Biologically active substances suppressing pathogenic bacteria, and method for inhibiting type iii secretion in pathogenic bacteria

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to indolyl-substituted derivatives of thiadiazinones prepared from oxamic acid thiohydrazide of general formula: , wherein R represents H; R1 represents pyridinyl; phenyl substituted by alkyl C1-C5, Hal, CF3; R2 represents H; alkyl C1-C5; -CH2COOR4; benzyl substituted by Hal, OR4; benzoyl substituted by Hal, OR4, while R4 represents unsubstituted alkyl C1-C4.

EFFECT: there are prepared new compound which can find application in medicine for developing the therapeutic agent possessing pathogenic bacteria inhibitory activity.

2 cl, 2 dwg, 2 tbl, 13 ex

 

The technical field

The invention relates to indolyl-substituted derivatives thiadiazine obtained on the basis of thiohydrazide examinavi acids of General formula

which can be used to suppress pathogenic bacteria, in particular to influence the system type III secretion from pathogens.

Prior art

According to who, almost 60% of deaths attributed to chronic diseases, which are based on chronic inflammation induced by pathogenic microorganisms. The General trend is the significant reduction of effectiveness used in the clinical practice of antibiotics for chronic infections. At the moment of effective antibiotics, have a pronounced therapeutic effect on chronic infection, on the market of medicinal products does not exist. This is due to the fact that during chronic infection is developed evolutionary adaptation of the pathogen, aimed at long-term survival in the host, including changes in metabolic activity. This reduces the sensitivity of microorganisms to antimicrobial agents effective in the acute stage of infection.

No less urgent is the problem of development of antibiotic resistance to the use of what has been created antibacterial drugs. The formation of microorganisms resistance to antibiotics is associated with a number of negative consequences for individual patients and for society as a whole. When resistance to infectious disease to basic antibiotics dramatically increases the likelihood of failure of empirical treatment of the individual patient. At the same time, it is clear that each specific disease caused by resistant microorganism, is a manifestation of the process of formation and spread of resistance in microbial populations. The situation is compounded by the fact that large pharmaceutical companies have significantly reduced the development of antibiotics as growth of antibiotic resistance limits the ability of the drug and, consequently, reduces the profits from sales.

If you look at the economic side of the issue under consideration, the main motivating factor in the development of new antibacterial drugs is currently the multi-drug resistance. However, the need for drugs to treat chronic and recurrent infections covers a much larger contingent of patients, nedopoluchili need an effective treatment that provides a broad perspective in the field of development and introduction of new medicines.

In connection of the foregoing it is obvious the necessity of choice of other search strategies medicines, based on the detection of a fundamentally new targets in bacterial pathogens.

A detailed study and understanding of the mechanisms of interaction of pathogens with the host organism and identifying the most vulnerable links in the chain of dynamic events manifestations pathogenic potential can be the basis for effective selection of targets for the action of drugs of new generation aimed at the suppression of virulence, the so-called antiviolent medicines. These drugs should have a number of advantages compared with conventional antibiotics. First, the effect on the virulence properties of the pathogen, which are important in the interaction in the system host-pathogen without suppression of viability, provides a basis to predict the absence of selective pressure and the selection of resistant strains of bacteria. Second, drugs that act on specific target pathogenic bacteria will not be toxic to eukaryotic cells and for normal microflora of a man that is a major problem when using antibiotics. Indeed, microbial cells that form the microbiota of healthy individuals outnumber human cells ten times, colonizer various organs and contributing to the realization of many vital processes, the role of the microbiota in the cat is, which only begins to be recognized. Microbiota is a dynamic state, and in violation of its population composition under the action of antibiotics leads to the loss of symbiotic benefits and the development of infections due to opportunistic pathogens.

The leading role in the implementation of the virulence properties of pathogenic bacteria belongs to the system the type III secretion, through which the transport protein virulence factors in the cell of the microorganism. The process is carried out by secretion and export of effector molecules through the membrane into the extracellular space or directly into the cytoplasm of the host cell, which alters its normal physiological state and promotes adhesion, invasion and intracellular multiplication of the pathogen. In addition, through the secretion implemented a range of adaptive mechanisms aimed at long-term survival in the host organism that is associated with their ability to inactivate a protective reaction of the organism.

In the prior art known compounds influencing the virulence properties of pathogenic bacteria. These compounds inhibit the secretory function of some gram-negative bacteria, such as Yersinia pseudotuberculosis, Salmonella enterica, Pseudomonas aeruginosa, pathogenic strains of E. coli, Chlamydia spp, and do not cause the development of resistance to drugs based on them. So with the dynenum include hydrazones, derived from benzoic acid hydrazides and pyridineboronic acids

("Small molecule inhibitors of type III secretion in Yersinia block the Chlamydia pneumoniae infection cycle," FEBS Letters, 581 (2007), 587-595 / low Molecular weight inhibitors of the system the type III secretion of Yersinia block the infectious cycle of Chlamydia pneumoniae;

"Small-Molecule Inhibitors Specifically Targeting Type III Secretion" Infection and Immunity, 2005, p.3104-3114, Vol.73, No.5 / low Molecular weight inhibitors, specifically acting on the system type III secretion;

"A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of Chlamydia trachomatis" PNAS, 26, 2006, vol.103, No. 39, 14566-14571 / low Molecular weight inhibitors of the system the type III secretion inhibit different stages of intracellular developmental cycle of Chlamydia trachomatis).

However, a disadvantage of these compounds is their significant toxicity for eukaryotic cells, which fundamentally limits their opportunities for further development as pharmaceuticals.

Disclosure of inventions

The objective of the invention is to provide compounds that suppress secretion of pathogenic bacteria, which are not toxic to normal microflora and the host cells, reducing the risk of development of resistance.

The technical result is achieved by the preparation of biologically active compounds having a high selective inhibitory activity against athogenic bacteria, including those that cause chronic disease. Thus, the compounds are non-toxic to human and animal cells, they are well soluble in organic solvents, and are characterized by a specific activity under conditions of biological systems effects on pathogenic bacteria and reduce the risk of development of resistance of pathogenic bacteria.

The technical result is ensured by the fact that the claimed biologically active compounds that inhibit pathogenic bacteria represent indolyl-substituted derivatives thiadiazine obtained on the basis of thiohydrazide examinavi acids of General formula

where

R represents H;

R1represents a pyridinyl, phenyl substituted by alkyl of C1-C5, Hal, CF3;

R2represents H, alkyl C1-C5, -CH2COOR4, benzyl, substituted by Hal, OR4, benzoyl, substituted by Hal, OR4and

R4represents an unsubstituted alkyl C1-C4.

The method of inhibition of type III secretion in pathogenic bacteria is exposed to bacteria an effective amount of compounds of the claimed compounds.

System secretion detected in taxonomically distant organisms (pathogenic bacteria) - causative agents of especially dangerous infections, such as Yersinia, Brucella, and pathogens with the socially significant infections, such as Chlamydia, Salmonella, Shigella and other known system of the type III secretion is conservative, it is absolutely necessary for the development of acute infection and chronic infection depends critically on its functioning. Therefore, inhibitors of type III secretion in pathogens will have a directional effect on the mechanisms responsible for the process of chronicity of infection, without affecting the viability of the bacteria, in fact, "obtrusive" pathogen. Unlike antibiotics, the effect of such specific inhibitors will not lead to the development of genetically determined resistance. In addition, the system III secretion is present only in pathogenic bacteria, hence its inhibitors are not toxic to normal human microflora and the host cells, i.e. are characterized by selectivity.

Examples of synthesis of compounds

Substituted thiadiazine calculated on the basis of thiohydrazide examinavi acids of General formula (I), which is produced by interaction of the respective chloracetamide with a pre-prepared solution of elemental sulfur with morpholine and the subsequent interaction monetization with hydrazine hydrate. Thus obtained thiohydrazide condense with the relevant indolylmaleimide, restore the sodium borohydride in methane is Les and cyclist with monochloracetic acid under alkaline catalysis with formation of the corresponding thiadiazine. Substituted thiadiazine based derivative thiohydrazide examinavi acids can be synthesized according to the following scheme:

A General method of obtaining chloracetamide

To a solution of (0.1 mol) of the corresponding aniline in 100 ml of DMF was added at the cooling rate of 8.75 ml (0.11 mol) of chloroacetanilide, ensuring that the temperature did not exceed 20°C. After the addition was stirred at room temperature a solution of 2 more hours. Then the reaction mixture is poured into 600 ml of cold water and the precipitate was filtered. Washed it on the filter with water and dried in the air.

