Phosphorus-containing fluorinated 1,4-naphthoquinone derivatives, possessing cytotoxic activity with respect to human cancer cells in culture

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel fluorinated 1,4-naphthoquinone derivatives of general formula , where 1 R=C6H5, X=F; 2 R=2, 5-F2C6H3, X=F; 3 R=CH3, X=F; 4 R=C6H5, X, , possessing cytotoxic activity with respect to cancer cells, which can be applied in medicine.

EFFECT: claimed are novel compounds with anti-cancer activity for therapy of malignant neoplasms.

1 dwg, 3 tbl, 5 ex

 

The invention relates to the field of organic chemistry and molecular biology, namely, fluorinated derivatives of 1,4-naphthoquinone, containing phosphorus, the General formula (I):

possessing cytotoxic activity towards cancer cells in culture.

Mammalian cells typically use the reversible phosphorylation of tyrosine residues in proteins to transmit an extracellular signal to an intracellular target. With this in mind, the violation of mediators of signal transduction through phosphorylation of proteins, such as kinases and phosphatases, is associated with the development of a large number of human diseases, including cancers. It is known that Cdc25A and Cd25B phosphatase important for controlling cell cycle and activate cyclin-dependent kinases, which play an important role in the regulation of cell proliferation. Cdc25A and Cd25B phosphatase person possess oncogenic properties and hyperexpression in various cancerous human cells. With this in mind, they are of interest as targets for anticancer drugs [R. Boutros, Dosier S., Ducommun C. Curr. Opin. Cell. Biol. 2006. V. 18, P. 185; Kristjansdottir K, Rudolf J. J. Chem. Biol., 2004. V. 11. P. 1043].

Depending on the structures of various compounds, including inhibitors of Cdc25 phosphatases may be polyfunctional and interact not only with the main target, but other to monentary cells, and also to show the General cytotoxicity, to be mutagens, carcinogens, or to be protective and antioxidant properties. In addition, they may vary in their ability to penetrate into various organs, tissues, cells, cellular organelles (mitochondria, nucleus). In this regard, it is obvious that one of the promising directions of development of cancer treatment is the development of new compounds exhibiting high activity at minimal concentrations in relation to the main target, but with a low total cyto - and genotoxicity. Another advantage of some anticancer drugs may be their ability not only to suppress the growth of cancer cells, but also in parallel to serve as antioxidants that inhibit oxidative stress, which is believed to be one of the main ways the emergence of cancer cells.

Among the large number of different investigated compounds only certain naphthoquinone derivatives [J. W. Eckstein Invest. New. Drugs. 2000. V. 18, p. 149; Pesttell K. E., Ducruet, A. P., P. Wipf, et al. Oncogene., 2002. V. 19. P. 6607], and especially the naphthoquinone NSC 95397 from the National Cancer Institute library [J. S. Lazo, K. Nemoto, Pestell K. E. et al., Mol. Pharmacol., 2002. V. 61. P. 720] possess the ability to effectively inhibit Cdc25A phosphatase.

It was shown that the pair-naftochinona, 7-aminoquinoline-5,8-quinone and substituted isoquinoline-5,8-quinones are core structures for the synthesis of potential is effective inhibitors of Cdc25 phosphatases; an example of such derivative is a compound DA3003-1 [J. S. Lazo, K. Nemoto, Pestell K. E. et al., Mol. Pharmacol., 2002. V. 61. R. 720; Wipf, P., Joo C., Nguyen T., Lazo, J. S. Org. Biol. Chem., 2004, V. 2. P. 2173].

It is known that derivatives of quinone inactivate Cdc25B phosphatase or Michael's reaction, either by oxidation of catalytically important residue cysteine [Brisson M., Nguyen T., P. Wipf, et al, Mol. Pharmocol., 2005. V. 68. P. 1810-1820].

It is known that certain substituted derivatives of the quinoline-5,8-quinone on the provisions of the C(2) C(3) C(4) are effective inhibitors of Cdc25B phosphatase and growth of cancer cells [J. Cossy, Belotti D., Brisson M., et al. Bioorg. Med. Chem., 2006. V. 14. P. 6283-6287].

Crustal structure of the para-quinone part 14 is widely used in the clinic drugs and seems to be fundamental for the synthesis of new potential inhibitors of enzymes that are targets in anticancer therapy [J. Cossy, Belotti D., Brisson M., et al. Bioorg. Med. Chem., 2006. V. 14. P. 6283-6287].

