or receptor tyrosine kinases HER-2 are obtained.

18 cl, 12 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula , wherein A means a six-merous aryl radical or a five-merous heteroaryl radical which contains one heteroatom specified in oxygen and sulphur; one or more hydrogen atoms in the above aryl or heteroaryl radicals can be substituted by substituting groups R1 which are independently specified in a group consisting of: F, Cl, Br, I, (C1-C10)-alkyl-, (C1-C10)-alkoxy-, -NR13R14; B means a radical with mono- or condensed bicyclic rings specified in a group consisting of: six-ten-merous aryl radicals, five-ten-merous heteroaryl radicals and nine-fourteen-merous cycloheteroalkylaryl radicals, wherein cycloheteroalkyl links can be saturated or partially unsaturated, while the heterocyclic groups can contain one or more heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, one or more hydrogen atoms in the radical groups B can be substituted by substituting groups R5 (as specified in the patent claim), L means a covalent bond, X means the group -O-, R2 is absent or means one or more substitutes specified in F and (C1-C4)-alkyl radical; R3 and R4 independently mean (C1-C10)-alkyl, (C3-C14)-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C19)-cycloheteroalkyl, (C3-C19)-cycloheteroalkylalkyl, (C6-C10)-aryl, (C7-C20)-arylalkyl, (C1-C9)-heteroaryl, (C2-C19)-heteroarylalkyl radicals, or R3 and R4 together with nitrogen attached whereto can form a four-ten-merous saturated, unsaturated or partially unsaturated heterocyclic compound which can additionally contain one or more heteroatoms among -O-, -S(O)n-, =N- and -NR8-; other radicals are such as specified in the patient claim. Also, the invention refers to using the compound of formula I for preparing a drug.

EFFECT: compounds of formula (I) as Na+/H+ metabolism inhibitors NHE3.

22 cl, 27 dwg, 1 tbl, 756 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to novel 2,5-dioxo-imidazolidine derivatives of general formula lb , or pharmaceutically acceptable salts and solvates thereof, or solvates of pharmaceutically acceptable salts, where X denotes O; R1 is H; or R1 is selected from C1-C6 alkyl and C1-C6 alkynyl, where the alkyl can optionally be substituted with a cyano group; R2a is selected from H, P(O)(OH)2 and C(O)(CH2)n1C(O)OH; or R2a is selected from -C(O)-C1-C6 alkyl, which is substituted with amino; n1 equals 1 or 2; each R2 and Rc is independently selected from H and C1-C6 alkyl; R3a is H, a halogen atom or cyano; each R3b is independently a halogen atom or cyano; or each R3b is independently C1-C6 alkyl, optionally substituted with three halogen atoms; each R4a and R4b is independently H or a halogen atom; or each R4a and R4b is selected from C1-C6 alkyl, and C1-C6 alkoxy, where the alkyl is substituted with three halogen atoms; R4c is a halogen atom or cyano; and ml equals 0 or 1. The invention also relates to a pharmaceutical composition based on a compound of formula lb and use thereof.

EFFECT: obtaining novel 2,5-dioxo-imidazolidine derivative which modulate androgen receptor activity.

20 cl, 5 tbl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely 12-imidazolyl-1-dodecantole or its pharmaceutically acceptable salts.

EFFECT: what is prepared is a new imidazole derivative effective in treating, including malignant pathological conditions.

4 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a fluorine-containing organosulphur compound of formula (I) and a composition based on said compound, which can be used in arthropod pest control: where m equals 0; n equals 0, 1 or 2; A is pyrazolyl, isoxazolyl, imidazolyl, oxazolyl or thiazolyl, optionally substituted with a group E1; R1 is C1-4 alkyl, a cyano group, a halogen atom or a hydrogen atom; R2 is C1-4 alkyl, a halogen atom or a hydrogen atom; Q is C1-5 haloalkyl containing at least one fluorine atom or a fluorine atom; group E1 is selected from halogen, tert-butyl, trifluromethyl, pentafluoroethyl, ethynyl, propargyl, propargyloxy, cyano, trifluoromethyl, trifluromethane thionyl and trifluoromethane sulphonyl.

EFFECT: efficient agent for arthropod pest control.

5 cl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention claims substituted O-[ω-(azol-1-yl)alkyl]-N-phenylthiocarbamates of formula I: where Z=CH, N, R=H, Alk, AlkO, Hal etc., m=1, 2, 3, n=0-5, obtained by acylation of ω-(azol-1-yl)alkanols of formula II by substituted phenylisothiocyanates in polar aprotonic solvents in the presence if tertiary amines. Invention allows for more efficient suppression of phytopathogenic fungi in vitro than by such reference material as triadimefon, due to application of fungicide composition including substituted O-[ω-(azol-1-yl)alkyl]-phenylthiocarbamates I, such as O-(imidazole-1-ylmethyl)-N-(2-methyl-phenyl)thiocarbamates.

EFFECT: efficient suppression of phytopatogenic fungi growth.