A General method of obtaining thiohydrazide

Preparing a solution of 0.15 mol of elemental sulfur in 50 ml of DMF and was added 0.06 mol of the research. The resulting mixture was stirred for 20-30 minutes and added to it a solution of 0.05 mol of the corresponding chloracetamide in minimum amount of DMF at cooling, ensuring that the temperature did not exceed 15°C. the resulting mixture was stirred 3-6 hours (control by TLC). After the reaction, the reaction mixture was poured into ice water, extracted substance with ethyl acetate, passed the organic layer through a column of silica gel, evaporated on a rotary evaporator, and then the obtained residue was dissolved in a small amount (5-6 ml) and DMF and was added 6 ml (0.12 mol) of hydrazine hydrate and stirred at to matnog temperature for 2 hours. Then poured into water and acidified with diluted hydrochloric acid to pH 7. The precipitate was filtered and dried it on the air.

A General method of obtaining N-indolyl-substituted thiohydrazide

To 10 mmol of the corresponding thiohydrazide examinados acid in 5 ml of methanol was added 11 mmol of the corresponding aldehyde and boiled under stirring for 5 minutes. Cooled the reaction mixture. Under ice cooling (0-5°C) and stirring was added 55 mg (1.5 mmol) sodium borohydride in small portions. The reaction mixture is left for 2 hours under cooling and stirring, then added 25 ml of water and neutralized with diluted hydrochloric acid to neutral environment. The precipitation was filtered and, if necessary, recrystallized from isopropanol.

A General method of obtaining indolyl-substituted thiadiazine

1 mmol of the corresponding N'-indolyl-substituted thiohydrazide examinados acid was added to a solution of 1.2 mmol Chloroacetic (or bromoxynil) acid in 5 ml of isopropanol. Was added to the reaction mixture a catalytic amount of ammonium acetate and boiled for 2-5 hours (monitoring by thin-layer the chromatogram). After the reaction was poured the reaction mixture into 50 ml of water and was extracted substance with ethyl acetate, washed organic layer with water 2×50 ml Then separated the organic layer, sushi is whether its over sodium sulfate and solvent was removed on a rotary evaporator. The residue was recrystallized from the minimum amount of ethanol.

Obtain the original thiohydrazide

N-chloroacetyl-2-aminopyridine (1)

Output: N-chloroacetyl-2-aminopyridine (1) 11.9 g (70%). TPL 140-141°C. NMR1N CDCl3(δ, ppm, J, Hz): 4,20 (s, 2H, CH2Cl); 7,41 was 7.45 (m, 2H, Ar); 8,07-8,11 (m, 2H, arene); 10,31 (s, 1H, NH). Found (%): 49.20, H 4.03, N 16.21. Calculated (%): 49.28, H 4.14, N 16.42. Mass spectrum, m/z: 170.

2 Hydrazino-N-pyridin-2-yl-2-thioxo-ndimethylacetamide (2)

Output: 2-hydrazino-N-pyridin-2-yl-2-thioxo-ndimethylacetamide (2) 1.2 g (60%). TPL 164-165°C. NMR1H DMSOd6(δ, ppm, J, Hz): 7,40-the 7.43 (m, 2H, Ar); 8,07-8,10 (m, 2H, arene); 10,59 (s, 1H, NH). Found (%): 42.76, H 4.01, N 28.44. Calculated (%): at 42.85, H 4.11, N 28.55. Mass spectrum, m/z: 196.

N-chloroacetyl-4-(trifluoromethyl)-aniline (3)

The output of chloracetamide (3) 19 g, 80%. TPL 115-116°C. NMR1H DMSOd6(δ, ppm, J, Hz): 4,20 (s, 2H, Ar-CH2-Cl); 7,07 (d, 2H, arene); 7,21 (d, 2H, arene). Found (%): 45.38, H 2.81, N, 5.96. Calculated (%): 45.49, H 2.97, N, 5.89. Mass spectrum, m/z: 237.

2 Hydrazino-2-thioxo-N-[4-(trifluoromethyl)phenyl]ndimethylacetamide (4)

Output thiohydrazide (4) 6.4 g, 60%. TPL 154-155°C. NMR1H DMSOd6(δ, ppm, J, Hz): was 7.08 (d, 2H, arene); from 7.24 (d, 2H, arene); 10,59 (s, 1H, NH). Found (%): 41.16, H 3.13, N 15.83. Calculated (%): 41.06, N 3.06, N 15.96. Mass spectrum, m/z: 263.

N-chloroacetyl-2,4-diptiranjan (5)

<> The output of chloracetamide (5) 87%. TPL 101-102°C. NMR1H CDCl3(δ, ppm, J, Hz): 4,20 (s, 2H, ArCH2Cl); 7,10-7,25 (m, 2H, Ar); 7,53 (m, 1H, Ar); of 10.25 (s, 1H, Ar-NH-CO). Found (%): at 46.62, H 2.99, N, 6.84. Calculated (%): 46.74, H 2.94, N, 6.81. Mass spectrum, m/z: 205.

2-[Hydrazino(thioxo)-acetylamino]-2,4-diptiranjan (6)

Output: (6) of 8.1 g, 70%. TPL 154-156°C. NMR1N CDCl3(δ, ppm, J, Hz): 7,10-7,26 (m, 2H, Ar); to 7.50 (m, 1H, Ar); 10,30 (s, 1H, Ar-NH-CO). Found (%): 41.40, H 3.18, N 18.25. Calculated (%): at 41.56, H 3.05, N 18.17. Mass spectrum, m/z: 231.

N-chloroacetyl-2-methylaniline (7)

The output of chloracetamide (7) 15.5 g, 85%. TPL 124-126°C. NMR1N CDCl3(δ, ppm, J, Hz): 1,74 (s, 3H, ArCH3); 4,20 (s, 2H, CH2Cl); 7,07 (m, 1H, Ar); 7,21 (m, 1H, Ar); 7,41 (m, 1H, Ar); 7,63 (m, 1H, Ar); 10,57 (s, 1H, Ar-NH-CH2Cl). Found (%): 58.86, H 5.47, N, 7.64. Calculated (%): 58.87, H 5.49, N, 7.63. Mass spectrum, m/z: 183.

2-[Hydrazino(thioxo)-acetylamino]-2-methylaniline (8)

Output thiohydrazide (8) 10.4 g, 60%. TPL 154-157°C. NMR1N CDCl3(δ, ppm, J, Hz): 1,74 (s, 3H,ArCH3); 7,07-to 7.61 (m, 4H, Ar); 10,32 (s, 1H, Ar-NH-CO). Found: 51.41, H 5.53, N 20,40. Calculated: 51.66, H 5.30, N 20.08. Mass spectrum, m/z: 209.

N-chloroacetyl-4-ftoranila (9)

Output (9) 80%. TPL 110-112°C. NMR1H DMSOd6(δ, ppm, J, Hz): 4,20 (s, 2H, ArCH2Cl); 7,21 (m, 2H, Ar); to 7.61 (m, 2H, Ar); of 10.21 (s, 1H, Ar-NH-CO). Found (%): 51.17, H 3.73, N, 7.44. Calculated (%): 51.22, N, N 7.47. Mass spectrum, m/z: 187.

2-[Hydrazino(thioxo)-acetylamino]-4-ftoranila (10)

Exit: (10) 6.4 g, 60%. TPL 154-155°C. NMR1H DMSOd6(δ, ppm, J, Hz): 7,22 (m, 2H, Ar); 7,63 (m, 2H, Ar); 10,17 (s, 1H, Ar-NH-CO). Found (%): 45.01, H 3.85, N 19.80. Calculated (%): 45.06, H 3.78, N, 19.71. Mass spectrum, m/z: 213.

Brief description of figures

Figure 1 shows the most characteristic morphological changes of the intracellular development of chlamydia infection in vitro under the influence of the studied compounds on the example compounds CL-79.

Figure 2. shows the analysis of the specific activity of selected compounds against III transport system of chlamydia.

Examples of execution of the claimed method

Example 1

(CL-79)

2-[2-(1H-indol-3-ylmethyl)hydrazino]-2-thioxo-N-[2-(trifluoromethyl) phenyl] ndimethylacetamide (11)

As starting compounds used thiohydrazide 4 and indole-3-carbaldehyde.

The output of the hydrazide (9) 255 mg, 75%. TPL 238-239°C. NMR1H CDCl3(δ, ppm, J, Hz): 5,32 (s, 1H, -NH-CH2-Indole); 7,07-to 7.77 (m, 8H, Ar); a 7.92 (s, 1H, (C-H) Indole); 10,12 (s, 1H, Ar-NH-CO); 10,92 (s, 1H, N-H) Indole). Found (%): 59.54, H 4.31, N 16.22. Calculated (%): 59.64, H 4.42, N at 16.36. Mass spectrum, m/z: 341.