Recently received a number of fluorinated derivatives of 1,4-naphthoquinone containing amino acid fragments of General formula (II):

,

possessing cytotoxic activity towards cancer cells in culture (patent RU 2443678 C1, 27.02.2012).

In addition, the above fluorinated derivatives of 1,4-naphthoquinone General formula (III):

where: 1) R1=NHC(CH3)3, R2,R 3=F; 2) R1=NHCH2CH2SCH3, R2, R3=F; 3) R1=N(CH2CH3)2, R2, R3=F; 4) R1=N(CH2CH2)2O, R2, R3=F; 5) R1=NHCH2CH2CH2CH3, R2, R3=F; 6) R1=NHC6H5, R2, R3=F; 7) R1=N(CH3)CH2CH2OH, R2, R3=F; 8) R1, R3=NHCH2CH2CH2CH3, R2=F; 9) R1=N(CH2CH2OH)2, R2, R3=F; 10) R1=NHC6H5, R2=CH3, R3=F; 11) R1=Co3, R2, R3=F; 12) R1=NH(CH2)2SS(CH2)2HN(2-pendaftar-1,4-naphtohinone), R2, R3=F; 13) R1=NHC2H5, R2, R3=F; 14) R1=N+C5H5, R2=O-, R3=F; 15) R1=NHCH2CH2OH, R2, R3=F; 16) R1, R2=Co3, R3=F possessing cytotoxic activity towards cancer cells in culture. These compounds are produced by interaction of hexamer-1,4-naphthoquinone or 2-methylpentane-1,4-naphthoquinone (compound 10) with nitrogen - and kislorodoterapii nucleophiles (patent RU 2387635 C2, 27.04.2010).

Compounds with the General formulas (II) and (III) less susceptible to reactions with the formation of toxic for cells radical PR is svodnik in the processes of oxidative stress.

Not described in literature examples of naftochinona containing phosphorus atoms. At the same time, such compounds may have other activities in comparison with the previously described polyfluorinated naphtohinone.

Closest to the claimed phosphorus-containing fluorinated derivatives of 1,4-naphthoquinone prototype is tetrafluorobenzyl 2-(2-mercaptoethanol)-3-methyl-5,6,7,8-titrator-1,4-naphthoquinone (fluorinated-Cpd 5), which has a higher activity in suppressing the growth of Hep3B cells than the original Cpd 5 (W. H. Ham et al., 2004, Bioorg. Med. Chem. Lett., 2004, V. 14. P. 4103-4105). Fluorinated Cpd 5 was obtained by the reaction of 2-methyl-3,5,6,7,8-pendaftar-1,4-naphthoquinone and 2-mercaptoethanol.

The disadvantages of the known fluorinated Cpd 5 connection is its high toxicity, because it contains sulfur atoms - thiol groups, which are easily oxidized (exposed to oxidative stress) with the formation of toxic radicals.

An object of the invention is the creation of a phosphorus-containing fluorinated derivatives of 1,4-naphthoquinone with cytotoxic activity against cancer cells in culture, as well as less prone to reactions with the formation of toxic for the cells of radical intermediates in the processes of oxidative stress.

This object is achieved by the proposed phosphorus is terashima fluorinated derivatives of 1,4-naphthoquinone General formula (I), where:

The proposed connection is produced by interaction of hexamer-1,4-naphthoquinone (1-3) triphenylphosphane (1), (2,5-differenl)diphenylphosphane (2), methyldiphenylphosphine (3), or quinone I (1) with pyrocatechin (4) and characterized using methods of mass spectroscopy high-resolution NMR spectra1H and19F.

The phosphorus-containing naftochinona may be more promising compounds for targeted suppression of the development of cancer cells that synthesize high amounts of oncogenic protein kinases and phosphatases; they have a noticeable antioxidant properties.

Table 1 shows the inventive phosphorus-containing fluorinated derivatives of 1,4-naphthoquinone and their structural formulas. The masses of the molecular ions are presented in table 2.

The invention is illustrated by the following specific examples of receipt of the proposed connections.

Example 1.

Getting 5,6,7,8-titrator-1,4-dioxo-3-(triphenylphosphane)-1,4-dihydro-2-naphtholate (1).

The mixture 0,048 g (0,180 mmol) sexafter-1,4-naphthoquinone, 0.05 g (0,187 mmol) of triphenylphosphane and 0.75 ml of methanol was stirred 48 h at room temperature. The precipitate was separated by centrifuge, washed with methanol (2×0.5 ml), was dried under vacuum (0.5 mm RT.CT.) and received 0,048 g (53%) of compound 1. After crystallization dry the th residue from ethanol was given 0,034 g of the product. The total yield amounted to 0,082 g (90%) of bright yellow crystals which decompose when heated without melting.