4 cl, 5 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of formula I R1 represents phenyl, possibly substituted with phenyl or heterocyclic group, or heterocyclic group, possibly substituted with phenyl, where said heterocyclic group represents mono- or bicyclic ring, containing 4-12 atoms, of which at least one atom is selected from nitrogen, sulfur or oxygen, each phenyl or heterocyclic group possibly being substituted with one or more than one of the following groups: C1-6alkyl group; phenylC1-6alkyl, alkyl, phenyl or alkylphenyl group is possibly substituted with one or more than one from Rb; halogen; -ORa; -OSO2Rd; -SO2Rd; -SORd; -SO2ORa; where Ra represents H, C1-6alkyl group, phenyl or phenylC1-6alkyl group; where R represents halogeno, -OH, -OC1-4alkyl, Ophenyl, -OC1-4alkylphenyl, and Rd represents C1-4alkyl; group -(CH2)m-T-(CH2)n-U-(CH2)p- is bound either in third, or in fourth position in phenyl ring, as shown with figures in formula I, and represents group selected from one or more than one of the following: O(CH2)2, O(CH2)3, NC(O)NR4(CH2)2, CH2S(O2)NR5(CH2)2, CH2N(R6)C(O)CH2, (CH2)2N(R6)C(O)(CH2)2, C(O)NR7CH2, C(O)NR7(CH2)2 and CH2N(R6)C(O)CH2O; V represents O, NR8 or single bond; q represents 1, 2 or 3; W represents O, S or single bond; R2 represents halogeno or C1-4alkoxyl group; r represents 0, 1, 2 or 3; s represents 0; and R6 independently represent H or C1-10alkyl group; R4, R5, R7 and R8 represent hydrogen atom; and to their pharmaceutically acceptable salts.

EFFECT: increase of composition efficiency.

12 cl, 31 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of imidazolyl derivative of the general formula (I) wherein each Ra and Rb represents independently (C1-C6)-alkyl, (C1-C6)-alkoxyalkyl, optionally substituted aryl or heteroaryl, or wherein Ra and Rb form in common additional homocyclic or heterocyclic system comprising one or some rings; each Ra' and Rb' represents hydrogen atom, or they in common form a carbon-carbon double bond wherein indicated carbon-carbon double bond is optionally part of aromatic system; Rc represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkoxyalkyl or halogen atom; Rd represents hydrogen atom or (C1-C4)-alkyl; Re represents hydrogen atom or (C1-C4)-alkyl; m = 1 or 2; R1 represents hydrogen atom or (C1-C4)-alkyl, and its salts after addition of acid and wherein compound of the general formula (II) wherein values Ra, Ra', Rb, and Rb' are given above is subjected for interaction with compound of the formula (III) wherein R represents hydrogen atom, (C1-C4)-alkyl group optionally substituted with hydroxy-group, or optionally substituted aryl group; each R', R'', R''' and R'''' represents independently hydrogen atom or (C1-C4)-alkyl group followed by interaction with compound of the formula (IV) wherein R, Rd and Re have values given above and the following optional interaction with the corresponding acid. Proposed method shows high effectiveness for synthesis of ondansetron and cilansetron.

EFFECT: improved method of synthesis.

10 cl, 10 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for synthesis of 2-imidazolylpropane-2-sulfoacid. Invention describes a method for synthesis of 2-imidazolylpropane-2-sulfoacid that involves dissolving imidazole in a solvent, such as lower alcohols or acetone, bubbling gaseous sulfurous anhydride in its at temperature 200C, not above, for 20-25 min in the mass ratio imidazole : sulfurous anhydride = 1:1 and addition of propanone-2 in the mass ratio imidazole : propanone-2 : water = 1:1:1. Method provides preparing the end product of high purity (99.2-99.8%) with the high yield (89-92%) and to exclude using a solvent prohibited by Pharmacological committee of Russian Federation. Synthesized compound possesses bacteriostatic, immunostimulating, anti-aggregating and de-aggregating activity with respect to platelets and enhancing contracting activity of skeletal muscles.

EFFECT: improved method of synthesis, valuable medicinal properties of compound.

3 ex

FIELD: organic chemistry, fungicides.

SUBSTANCE: invention describes substituted 1-(pyridinyl-2)-2-azolylethanols of the general formula (I): wherein R means hydrogen atom, direct or branched alkyl with 1 to 8 carbon atoms, cycloalkyl with from 3 to 8 carbon atoms; X means nitrogen atom or CH-group. Also, invention relates to a method for synthesis of these compounds and a fungicide composition that contains compound of the formula (I). Invention provides expanding assortment of fungicides for carrying out the effective control of harmful fungi.

EFFECT: valuable fungicide properties of compounds and composition.

5 cl, 1 tbl, 7 ex

FIELD: organic chemistry, medicine, hormones.

SUBSTANCE: invention describes imidazole derivatives of the formula (I) , racemic-diastereomeric mixtures and optical isomers, pharmaceutical salts wherein ---- represents an optional bond; R1 represents hydrogen atom (H), -(CH2)m-C(O)-(CH2)m-Z1, -(CH2)m-Z1; R2 represents hydrogen atom (H), or R1 and R2 are joined with nitrogen atoms to which they are bound forming compounds represented by formulae (Ia), (Ib) or (Ic) wherein R3 represents -(CH2)m-E-(CH2)m-Z2; R4 represents hydrogen atom (H) or -(CH2)m-A1; R5 represents (C1-C12)-alkyl, (C0-C6)-alkyl-C(O)-NH-(CH2)m-Z3 and optionally substituted phenyl; R6 represents hydrogen atom (H); R7 represents (C1-C12)-alkyl or -(CH2)m-Z4; m = 0 or a whole number from 1 to 6; n is a whole number from 1 to 5. Proposed compounds bind with subtypes of somatostatin receptors selectively.

EFFECT: valuable properties of compounds.

20 cl, 13776 ex

FIELD: chemistry.

SUBSTANCE: starting reagent used is benzyl alcohol and the chlorinating agent used is cyanuric chloride, wherein the reaction is carried out in standard conditions in a dichloromethane medium.

EFFECT: method enables to conduct the reaction in normal conditions and obtain the desired benzyl chloride with high output and purity.

1 ex

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