4-(1H-indol-3-ylmethyl)-5-oxo-N-[2-(trifluoromethyl) phenyl]-5,6-dihydro-4H-1,3,4-thiadiazin-2-carboxamide (CL-79)

Output (CL-79)250 mg, 75%. TPL >250°C. with decomp. NMR1H CDCl3(δ, ppm, J, Hz): was 4.02 (s, 2H, -S-CH2); are 5.36 (s, 1H, -NH-CH2-Indole); 7,07-7,79 (m, 8H, Ar); of 7.90 (s, 1H, (C-H) Indole); 10,10 (s, 1H, Ar-NH-CO); 10,94 (s, 1H, N-H) Indole). Found (%): 59.60, H 4.02, N, 14.60. Calculated (%): 59.68, H 3.95, N, 14.65. Mass spectrum, m/z: 387.

Example 2

(CL-80)

2-(2-{[1-(4-Terbisil)-1H-indol-3-yl]methyl}hydrazino)-2-thioxo-N-[2-(trifluoromethyl)phenyl]ndimethylacetamide (13)

As starting compounds used thiohydrazide 4 and N-(4-terbisil)-indole-3-carbaldehyde.

The output of the hydrazide (13) 269 mg, 60%. TPL 279-280°C. NMR1H CDCl3(δ, ppm, J, Hz): 4,32 (d, 2H, -NH-CH2-Indole); to 4.98 (s, 2H, -NHIndole-CH2-Ar); 5,32 (s, 1H, NH); 6,77-8,18 (m, 13H, Ar); 10,14 (s, 1H, Ar-NH-CO); 10,92 (s, 1H, CS-NH). Found (%): 63.92, H 4.57, N, 12.38. Calculated (%): 63.99, H 4.47, N, 12.44. Mass spectrum, m/z: 449.

4-{[1-(4-Terbisil)-1H-indol-3-yl]methyl}-5-oxo-N-[2-(trifluoromethyl)phenyl]-5,6-dihydro-4H-1,3,4-thiadiazin-2-carboxamide (CL-80)

Output (CL-80) 367 mg, 75%. TPL >250°C. with decomp. NMR1N CDCl3(δ, ppm, J, Hz): of 4.05 (s, 2H, -S-CH2); to 4.98 (s, 2H, -NHIndole-CH2-Ar); are 5.36 (s, 1H, -NH-CH2-Indole); 7,07-7,79 (m, 8H, Ar); of 7.90 (s, 1H, (C-H) Indole); 10,10 (s, 1H, Ar-NH-CO); 10,94 (s, 1H, N-H) Indole). Found (%): 63.60, H 4.19, N 11.37. Calculated (%): 63.66, H 4.11, N 11.42. Mass spectrum, m/z: 489.

Example 3

(CL-81)

2-{2-[(1-Methyl-1H-indol-3-yl)methylene]hydrazine is}-2-thioxo-N-[2-(trifluoromethyl) phenyl] ndimethylacetamide (15)

As starting compounds used thiohydrazide 4 and N-methyl-indole-3-carbaldehyde.

The output of the hydrazide (15) 220 mg, 62%. TPL 253-254°C. NMR1N CDCl3(δ, ppm, J, Hz): 3,61 (s, 3H, CH3); of 4.35 (d, 2H, -NH-CH2-Indole); the 4.90 (s, 2H, -NHIndole-CH2-Ar); 5,33 (s, 1H, NH); 6,79-8,10 (m, N, Ar); 10,12 (s, 1H, Ar-NH-CO); 10,89 (s, 1H, CS-NH). Found (%): 60.61, H 4.85, N 15.66. Calculated (%): at 60.66, H 4.81, N 15.72. Mass spectrum, m/z: 355.

4-[(1-Methyl-1H-indol-3-yl)methyl]-5-oxo-N-[2-(trifluoromethyl) phenyl]-5,6-dihydro-4H-1,3,4-thiadiazin-2-carboxamide (CL-81)

Output (CL-81) 316 mg, 75%. TPL >250°C. with decomp. NMR1N CDCl3(δ, ppm, J, Hz): 3,62 (s, 3H, CH3); as 4.02 (s, 2H, -S-CH2); 5,31 (s, 1H, -NH-CH2-Indole); 6,89-7,71 (m, 8H, Ar); a 7.92 (s, 1H, (C-H) Indole); 10,11 (s, 1H, Ar-NH-CO). Found (%): 60.52, H 4.36, N 14.10. Calculated (%): 60.59, H 4.32, N 14.13. Mass spectrum, m/z: 395.

Example 4

(CL-82)

2-[2-(1H-indol-3-ylmethyl)hydrazino]-N-(2-were)-2-dioxazine (17)

As starting compounds used thiohydrazide 8 and indole-3-carbaldehyde.

The output of the hydrazide (17) 179 mg, 52%. TPL 251-252°C. NMR1H CDCl3(δ, ppm, J, Hz): of 2.23(s, 3H, CH3) 4,34 (d, 2H, -NH-CH2-Indole); 5,32 (s, 1H, NH) 6,79-8,11 (m, N, Ar); 10,11 (s, 1H, Ar-NH-CO); 10,87 (s, 1H, CS-NH). Found (%): 63.74, H 5.39, N 16.50. Calculated (%): 63.88, H 5.36, N 16.55. Mass spectrum, m/z: 337.

4-(1H-indol-3-ilma who yl)-N-(2-were)-5-oxo-5,6-dihydro-4H-1,3,4-thiadiazin-2-carboxamide (CL-82)

Output (CL-82) 324 mg, 86%. TPL >250°C. with decomp. NMR1H CDCl3(δ, ppm, J, Hz): of 2.23 (s, 3H, CH3); 4,08 (s, 2H, -S-CH2); 5,33 (s, 1H, NH); 5,38 (s, 1H, -NH-CH2-Indole); 6,77-8,09 (m, N, Ar); 10,11 (s, 1H, Ar-NH-CO). Found (%): 63.32, H 4.81, N at 14.72. Calculated (%): at 63.47, H 4.79, N 14.80. Mass spectrum, m/z: 377.

Example 5

(CL-83)

2-(2-{[1-(4-Methoxybenzyl)-1H-indol-3-yl]methyl}hydrazino)-2-thioxo-N-[2,4-differenl]ndimethylacetamide (19)

As starting compounds used thiohydrazide 6 and N-(4-methoxybenzyl-indole-3-carbaldehyde.

The output of the hydrazide (19) 388 mg, 81%. TPL 281-282°C. NMR1N CDCl3(6, ppm, J, Hz): a 3.87 (s, 3H, CH3); 4,36 (d, 2H, -NH-CH2-Indole); to 4.87 (s, 2H, -NHIndole-CH2-Ar); and 5.30 (s, 1H, NH); 6,82-8,23 (m, N, Ar); of 10.05 (s, 1H, Ar-NH-CO); 10,84 (s, 1H, CS-NH). Found (%): 62.42, H 4.69, N 11.52. Calculated (%): 62.49, H 4.61, N, 11.66. Mass spectrum, m/z: 479.

4-{[1-(4-Methoxybenzyl)-1H-indol-3-yl]methyl}-5-oxo-N-[2,4-differenl]-5,6-dihydro-4H-1,3,4-thiadiazin-2-carboxamide

Output (CL-83) 436 mg, 86%. TPL >300°C decomp. NMR1N CDCl3(δ, ppm, J, Hz): a 3.87 (s, 3H, CH3); of 4.05 (s, 2H, -S-CH2); a 4.86 (s, 2H, -NHIndole-CH2-Ar); 5,31 (s, 1H, -NH-CH2-Indole); 6,82-8,24 (m, N, Ar); 10,06 (s, 1H, Ar-M/-CO). Found (%): 62.20, H 4.32, N, 10.61. Calculated (%): 62.30, H 4.26, N, 10.76. Mass spectrum, m/z: 519.

Example 6

(CL-84)

2-(2-{[1-(4-Terbisil)-1H-indol-3-yl]methyl}hydrazino)-2-thioxo-N-[4-forfinal]ndimethylacetamide

As starting compounds used thiohydrazide 10 and N-(4-terbisil)-indole-3-carbaldehyde.

The output of the hydrazide (21) 328 mg, 72%. TPL 254-255°C. NMR1N CDCl3(δ, ppm, J, Hz): 4,32 (d, 2H, -NH-CH2-Indole); to 4.98 (s, 2H, -NHIndole-CH2-Ar); 5,32 (s, 1H, NH); 7,13-to 8.20 (m, 13H, Ar); 10,11 (s, 1H, Ar-NH-CO); was 10.82 (s, 1H, CS-NH). Found (%): 63.90, H 4.53, N, 12.40. Calculated (%): 63.99, H 4.47, N, 12.44. Mass spectrum, m/z: 449.