Example 2.

Obtaining 3-((2,5-differenl)diphenylphosphane)-5,6,7,8-titrator-1,4-dioxo-1,4-dihydro-2-naphtholato (2).

The mixture 0,076 g (0,285 mmol) sexafter-1,4-naphthoquinone, of 0.085 g (0,285 mmol) of (2,5-differenl)diphenylphosphane and 1.3 ml of methanol was stirred 48 h at room temperature. The precipitate was separated by centrifuge, washed with methanol (2×0.2 ml) and dried under vacuum (0.5 mm RT.CT.) and received 0,096 g (62%) of compound 2, bright yellow crystals which decompose when heated without melting.

Example 3.

Getting 5,6,7,8-titrator-3-(methyldiphenylphosphine)-1,4-dioxo-1,4-dihydro-2-naphtholate (3).

The mixture 0,100 g (0,376 mmol) sexafter-1,4-naphthoquinone, 0.075 g (0,376 mmol) of diphenylmethylphosphine and 1.5 ml of methanol was stirred 48 h at room temperature. The solvent is kept off, the residue was led from ethanol (1 ml) and purified by TLC (Sorbfil, chloroform, RF0.2). Received 0.05 g (30%) of compound 3, bright yellow crystals, so pl. 179°C.

Example 4.

Getting 6,11-debtor-7,10-dioxo-9-(triphenylphosphane)-7,10-dihydrobenzo[b]dibenzo[b,e][1,4]dioxin-8-olate (4).

A mixture of 0.05 g (0.101 mmol) of betaine 1, 0.011 g (0.101 mmol) of pyrocatechin, 0.028 g (0.203 mmol) of potassium carbonate and 1.5 ml of DMSO was stirred 6 h at room temperature. Was added water (3 ml), the precipitate was separated by centrifuge, washed and water and dried in the air. By TLC (Sorbfil, chloroform-methylene chloride, 1:1; RF0.2) identified 0.048 g (83%) of compound 4, bright yellow crystals which decompose when heated without melting.

Example 5.

Conducted testing of the impact of the compounds on the growth of different lines of cancer cells in culture. Cell adenocarcinoma human breast MCF-7 were grown in IMDM medium, myeloma cells human (line RPMI 6228) were grown by using RPMI 1640 with 40 µg/ml gentamycin and in the presence of 10% fetal bovine serum production company "Bilat" in an atmosphere with 5% CO2in 96-well plates.

To compare the relative activity of all compounds in the same conditions they were dissolved in DMSO at high concentrations (10 mg/ml), and then the stock solution was diluted in DMSO to obtain a series of solutions with the desired concentration. When using cell adenocarcinoma of the breast after the formation of 50-70% of the monolayer in culture medium was added investigational drugs phosphorus-containing fluorinated derivatives of 1,4-naphthoquinone (volume of added reagents was 1 / 100th of the total volume of culture medium, the amount of DMSO was 1% of final volume) and watched the growth of cell cultures for 3 days.

When using a cell line of human myeloma, which is a suspension culture of cells and subcultured in 96-well plate in an amount of 100 μl per well, the concentration of 2×105cells/ml; after 12-24 hours added investigational drugs phosphorus-containing fluorinated derivatives of 1,4-naphthoquinone (volume of added reagents was 1 / 100th of the total volume of culture medium, the amount of DMSO was 1% of the final volume of the mixture in the hole).

The effect of phosphorus-containing fluorinated derivatives of 1,4-naphthoquinone cells MCF-7 and RPMI 6228 in culture and the suppression of their growth was performed using a test based on the ability of mitochondrial dehydrogenase to convert water-soluble 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) formazan (MTT-test), which crystallizes inside the cell. As nonviable cells enzymes are not functioning and there are no cofactors of this transformation, they are not stained with MTT. The precipitate of formazan in viable cells was dissolved in isopropanol and its quantity was determined spectrophotometrically by absorption at the wavelength of λ=560 nm.