4-{[1-(4-Terbisil)-1H-indol-3-yl]methyl}-5-oxo-N-[4-forfinal]-5,6-dihydro-4H-1,3,4-thiadiazin-2-carboxamide

Output (CL-84) 316 mg, 75%. TPL >250°C. with decomp. NMR1N CDCl3(δ, ppm, J, Hz): of 4.05 (s, 2H, -S-CH2); 4,32 (d, 2H, -NH-CH2-Indole); equal to 4.97 (s, 2H, -NHIndole-CH2-Ar); 7,13 is 8.22 (m, 13H, Ar); 10,13 (s, 1H, Ar-NH-CO). Found (%): at 63.56, H 4.18, N, 11.34. Calculated (%): 63.66, H 4.11, N 11.42. Mass spectrum, m/z: 489.

Example 7

(CL-85)

N-(2,4-Differenl)-2-(2-{[1-(4-perbenzoic)-1H-indol-3-yl]methyl}hydrazino)-2-dioxazine

As starting compounds used thiohydrazide 6 and N-(4-terbisil)-indole-3-carbaldehyde.

The output of the hydrazide (23) 414 mg, 86%. TPL >300°C decomp. NMR1N CDCl3(5, ppm, J, Hz): 4,12 (d, 2H, -NH-CH2-Indole); 5,38 (s, 1H, NH); 6,92-8,32 (m, N, Ar); 10,11 (s, 1H, Ar-NH-CO); 10,98 (s, 1H, CS-NH). Nide what about the (%): 59.61, H 3.59, N 11.52. Calculated (%): 59.75, H 3.55, N, 11.61. Mass spectrum, m/z: 481.

N-(2,4-differenl)-4-{[1-(4-perbenzoic)-1H-indol-3-yl]methyl}-5-oxo-5,6-dihydro-4H-1,3,4-thiadiazin-2-carboxamide

Output (CL-85) 316 mg, 75%. TPL >300°C decomp. NMR1H CDCl3(δ, ppm, J, Hz): was 4.02 (s, 2H, -S-CH2); of 4.45 (d, 2H, -NH-CH2-Indole); 5,38 (s, 1H, NH); 6,92-8,32 (m, N, Ar); 10,11 (s, 1H, Ar-NH-CO). Found (%): 59.70, H 3.31, N, 10.68. Calculated (%): 59.77, H 3.28, N, 10.72. Mass spectrum, m/z: 521.

Example 8

(CL-86)

N-(2,4-differenl)-2-(2-{[1-(4-methoxybenzoyl)-1H-indol-3-yl]methyl}hydrazino)-2-dioxazine

As starting compounds used thiohydrazide 6 and N-(4-perbenzoic)-indole-3-carbaldehyde.

The output of the hydrazide (25) 409 mg, 83%. TPL >300°C decomp. NMR1N CDCl3(δ, ppm, J, Hz): a 4.03 (d, 2H, -NH-CH2-Indole); and 5.30 (s, 1H, NH); 6,98-8,21 (m, N, Ar); to 10.09 (s, 1H, Ar-NH-CO); 10,92 (s, 1H, CS-NH). Found (%): 60.61, H 4.14, N, 11.23. Calculated (%): 60.72, H 4.08, N, 11.33. Mass spectrum, m/z: 493.

N-(2,4-differenl)-4-{[1-(4-methoxybenzoyl)-1H-indol-3-yl]methyl}-5-oxo-5,6-dihydro-4H-1,3,4-thiadiazin-2-carboxamide

Output (CL-86) 442 mg, 83%. TPL >300°C decomp. NMR1H CDCl3(δ, ppm, J, Hz): a 3.87 (s, 3H, CH3); of 4.05 (s, 2H, -S-CH2); a 4.03 (d, 2H, -NH-CH2-Indole); and 5.30 (s, 1H, NH); 6,98-8,21 (m, N, Ar); to 10.09 (s, 1H, Ar-NH-CO); 10,92. Found (%): 60.52, H 3.81, N 10.31. Calculated (%): 60.67, H 377, N 10.48. Mass spectrum, m/z: 533.

Example 9

(CL-87)

Methyl{3-[(2-{2-[(2,4-differenl)amino]-2-oxetanyl}hydrazino)methyl]-1H-indol-1-yl}acetate

As starting compounds used thiohydrazide 6 and methyl-(3-formyl-1H-indol-1-yl)-acetate.

The output of the hydrazide (27) 336 mg, 78%. TPL 247 - 248°C. NMR1H CDCl3(δ, ppm, J, Hz): 3,61 (s, 3H, CH3); to 4.28 (d, 2H, -NH-CH2-Indole); of 4.45 (s, 2H, -NHIndole-CH2-COOMe); are 5.36 (s, 1H, NH); 6,82-of 7.96 (m, 8H, Ar); 10,12 (s, 1H, Ar-NH-CO); 10,78 (s, 1H, CS-NH). Found (%): C 55.42, H 4.25, N, 12.85. Calculated (%): at 55.55, H 4.20, N, 12.96. Mass spectrum, m/z: 431.

Methyl{3-[(2-{[(2,4-differenl)amino]carbonyl}-5-oxo-5,6-dihydro-4H-1,3,4-thiadiazin-4-yl)methyl]-1 H-indol-1-yl}acetate (CL-87)

Output (CL-87) 316 mg, 75%. TPL >250°C. with decomp. NMR1H CDCl3(δ, ppm, J, Hz): 3,62 (s, 3H, CH3); Android 4.04 (s, 2H, -S-CH2); 4,27 (d, 2H, -NH-CH2-Indole); to 4.46 (s, 2H, -NHIndole-CH2-COOMe); 6,80-a 7.92 (m, 8H, Ar); 10,14 (s, 1H, Ar-NH-CO). Found (%): 55.85, H 3.88, N, 11.72. Calculated (%): 55.93, H 3.84, N, 11.86. Mass spectrum, m/z: 471.

Example 10

(CL-88)

2-{2-[(1-Methyl-1H-indol-3-yl)methyl]hydrazino}-N-pyridin-2-yl-2-dioxazine

As starting compounds used thiohydrazide 2 and N-methyl-indole-3-carbaldehyde.

The output of the hydrazide (29) 139 mg, 44%. TPL 279-280°C. NMR1The CDCl 3(δ, ppm, J, Hz): 3,62 (s, 3H, CH3); 4,34 (d, 2H, -NH-CH2-Indole); lower than the 5.37 (s, 1H, NH); 6,67-8,30 (m, N, Ar); 10,27 (s, 1H, Ar-NH-CO); was 10.82 (s, 1H, CS-NH). Found (%): 60.12, H 5.11, N 20.53. Calculated (%): 60.16, H 5.05, N 20.63. Mass spectrum, m/z: 338.

4-[(1-Methyl-1H-indol-3-yl)methyl]-5-oxo-N-pyridin-2-yl-5,6-dihydro-4H-1,3,4-thiadiazin-2-carboxamide (CL-88)

Output (CL-88) 223 mg, 59%. TPL >300°C decomp. NMR1H CDCl3(δ, ppm, J, Hz): 3,62 (s, 3H, CH3); of 4.12 (s, 2H, -S-CH2); of 4.45 (d, 2H, -1H,-CH2-Indole); 6,74-8,32 (m, N, Ar); 10,29 (s, 1H, Ar-NH-CO). Found (%): 60.10, H 4.58, N 18.41. Calculated (%): 60.14, H 4.52, N 18.46. Mass spectrum, m/z: 378.

Biological examples

To determine the toxicity and biological activity of indolyl-substituted derivatives thiadiazine obtained on the basis of thiohydrazide examinavi acids, the following methods were used.

1. Methods for the determination of cytotoxic effect

A) To determine the toxicity against eukaryotic cells used method of staining cells with methylene blue (standard method) with subsequent spectrometric based results. The work was carried out in the format of 96-well plates.

In the daily monolayer of McCoy cells (hybrid line synovial cells of human and murine fibroblasts) was replaced by the cultural medium with fresh medium and were made of different doses of the investigated chemical compounds. Cells which were inkubirovali in 24 hours in CO 2incubator at 37°C. After 24 hours from the wells were collected culture medium and washed cells 0.1 mm solution of phosphate-saline buffer (FSB). The cells were fixed with chilled methanol (20 ml) for 15 min at 4°C. fixed cells were added 40 μl of 0.5% methylene blue, and incubated 20 min at room temperature. After incubation methylene blue were taken from the wells and washed cells FSB 4 times. To the wells were added with 100 μl of 5% sodium dodecyl sulfate (SDS) in the FSB, and incubated for 1 hour at room temperature until complete lysis of the cells. The number of living cells was determined spectrophotometrically at a wavelength of 540 nm on a spectrophotometer MultiscanEX.

B) the Method is intended for determining the metabolic activity of cells the MTT-test (Niks, M., Otto, M. Towards an optimized MTT assay. // J Immunol. 1900. V.130, no. 1, p.149-151)based on the reduction of a colorless salt of tetrazole (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazole bromide, MTT) mitochondrial and cytoplasmic dehydrogenase living metabolically active cells with the formation of blue crystals formazan, the amount of which is measured spectrophotometrically.

The method is conducted in the format of a 96-well culture plate. In the daily monolayer of McCoy cells was replaced by the cultural medium with fresh medium and were made of different doses of the investigated chemical compounds. CL the TCI were incubated for 24 hours in CO 2incubator at 37°C. For 4 hours before the end of the experiment was made 1:10 volume of culture medium 10x solution of MTT (5 mg/ml). Incubated 4 hours at 37°C, 5% CO2. Selected culture medium, washed once FSB. Was added to each well 100 ál of isopropanol (propanol-2). Incubated at room temperature for 30 minutes. Was assessed by optical density at a wavelength of 540 nm on a Multiscan photometer EX. Substrate uptake was assessed at 405 nm.

1. The method of suspension of infection of eukaryotic cells

The method of suspension of infection of eukaryotic cells by chlamydia allows you to standardize the conduct biological experiments in a screening format in 96-well plates. To obtain a cell suspension used daily monolayer of McCoy cells, which were treated with trypsin solution and versene (ratio 1:3 respectively) to release cells from the surface of the bottle. The vial was placed in a thermostat for 5 min Then took the trypsin solution and versene and cells suspended in the cultural medium (RPMI 1640 with 10% fetal serum).

To obtain a monolayer of the prepared cell suspension was made a count of the cells in the cell Goryaeva rate of 1,5x105cells/ml of Infected cell strain Bu-434 Chlamydia trachomatis serovar L2 was made in the ratio of bacteria : cell 1:1 in SCR is the Imam of transport medium (RPMI medium with 5% fetal serum, 25 mm glucose solution, 5 μg/ml amphotericin b and 4 μg/ml gentamicin), which provides 80-90% of the infected cells. The prepared suspension was introduced into the wells of 96 - or 24-well plates in a volume of 100 μl or 1000 μl, respectively. For the deposition of cells and stimulation interact with chlamydia tablets centrifuged at 3000 rpm for 1 hour at 25°C. After that, the tablet was placed in the incubator for 48 h at 37°C.

2. Determination of the influence indolyl-substituted derivatives thiadiazine obtained on the basis of thiohydrazide examinavi acid on the viability of chlamydia

The analyzed chemical compounds in varying concentrations were made in cell culture, simultaneously with the pathogen to assess their impact on the intracellular multiplication of chlamydia. The effect was evaluated by direct immunofluorescence.

Methods immunofluorescence aimed at identifying objects containing a certain antigen, and based on the treatment of the corresponding antibody labeled with a fluorochrome, followed by microscopy in the ultraviolet range.

In this paper, we used the method of direct immunofluorescence (standard method)that allows for a semi-quantitative account of the development of chlamydial infection using monoclonal antibodies to species-specific protein antigen .trachomatis.

The work shall rowdily on cell lines McCoy, infected by the method of suspension of infection VI-434 .trachomatis serovar L2 in the format of 96-well plates or 24-hole with glass. The analyzed chemical compounds were added at various doses directly in infected cells. After 48 h from the wells were collected adosados and fixed cells. When you work with 96-well plates fixation was carried out by ice 72° ethanol with subsequent location of the tablet for 30-40 min at -20°C. When working with 24-hole tablets, the slides were washed in a 0.1 mm solution of the FSB and dried. After that, the cells were fixed with acetone for 15 min at room temperature. Fixed cells were inflicted 30-50 ál of labeled monoclonal FITZ antibodies to protein antigen .trachomatis (Humanskin-2, LLC "NEARMEDIC PLUS"), and incubated for 30 min in a humid chamber at 37°C. After incubation, the cells were washed 2 times with a solution of the FSB. The product is fully dried. In the format of 24-well plates thus prepared glass was mounted on a glass slide using a mounted liquid (glycerin in the FSB). Preparations were examined in a fluorescent microscope.

3. Determination of the influence indolyl-substituted derivatives thiadiazines and obtained on the basis of thiohydrazide examinavi acids on III transport system chlamydia

Assessing the impact of these compounds on II transport system (TSS) of chlamydia was carried out on the basis of detection of translocation of the effector protein IncA .trachomatis on the membrane of intracellular chlamydial inclusions. Protein IncA were detected using the method of indirect immunofluorescence (standard method) using a commercial antibody to the effector protein TTC IncA .trachomatis (polyclonal rabbit serum specific for IncA, "Innovagen, Sweden) followed by detection of anti-rabbit antibodies labeled FITZ.

For this daily monolayer was infected to obtain 80-90% of infected cells, was centrifuged at 3000 rpm for 30 min at 25°C. After 8 h after infection (the start time of the translocation of the effector protein into the membrane of the inclusion) was added to different doses of the investigated chemical compounds. After 24 h from the wells were collected culture medium, the slides were washed in a 0.1 mm solution of the FSB and dried. After that, the cells were fixed with acetone for 15 min at room temperature. Fixed cells were inflicted 50 ál of primary anti-IncA antibodies, and incubated for 30 min at 37°C. Then the slides were washed in this solution FSB and inflicted antibodies labeled FITZ. Incubated for 30 min in a humid chamber at 37°C. After incubation, the glass cells were washed 2 times with a solution of the FSB. The product is fully dried. The thus prepared glass was mounted on a glass slide with the help of Assembly fluids. Preparations were examined in a fluorescent microscope. Both conducted OCD is ska monoclonal antibody to protein MOMR outer membrane of the cell wall, that made it possible to assess the development of chlamydial infection.

Example 11

The influence of compounds of class indolyl-substituted derivatives thiadiazine obtained on the basis of thiohydrazide examinavi acid on the viability of eukaryotic cells

The compounds are characterized by a high degree of solubility in dimethylformamide (DMF), do not form a precipitate during storage and when converting to the transport medium.

Analysis of the toxicity of 10 of the studied compounds and 1 connection, which is the prototype and related hydrazones derived from benzoic acid hydrazides (INP0400), in vitro when added to the environment of the cultivation of eukaryotic cells at doses of 12.5, 25 and 50 μm and subsequent incubation for 24 hours at 37°C, were performed using 1.A and B, showed no negative impact on the viability of eukaryotic cells connections class indolyl-substituted derivatives thiadiazine obtained on the basis of thiohydrazide examinavi acids. The results are presented in table 1.

The lowest cytotoxic effect on the results of the two used tests was shown for compounds CL-79 CL-82. Even with the greatest concentration of 50 μm of these compounds caused no more than 1-5% of cell death and reduced metabolic activity no more than 10-14% to ATOC. The other 8 compounds also showed satisfactory results in cytotoxicity, which testifies to the fact that the selected compounds are of low toxicity. In contrast, a connection-prototype LHC-540 showed strong toxicity for eukaryotic cells, which limits the possibility of its further development as a therapeutic agent and indicates the benefits claimed in this patent compounds.

Example 12

The influence of compounds of class indolyl-substituted derivatives thiadiazine obtained on the basis of thiohydrazide examinavi acids on the development of chlamydial infection

The ability of ten presented in examples 1-10 compounds to inhibit the intracellular life cycle of chlamydia in vitro was evaluated using methods 2-3, the results of which are presented in table 2.

The best effect is exerted connection CL-79, CL-83, CL-88, suppressing the intracellular accumulation of chlamydia at 98-99% at a concentration of 50 μm in terms of adding connections in the transport environment simultaneously with infectious material (strain .trachomatis L2) and subsequent cultivation for 48 hours. It is shown that under these conditions, infected cells in the analyzed monolayer virtually absent.

Connection CL-81, CL-82 and CL-84 enough is effective inhibited the development of chlamydia dose of 50 μm. Analysis of the activity of these compounds at a dose of 50 μm under the same conditions as the experiment has revealed a pronounced decrease in the size of the inclusions and the reduction of their number 88, 85 and 93%. Connection CL-80, CL-85, CL-86 and CL-87 showed inhibitory effect at a concentration of 50 μm, suppressing the development of infection 78, 50, 38, and 48%, respectively.

Figure 1 shows the most characteristic morphological changes of the intracellular development of chlamydia infection in vitro under the influence of the studied compounds on the example compounds CL-79. In the control preparation without addition of compounds observed typical intracellular chlamydial inclusions, corresponding to the period of infection. When the concentration of the compound CL-79 12.5 μm was observed by reducing the number of inclusions in the monolayer. Identify inclusions were significantly smaller when compared to the control drug. When the concentration of the compound 25 μm observed the growth of small inclusions. At a concentration of 50 μm chlamydial inclusions were not detected. Thus, the use of different concentrations of compounds CL-79 showed dose-dependent drug effect of suppressing infection in cell culture.