As a positive control used cells that were grown in the absence of phosphorus-containing fluorinated derivatives of 1,4-naphthoquinone. It was found that DMSO used in concentration (1%) significant effect on the growth of cancer cells has not. In addition, it was found that the compounds do not affect the color of the cells in MT the test, if they added in the wells with the cells immediately before the test. To evaluate the relative activity of all proposed phosphorus-containing compounds in suppressing the growth of cancer cells were investigated according to the number of living cells on the concentration of these compounds. As an example in Fig.1 shows inhibition of growth of RPMI 6228 cells for the four investigated compounds. The concentration of compounds (C50), in which there is suppression (inhibition) of cell growth by half (50%), was performed using the MTT-test. In Fig.1 shows the data for connection 1 (5,6,7,8-titrator-1,4-dioxo-3-(triphenylphosphane)-1,4-dihydro-2-naphtalate), compound 2 (3-(2,5-differenl)diphenylphosphane)-5,6,7,8-titrator-1,4-dioxo-1,4-dihydro-2-naphtalate), compound 3 (5,6,7,8-titrator-3-(methyldiphenylphosphine)-1,4-dioxo-1,4-dihydro-2-naphtalate) and connections 4 (6,11-debtor-7,10-dioxo-9-(triphenylphosphane)-7,10-dihydrobenzo[b]dibenzo[b,e][1,4]dioxin-8-Alat). The number of live cells in control (incubation of cells without compounds) were taken as 100%.

Using such curves was determined by the concentration (C50), in which there is suppression (inhibition) of cell growth by half. Data on the impact of the claimed compounds (inhibition of 50%, C50) on the growth of cancer cells of human myeloma (RPMI 6228) and adanac is rcinoma human (MCF-7), as well as control cells (murine fibroblast line LMTK after incubation for 48 h, which are given in table.3.

As seen from table 3 that the compounds inhibit the growth of cancer cells myeloma (RPMI 6228) and human adenocarcinoma (MCF-7) in culture at concentrations of 3,4-50,3 μm. Three phosphorus-containing fluorinated derivatives of 1,4-naphthoquinone (compounds 1-3) shows the close values of C50(3,4-7,7 mm) in the case of two types of cancer cells (RPMI 6228 and MCF-7), while compound 4 inhibited the growth of these cells at higher concentrations (40-50,3 μm). All compounds exhibit inhibition of cell line RPMI 6228 at lower concentrations (3,4-40,0 μm) than MCF-7 (5,2-a 50.5 μm) cells (PL.3).

From table.3 also shows that the suppression of cell growth by 50% using compounds 1-4 occurs at concentrations of 1.4-3.8 times lower than that of fibroblast cells. In addition, these compounds exhibit antioxidant properties.

Thus, the proposed new phosphorus-containing fluorinated derivatives of 1,4-naphthoquinone are effective inhibitors of the growth of cancer cells and are potentially promising for their use in cancer therapy.

Table 1
1 5,6,7,8-Titrator-1,4-dioxo-3-(triphenylphosphane)-1,4-dihydro-2-naphtalate
23-((2,5-Differenl)diphenylphosphane)-5,6,7,8-titrator-1,4-dioxo-1,4-dihydro-2-naphtalate
35,6,7,8-Titrator-3-(methyldiphenylphosphine)-1,4-dioxo-1,4-dihydro-2-naphtalate
46,11-Debtor-7,10-dioxo-9-(triphenylphosphane)-7,10-dihydrobenzo[b]dibenzo[b,e][1,4]dioxin-8-OST
Table 2.
15,6,7,8-Titrator-1,4-dioxo-3-(triphenylphosphane)-1,4-dihydro-2-naphtalateFound [M]+506.0685. C28F4H15O3P. The Calculated M 506.0690.
23-((2,5-Differenl)diphenylphosphane)-5,6,7,8-titrator-1,4-dioxo-1,4-dihydro-2-naphtalateFound [M]+542.0490. C28F6H13O3P. The Calculated M 542.0501.
35,6,7,8-Titrator-3-(methyldiphenylphosphine)-1,4-dioxo-1,4-dihydro-2-naphtalateFound [M]+444.0535. C23F4H13O3P. The Calculated M 444.0533.
46,11-Debtor-7,10-dioxo-9-(triphenylphosphane)-7,10-dihydrobenzo[b]-dibenzo[b,e][1,4]-dioxin-8-OSTFound [M+H]+577.1310. C34F2H19O5P. The Calculated M+H 577.1011.

Table 3.
The type of cells
The connection number
The value of C50, mcmRelationship With50for LMTK and cancer cells
RPMI 6228MCF-7LMTK
13,4±0,35,2±0,512,8±1,02,5-3,8
23,7±0,37,9±0,712,9±1,11,6-3,5
34,8±0,47,7±0,6 11,0±1,0of 1.4-2.3
440±3,550,3±5,080,0±7,31,6-2,0

Phosphorus-containing fluorinated derivatives of 1,4-naphthoquinone General formula (I):

possessing cytotoxic activity towards cancer cells in culture.