Example 13

The characteristic action of the compounds of class indolyl-substituted derivatives thiadiazine obtained on the basis of thiohydrazide examinavi acids, is a III transport system chlamydia

Research on the specific activity of indolyl-substituted derivatives thiadiazine obtained on the basis of thiohydrazide examinavi acids in relation to inhibition of the function of the third transport system (TTS) was carried out according to method 4.

When immunochemical detection of effector protein IncA on the surface of chlamydial inclusions in the control preparations revealed inclusions, corresponding in size to the time of infection. In the case of drug action on TTC specific staining should not be detected.

The characteristic action of compounds CL-79, CL-83 and CL-88 on TTC showed that making these connections after 8 hours after infection inhibited the translocation of the effector protein IncA.

Another test for the specificity of the compounds in respect of TTC is that translatively using TTC chlamydial protein IncA involved in the process of merging individual developing inside the cell inclusions. At colouring of infected cells by antibodies to the protein of MOMS in the format of the experiment: infected - 8 hours making connections - incubation up to 24 hours from the moment of infection in the control cells was observed coarse inclusions, one in each cell, and in the case of the connections on the TTC - a few small nalivshihsya inclusions in the cytoplasm of the cell.

Specific inhibitory TTC effect was showing the n for compounds CL-79, CL-83 and CL-88. Figure 2 shows typical for these compounds suppress the translocation of the effector protein IncA C.trachomatis on the example of activity of a compound CL-79. In the control drug in the color of antibodies to protein MOMR observed typical inclusions, corresponding in size of 30 hours of infection. In case you make 50 μm compound CL-79 8 hours after infection and subsequent cultivation for 22 hours in the monolayer was observed by small and medium-sized inclusions, several in the same cage. When stained with antibodies to the protein of the IncA in the control drug was also revealed typical inclusions, and in the case of chemical compounds inclusions were not detected.

Tests indicate that biologically active compounds, indolyl-substituted derivatives thiadiazine obtained on the basis of thiohydrazide examinavi acids, show a specific activity against TTC .trachomatis, inhibiting the process of translocation of the effector protein IncA and preventing process genotyping merge primary inclusions. The compounds inhibit system type III secretion in pathogenic bacteria, reducing the risk of development of resistance to drugs in the selection of resistant mutants, as well as providing directional effect on the mechanisms responsible for the process of chronicity and the burden.

Examples of synthesis, and biological examples confirm the industrial applicability of the claimed invention.

The above leads to the conclusion that the technical problem solved.

1. Biologically active compounds that inhibit pathogenic bacteria, which represents an indolyl-substituted derivatives thiadiazine obtained on the basis of thiohydrazide examinavi acids of General formula

where R represents H;
R1represents pyridinyl; phenyl substituted by alkyl of C1-C5, Hal, CF3;
R2represents H; alkyl C1-C5; -CH2COOR ____ 4; benzyl, substituted by Hal, OR4; benzoyl, substituted by Hal, OR4and
R4represents an unsubstituted alkyl C1-C4.

2. The method of inhibition of type III secretion in pathogenic bacteria, is the impact on bacteria an effective amount of a compound according to claim 1.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel heterocyclic nitrogen- and oxygen-containing compounds having insecticidal activity. In formulae (A) (B) (C) (D) R1 is a 5- or 6-member heterocyclic ring containing a nitrogen, oxygen and/ or sulphur atom, a halogen-substituted 5- or 6-member heterocyclic ring containing a nitrogen, oxygen and/or sulphur atom, a substituted or unsubstituted phenyl, where the substitutes are one or more groups selected from a group consisting of halogen atoms, C1-4 halogen alkyl or C1-4 chloroalkoxyl; R5, R6, R7, R8 and R9 are H, saturated or unsaturated C1-4 alkyl, halogen atom, saturated or unsaturated C1-4 alkoxyl, saturated C1-4 halogenalkoxyl, C1-4 alkylcarbonyl, C1-8 alkyl ester, C1-4 alkylsulphonyl, phenyl, benzyl or trifluoromethane sulphonyl ether group; Y is nitro, cyano, trifluoromethyl, trifluoroacetyl or trifluoromethylsuphonyl. Values of radicals R, R2-R4 are given in the claim.

EFFECT: invention also relates to an agrochemical composition containing said compounds, use of the agrochemical composition in pest control and a method of producing said compounds.

12 cl, 7 tbl, 36 ex

Azole compounds // 2493154

FIELD: chemistry.

SUBSTANCE: invention relates to compounds which are pyridin-3-yl 4-(3-phenyl-1H-1,2,4-triazol-5-yl)piperidine-1-carboxylate, 6-methylpyridin-3-yl 4-[3-(4-fluoromethyl)-1H-1,2,4-triazol-5-yl]piperidine-1-carboxylate, 6-methylpyridin-3-yl 4-[5-(4-fluorophenyl)-1,3-oxazol-2-yl]piperidine-1-carboxylate, 2,6-dimethylpyridin-3-yl 4-[5-(3,4-difluorophenyl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxylate, 2-methylpyridin-3-yl 4-[3-(2-fluorophenyl)-1H-1,2,4-triazol-5-yl]piperidine-1-carboxylate, 6-methylpyridin-3-yl 4-(3-phenyl-1H-pyrazol-1-yl)piperidine-1-carboxylate, 2-methylpyridin-3-yl 4-[5-(3-fluorophenyl)-1,3-oxazol-2-yl]piperidine-1-carboxylate and 6-methylpyridin-3-yl 4-[4-(4-fluorophenyl)-1,3-oxazol-2-yl]piperidine-1-carboxylate or to a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on said compounds, having inhibiting effect on fatty acid amide hydrolase (FAAH).

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine for treating neuropathic pain.

13 cl, 38 tbl, 159 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound, which is N3-1H-indol-5-yl-5-pyridin-4-ylpyrazine-2,3-diamine, or a pharmaceutically acceptable salt thereof, which can act as inhibitors of protein kinase, especially FLT3 tyrosine kinase. The invention also relates to a pharmaceutical composition which contains said compound in combination with another molecularly directed (target) agent, which is a traditional cytotoxic agent or a compound used after chemotherapy, supporting therapy targeted on stem cells and in case of MLL rearrangement acute lymphoblastic leukaemia in children.

EFFECT: obtaining a novel compound which can be used in medicine for preventing or treating haematological malignant growths such as AML, MLL, T-ALL, B-ALL and CMML, myeloproliferative diseases, autoimmune diseases and skin diseases, such as psoriasis and atopic dermatitis.

16 cl, 2 tbl, 26 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to antibacterial compounds of formula (I) , where one or two of U, V, W and X represent N, the remaining ones represent CH or, in case X, can also represent CRa, where Ra represents fluorine; R1 represents alcoxygroup, halogen or cyanogroup; R2 represents H, CH2OH, CH2N3, CH2NH2, alkylcarbonylaminomethyl or triazol-1-ylmethyl; R3 represents H or, when n=1, R3 can also represent OH, NH2, NHCOR6 or triazol-1-yl; A represents CR4; K represents O, NH, OCH2, NHCO, NHCH2; CH2NH5 CH2CH2, CH=CH, CHOHCHOH or CHR5; R3 represents H or together with R5 forms bond, or R4 can also represent OH, when K is not O, NH, OCH2 or NHCO; R5 represents OH or together with R4 forms bond; R6 represents alkyl; m=0 or 1 and n=0 or 1; and G is specified in i.1 of the formula; and to salt of such compound.

EFFECT: obtaining antibacterial compounds.

19 cl, 1 tbl, 44 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel pyridine derivatives pyridine1-A-pyridine2 of formula (1), where pyridine1 represents

, , or , ,

where asterisks stand for bond, which contains pyridine1 ring with A; R1 represents C1-5alkyl, C1-4alkoxygroup, C3-6-cycloalkyl, hydroxymethyl or NR1aR1b, R1a represents C1-4alkyl; R1b represents hydrogen or C1-3alkyl; or R1a and R1b, together with nitrogen atom, which is bound to pyridine, form pyrrolidine ring; R2 represents hydrogen or C1-4alkyl, or in case, when R1 represents C1-5alkyl or C3-6-cycloalkyl, R2 can additionally represent methoxygroup; R3 represents C1-4alkyl, C1-4alkoxygroup, C3-6-cycloalkyl or NR3aR3b; R3a represents C1-4alkyl; R3b represents hydrogen or C1-3alkyl; R4 represents C1-4alkyl or hydrogen; R5 represents C1-5alkyl, methoxygroup or NR5aR5b; and R6 represents C1-2alkyl; R5a represents C1-4alkyl; R5 represents hydrogen or C1-3alkyl; or R5 represents C1-2alkyl or methoxygroup; and R6 represents C1-5alkyl or NR6aR6b; R6a represents C1-4alkyl; R6b represents hydrogen or C1-3alkyl; R7 represents C1-5alkyl; R8 represents C1-2alkyl or methoxygroup; R9 represents C1-5alkyl; R10 represents C1-2alkyl; A represents

, , or ,

where asterisks stand for bond, binding pyridine1 ring with A; pyridine2 represents

, , or , ,

where asterisks stand for bond, which binds pyridine ring with A; R11 represents C1-4alkyl; C1-3alkyloxy group, hydroxymethyl or NR11aR11b; R,1a represents C1-3alkyl; R11b represents hydrogen or C1-2alkyl; R12 represents hydrogen or C1-4alkyl; R13 represents C1-4alkyl or NR13aR13b; R13a represents C1-4alkyl; R13b represents hydrogen or C1-2alkyl; R14 represents C1-2alkyl; R15 represents C1-4alkyl or NR15aR15b; and R16 represents C1-2alkyl; R15a represents C1-3alkyl; R15b represents hydrogen or C1-3alkyl; or R15 represents C1-2alkyl; and R16 represents C1-4alkyl or NR16aR16b; R16a represents C1-3alkyl; R16b represents hydrogen or C1-2alkyl; R17 represents C1-4alkyl; R18 represents C1-2alkyl or methoxygroup; R19 represents C1-4alkyl; and R20 represents C1-2alkyl; with exception of 3-(2-ethyl-4-pyridyl)-5-(2-ethyl-4-pyridyl)-1,2,4-oxadiazole; or pharmaceutically acceptable salt of such compound.

EFFECT: obtaining pyridine derivatives, which possess agonistic activity with respect to S1P1/EDG1.

15 cl, 2 tbl, 131 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are novel aminitriazole derivatives of formula (I), where A is phenyl, heterocyclyl or propan-1,3-diyl; E is *-C1-4alkyl-O-, -CH=CH- or , where asterisks stand for bond, through which binding with R1; Q- O or S occurs; R3 is hydrogen, C1-4alkyl, cyclopropyl, C1-4alkoxy-C1-4alkyl, benzyl or -CH2CH2C(O)O-tert-Bu; R1 is pyridyl or phenyl, possibly substituted with halogen, C1-4alkyl, C1-4alkoxy, C1-4fluoroalkyl, C1-4fluoroalkoxy, di-( C1-3alkyl)amino or C1-4alkoxy-C1-2alkyl; and R2 is -CO-C1-3alkyl,-CF2-C1-3alkyl or -SO2-C1-3alkyl; or their pharmaceutically acceptable salts, pharmaceutical composition, which contains them.

EFFECT: obtaining novel compounds for treatment of inflammatory disease or Alzheimer's disease.

20 cl, 105 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula 1:

or pharmaceutically acceptable salts thereof, where values of Cy1; Cy2; L1; L2, R; R1; Rx and Ry and R2 are given in claim 1.

EFFECT: compounds are suitable for use as Raf protein kinase inhibitors.

36 cl, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to polymorphous form of compound

,

which is characterised by picture of X-ray diffraction, including discriminatory peaks approximately 7.269, 9.120, 11.038, 13.704, 14.481, 15.483, 15.870, 16.718, 17.087, 17.473, 18.224, 19.248, 19.441, 19.940, 20.441, 21.469, 21.750, 22.111, 23.319, 23.763, 24.120, 24.681, 25.754, 26.777, 28.975, 29.609, 30.073 degree 2Θ. Invention also relates to method of obtaining polymorphous form of compound (IX), which includes processing of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-ylthiazol-2-ylamino)phenyl]benzamide with methanesulfonic acid at temperature from 20 to 80°C in solvent, selected from group, which includes methanol, ethanol, acetone, diethyl ether, dioxane and their mixtures.

EFFECT: obtaining polymorphous form of compound (IX), which remains dry at 80% relative humidity and thermodynamically stable at temperatures lower than 200°C.

7 cl, 3 dwg, 4 ex

Organic compounds // 2491285

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein V is specified in -O- or a single bond; W is specified in -N(R5)C(O)-, -S(O)t- and -C(O)O-; X is specified in C(H) or N; Y is specified in S, N(H) or N(CH3); p means 0 or 2; t means 1 or 2; R1 is specified in a group consisting of hydrogen, C1-6alkyl optionally substituted by 1 or 2 halogroups, C3-7cycloalkylC1-6alkyl, 2,3-dihydro-1H-indenyl, C6arC1-6alkyl optionally substituted by one or two halogroups and heteroarylC1-6alkyl, wherein a heteroaryl fragment of the heteroarylalkyl group means 5-6-member monocyclic heteroaryl containing 1 or 2 heteroatoms independently specified in a group consisting of nitrogen optionally oxidated, oxygen and sulphur, or a heteroaryl fragment of the heteroarylalkyl group means 9-member bicyclic heteroaryl containing 1 or 2 heteroatoms independently specified in a group consisting of nitrogen, oxygen and sulphur, wherein monocyclic heteroaryl of the heteroarylalkyl group may be optionally substituted by one or two substitutes independently specified in a group consisting a halogroup, a cyanogroup, C1-6alkyl, haloC1-6alkyl and C1-6alkyl-O-C(O)-; R2 is specified in a group consisting of hydrogen, C1-6alkyl optionally substituted by phenoxy, hydroxy C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl, phenyl optionally substituted by a halogroup, haloC1-6alkyl, C6arC1-6alkyl (optionally substituted by a halogroup, haloC1-6alkyl or haloC1-6alkoxygroup), 2-oxo-imidazolidinyl, heterocyclylC1-6alkyl and heteroarylC1-6alkyl, wherein heterocyclyl of heterocyclylalkyl means 5- or 6-member monocycle containing oxygen, and wherein a heteroaryl fragment of the heteroarylalkyl group means 5-6-member monocycle containing 1-3 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, or a heteroaryl fragment of the heteroarylalkyl group means 9- or 10-member bicycle containing 1 to 2 heteroatoms specified in a group consisting of nitrogen and sulphur, wherein monocyclic heteroaryl of the heteroaryl alkyl group may be optionally substituted by 1 or 2 substitutes independently specified in a group consisting of a halogroup, C1-6alkyl, haloC1-6alkyl and phenyl optionally substituted by a halogroup; R3 is specified in a group consisting of hydrogen and alkyl; two adjacent R4 groups together with carbon atoms whereto attached can form phenyl; R5 means hydrogen; or a pharmaceutically acceptable salt thereof.

EFFECT: preparing the heterocyclic derivatives which modulate activity of stearoyl CoA desaturase, methods of using the above derivatives for modulating activity of stearoyl CoA desaturase and pharmaceutical compositions containing the above derivatives.

26 cl, 1 tbl, 153 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a 2H-chromen compound or a derivative thereof having action of a S1P1 agonist. The above may be used for preventing and/or treating a disease caused by undesired lymphocyte filtration, or a disease caused by abnormal cell proliferation or accumulation.

EFFECT: preparing the compounds for preventing and/or treating the disease caused by undesired lymphocyte filtration, or the disease caused by abnormal cell proliferation or accumulation.

8 cl, 131 tbl, 156 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are novel aminitriazole derivatives of formula (I), where A is phenyl, heterocyclyl or propan-1,3-diyl; E is *-C1-4alkyl-O-, -CH=CH- or , where asterisks stand for bond, through which binding with R1; Q- O or S occurs; R3 is hydrogen, C1-4alkyl, cyclopropyl, C1-4alkoxy-C1-4alkyl, benzyl or -CH2CH2C(O)O-tert-Bu; R1 is pyridyl or phenyl, possibly substituted with halogen, C1-4alkyl, C1-4alkoxy, C1-4fluoroalkyl, C1-4fluoroalkoxy, di-( C1-3alkyl)amino or C1-4alkoxy-C1-2alkyl; and R2 is -CO-C1-3alkyl,-CF2-C1-3alkyl or -SO2-C1-3alkyl; or their pharmaceutically acceptable salts, pharmaceutical composition, which contains them.

EFFECT: obtaining novel compounds for treatment of inflammatory disease or Alzheimer's disease.

20 cl, 105 ex, 1 tbl

FIELD: biotechnologies.

SUBSTANCE: invention relates to derivatives of aminopyrazol with the formula of , where A, E, R1 and R2 have values specified in the invention claims, and to their pharmaceutically acceptable salts. Compounds of the formula (I) are agonists of the ALX receptor. Besides, the invention relates to a pharmaceutical composition on the basis of the compound of the formula (I) or its pharmaceutically acceptable salt and to application of these compounds for production of a medicinal agent for prevention or treatment of a disease selected from inflammatory diseases, wheezing diseases, allergic states, HIV-mediated retrovirus infections, cardiovascular diseases, neuroinflammations, neurological disorders, pain, prion-mediated diseases and amiloid-mediated diseases; and for modulation of immune responses.