 

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wherein A1 represents N or C (A2); A2 represents H, F, Cl or CN; B1 represents H, OR1, SO2R1, NHR1, NHC(O)R1, F or Cl; D1 and E1 represents H or Cl; Y1 represents H, CN, NO2, F, Cl, Br, CF3, R17, OR17, SO2R17 or C(O)NH2; or Y1 and B1 together with atoms to which they are attached, represent 5- or 6-merous heteroarene having 2-3 nitrogen atoms, wherein heteroarene rings are unsubstituted or substituted by (O); G1 represents H; Z1 represents uncondensed phenylene substituted by OR41; R41 represents 6-merous heteroaryl having 1 N atom, wherein heteroaryl is condensed with R43A, R43A represents 5-merous heteroarene having 1 N atom; Z2 represents monocyclic 6-merous heterocycloalkylene having 1-2 N atoms and 0 double bonds; Z1A and Z2A are both absent; L1 represents -CH2-; Z3 represents R38 or R40; R38 represents uncondensed phenyl; R40 represents cycloalkyl, wherein cycloalkyl represents a monocyclic ring system having 3 to10 C atoms and 0 double bonds, cycloalkenyl, wherein cycloalkenyl represents monocyclic 6-merous ring having 1 heteroatom specified in a group consisting of O and N, and 1 double bond, wherein cycloalkenyl is uncondensed or condensed with R40A; R40A represents cycloalkane, wherein cycloalkane represents a monocyclic ring having 3-10 C atoms and 0 double bonds, or heterocycloalkane, wherein heterocycloalkane represents monocyclic 6-merous ring having 1 N atom and 0 double bonds (the rest substitutes are those as specified in cl. 1 of the patent claim). The invention also refers to compounds of formula

and a pharmaceutical composition containing an effective amount of the compound of formula (I) or (II) or its pharmaceutically acceptable salt.

EFFECT: compounds of formula (I) or (II) inhibiting the activity of anti-apoptotic Bcl-2 proteins.

6 cl, 5 tbl, 378 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of general formula [1] or their pharmaceutically acceptable salts, which possess properties of an inhibitor of the JAK2 thyrokinase activity. In general formula radicals are selected from group (I) or (II). In group (I) X represents CH or N; R1 represents a halogen atom and R2 represents H, a halogen atom, CN, or is selected from the groups of formulas

,

or a group -ORP or 5-6-membered heteroaryl, containing 1-4 nitrogen atoms and optionally additionally containing an oxygen or sulphur atom or containing an oxygen atom as a heteroatom, optionally substituted; or (II) X represents -CRA; and RA represents a group of formula , RB represents (a) amino, optionally substituted with one or two groups, selected from the group, consisting of C1-6alkyl, C3-6cycloalkyl, (C3-6cycloalkyl)C1-6alkyl and C1-3alcoxyC1-3alkyl, (b) C1-3alcoxy, (c) hydroxy or (d) a 5-6-membered saturated cyclic amino group, which additionally can contain a heteroatom, selected from an oxygen atom; R1 represents a halogen atom and R2 represents H; R3 -R5 have values given above. Other values of the radicals are given in the invention formula.

EFFECT: compounds can be applied for the prevention or treatment of cancer, for instance hematologic cancer disease or a solid form of cancer, inflammatory disorder, for instance, rheumatoid arthritis, inflammatory intestinal disease, osteoporosis or multiple sclerosis and angiopathy, for instance, pulmonary hypertension, arteriosclerosis, aneurism or varicose veins.

14 cl, 19 tbl, 234 ex

FIELD: medicine, pharmaceitics.

SUBSTANCE: invention relates to particular derivatives of N-(phenylsulphonyl)benzamide, given in i.1 of the invention formula. The invention also relates to a pharmaceutical composition, possessing an inhibiting activity with respect to anti-apoptotic proteins Bcl-2, containing an effective quantity of one of the said compounds or a therapeutically acceptable salt of such a compound.

EFFECT: N-(phenylsulphonyl)benzamide derivatives as inhibitors of the anti-apoptotic proteins Bcl-2.