EFFECT: higher efficiency of compound application.

23 cl, 1 tbl, 466 ex

Amide compound // 2479576

FIELD: chemistry.

SUBSTANCE: compounds exhibit antagonistic activity towards the EP4 receptor, which enables use thereof as an active ingredient in a pharmaceutical composition for treating chronic kidney disease or diabetic nephropathy.

EFFECT: high efficiency of the compounds.

27 cl, 228 tbl, 86 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to a method of producing α,ω-bis-(1,5,3-dithiazepinan-3-yl)-alkanes of general formula (1):

n=1-8, which involves reaction of α,ω-alkanediamines of general formula H2N-CH2-(CH2)n-NH2, where n=1-8, with tert-N-butyl-1,5,3-dithiazepinane in chloroform in the presence of a SmCl3·6H2O catalyst with molar ratio α,ω-alkanediamine:tert-N-butyl-1,5,3-dithiazepinane:SmCl3·6H2O = 10:20:(0.3-0.7) at room temperature (about 20°C) for 2.5-3.5 hours.

EFFECT: method of obtaining novel α,ω-bis-(1,5,3-dithiazepinan-3-yl)-alkanes which can be used as antibacterial, antifungual and antiviral agents, as biologically active complexing agents, selective sorbents and extractants of precious metals, special reagents for inhibiting bacterial activity in different process media (from light industry to oil industry).

1 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 3-aza-bicyclo[3.3.0]octane derivatives of formula , where R1 and R2 are hydrogen, C1-4alkyl or fluorine; R3 is a phenyl which is unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, trifluoromethyl, trifluoromethoxy group and halogen; 2,3-dihydrobenzofuranyl; 2,3-dihydrobenzo[1,4]dioxynyl; or isoxazolyl, pyridyl, indazolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, pyrrolo[2,1b]thiazolyl, imidazo[ 1,2-a]pyridinyl or imidazo[2,1-b]thiazolyl, where said groups are unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, halogen and trifluoromethyl; A is or ; R4 is C1-4alkyl or -NR6R7; R6 is hydrogen or C1-4alkyl; R7 is hydrogen or C1-4alkyl; and D is a phenyl which is unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, trifluoromethyl and halogen; or a pharmaceutically acceptable salt of such a compound. 3-aza-bicyclo[3.3.0]octane derivatives or a pharmaceutically acceptable salt thereof are used as a medicinal agent having the activity of orexin receptor antagonists.

EFFECT: novel 3-aza-bicyclo[3,3,0]octane derivatives as nonpeptide antagonists of human orexin receptors.

9 cl, 1 tbl, 85 ex

FIELD: chemistry.

SUBSTANCE: invention relates phenyl pyrrole derivatives formula (I) where: A denotes =NOR4, O; R4 denotes, C1-C6 alkyl; R1 denotes C1-C6 alkyl, C1-C6 alkoxy, halogen-C1-C6 alkyl, halogen-C1-C6 alkoxy, NH2, mono- C1-C6 alkylamino, halogen-mono-C1-C6 alkylamino, di(C1-C6 alkyl)amino, halogen-di-(C1-C6 alkyl)amino; or A and R1 together with the carbon atom with which they are bonded form a 5- or 6-member heterocyclic aromatic group or a heterocyclic group with partially or completely reduced saturation, which can be benzo-condensed, can contain 1-3 heteroatoms selected from N, O and S, which can be substituted and contain 1 or 2 α substitutes; R2 denotes phenyl which can be substituted with 1 or 2 α substitutes, or a 6-member heteroaryl group containing 1 or 2 N atoms, which can be substituted with 1 or 2 α substitutes; R3 denotes OH, C1-C6 alkoxy, values of α are given in claim 1, or a pharmaceutically acceptable salt thereof.

EFFECT: compounds exhibit glucokinase activating activity, which enables use thereof in treating diabetes.

51 cl, 1 tbl, 132 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining α,ω-bis-(1,5,3-dithiazepinan-3-yl)-alkanes, which can be applied as antibacterial, antifungal and antiviral agents, as biologically active complexing agents, selective sorbents and extractants of precious metals, special reagents for suppression of vital activity of bacteria in various technical media (from light industry to oil). Essence of method lies in interaction of α,ω-alkanediamine with 1,3,6-oxadithiapinane in presence of catalyst SmCl3·6H2O with mole ratio α,ω-alkanediamine : 1,3,6-oxadithiapinane : SmCl3·6H2O=10:20:(0.3-0.7) at temperature ~20°C and atmospheric pressure for 2.5-3.5 h. Output of α,ω-bis-(1,5,3-dithiazepinan-3-yl)-alkanes (1) constitutes 72-85%.

EFFECT: increase of compound application efficiency.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula or a pharmaceutically acceptable salt thereof, in which R1 denotes hydrogen or C1-6alkyl; R2 denotes isooxazolyl group, substituted with C1-6alkyl; RB denotes -CF3, -CHF2, -CH2F, or C1-6alkyl. The invention also relates to pharmaceutical compositions for treating cancer which contain the disclosed compounds.

EFFECT: obtaining novel compounds and a pharmaceutical compositions based on said compounds, which can be used in medicine for treating cancerous diseases.

15 cl, 77 dwg, 10 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new substituted heteroaryl derivatives of general formula I: , wherein: A means N, CR7-10, with A at the most twice meaning N; W means O, S or NR4, the values B, C, R7-10 are presented in clause 1 of the patent claim. The method for preparing the compound I is described.

EFFECT: compounds show analgesic activity that enables using them for a variety of diseases, especially acute pain, neuropathic, chronic or inflammatory pain.

16 cl, 2 tbl, 307 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I),

, where groups and radicals R1, R2 independently denote H, C1-8-alkyl or C3-7-cycloalkyl, where the alkyl or cycloalkyl group can be mono- or poly-substituted with identical or different groups R11; or R2 denotes a -CH2- or -CH2-CH2- bridge which is bonded with a group Y, and R1 is as defined above, or denotes a group selected from C1-4-alkyl-CO-, C1-4-alkyl-O-CO-, (C1-4-alkyl)NH-CO- or (C1-4-alkyl)2N-CO-, where the alkyl groups can be mono- or polyfluorinated; or R1 and R2 form an alkylene bridge such that R1R2N- denotes a group selected from: azetidine, pyrrolidine, piperdine, azepan, 2,5-dihydro-1H-pyrrole, 1,2,3,6-tetrahydropyridine, 2,3,4,7-tetrahydro-1H-azepine, 2,3,6,7-tetrahydro-1H-azepine, piperazine, in which the free amino group is substituted with R13, piperidin-4-one, morpholine, thiomorpholine, 4-C1-4-alkoxy iminopiperidin-1-yl and 4-hydroxy iminopiperidin-1-yl. Wherein, when R1 and R2 form an alkylene bridge, one or more H atoms in the alkylene bridge can be substituted with identical or different groups R14, and X denotes a C1-3-alkylene bridge which can contain one, two or three identical or different C1-3-alkyl substitutes; and Y denotes a group of subformula selected from: and , where the group can be mono-substituted with a substitute R20; Z denotes -CH2-CH2- or -C(=O)-CH2-; U, V both denote CH, one of groups U, V denotes N, and the other of U, V denotes CH, where CH can be substituted with L; and L independently denotes halogen, cyano or C1-3-alkyl; and k equals 0, 1 or 2; W is selected from a group consisting of -CH2-O- and -O-CH2-; B is selected from a group consisting of phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thiophenyl and thiazolyl; each of which can be mono- or poly-substituted with identical or different substitutes R20; radicals R11, R13, R14, R20 assume values given in claim 1. The invention also relates to a pharmaceutical composition containing at least one compound of formula I and having action on MCH receptor.

EFFECT: disclosed pharmaceutical compositions are useful in treating metabolic disorders or eating disorders, especially obesity, bulimia, anorexia, hyperphagia and diabetes.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents an antibacterial composition of chitosan and a gel former, containing polyvinyl alcohol, and/or glycerol, and/or polyethylene glycol and/or polyvinyl pyrrolidone, differing by the fact that the antibacterial agent is presented by low-molecular water-soluble chitosan of molecular weight 3.5 to 4.9 kDa in the amount of 0.01 to 10 wt %; the gel former is polyvinyl alcohol 2 to 15 wt %, and/or glycerol 10 to 90 wt %, and/or polyethylene glycol 1 to 20 wt %, and/or polyvinyl pyrrolidone 10 to 50 wt %; water is the rest.

EFFECT: invention provides high solubility and antibacterial activity of chitosan in the wide range of the medium acidity.

5 ex, 4 tbl, 3 dwg

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