2 cl, 2 tbl, 458 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the field of cosmetology. Described is a stable and safe antioxidant composition, which can be applied daily. In particular, described is the antioxidant composition, which contains one or more compounds, selected from the group, which consists of D-aspartic acid, its derivatives and/or its salts. The composition can be applied with the purpose of suppressing and/or relief of a skin condition. Conditions of skin can include, but are not limited by them, small wrinkles, rough skin, dry skin, skin cancer, skin allergy, skin inflammation, and light-sensitive dermatosis. The composition can be applied as a medication for the external application on the skin.

EFFECT: invention ensures an increase of the antioxidant effect of the composition.

4 cl, 5 dwg, 31 ex

FIELD: chemistry.

SUBSTANCE: claimed is method of obtaining photosensibiliser, which consists in the following: 3-pyridylcarboxaldehide is condensed with pyrrole in mixture propionic acid-propionic anhydride with their ratio 3-4:1-2 in boiling for 80-100 min. product of condensation is reduced with p-toluenesulfonylhydrazide in pyridine medium in presence of potassium carbonate with its 30-35-fold excess and 5-10% quinoline at temperature 85-95°C for 4-5 hours. After that, obtained product is N-methylated in dimethylformamide in boiling for 50-65 min, precipitated with benzene, filtered and dried. Also claimed is photosensibiliser, obtained in accordance with claimed method, which contains 5,10,15,20-tetrakis(N-methyl-3'-pyridyl)chlorine in quantity 15-25% and 5,10,15,20-tetrakis(N-methyl-3'-pyrydyl)bacteriochlorine in quantity 75-85%.

EFFECT: increase of target product output, reduction of tumour growth rate and dissemination, prevention of tumout tissue necrotisation, complete and uniform saturation of tumour tissue with medication.

3 cl, 1 dwg, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine and represents a method of treating hematologic malignant diseases, which includes the introduction to a subject of a therapeutically effective quantity of an Aurora kinase inhibitor simultaneously or successively with an anti-CD20 antibody, where the Aurora kinase inhibitor represents 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido [5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid or its pharmaceutically acceptable salt and where the anti-CD20 antibody represents rituximab.

EFFECT: invention provides more efficient treatment in comparison with monotherapy.

8 cl, 4 ex, 27 tbl

FIELD: biotechnology.

SUBSTANCE: invention relates to 6-oximes of 16α, 17α- cyclohexanepregnenes of general formula I , where X+Y together form O or X=H, Y=OH; R=H or CH3.

EFFECT: compounds have cytotoxic activity and can find application for treatment of malignant tumours.

3 cl, 3 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: in general formula

A represents optionally substituted aminocarbonyl group -N-C(O)-, in which amino group can be substituted and substituents can be selected from hydrogen, C1-C5alkyl, possibly substituted with C1-C3alkoxy, C3-C6cycloalkyl, 5-6-membered heteroaryl, in which heteroatoms are selected from oxygen or nitrogen; aryl, selected from phenyl, possibly substituted with hydroxy, C1-C5alkyl, C1-C5alkoxy, halogen, C1-C5acylamino group, or naphthyl; or amino group is selected from C3-C7heterocyclyl, containing 1-2 heteroatoms in cycle, selected from nitrogen, oxygen or sulphur, possibly substituted with hydroxy, C1-C3alkyl, benzyl, phenyl, which can be substituted with halogen, and said heterocyclyl can be condensed with benzene ring; acylamino group, in which acyl is selected from C1-C6alkylcarbonyl, where alkyl can be substituted with phenyl, substituted with phenyl, in which substituents are selected from C1-C5alkoxy; 5-membered heteroaryl with heteroatom, selected from atom of oxygen or sulphur; benzoyl, possibly substituted with C1-C5alkyl, C1-C5alkoxy, C1-C5alkylthio or halogen, methylenedioxy; heterocyclylcarbonyl, in which heterocyclyl is selected from 5-6-membered heterocyclyl, with 1-2 heteroatoms, selected from nitrogen, oxygen or sulphur, possibly condensed with benzene ring and possibly substituted with C1-C5alkyl, halogen; or ureido group, in which one of substituents of terminal amido group represents hydrogen, and the second substituent is selected from: C1-C3alkyl, substituted with phenyl, 5-membered saturated or aromatic heterocyclyl, in which heteroatoms are selected from oxygen or sulphur; C2-C6alkenyl; aryl, selected from phenyl, substituted with C1-C5alkyl, C1-C5alkoxy, ethylenedioxy, methylenedioxy, halogen, C1-C3alkylcarbonyl; 5-membered heterocyclyl, in which heteroatoms are selected from sulphur or oxygen atom, and possibly substituted with alkyloxycarbonyl group; B represents non-aromatic cyclic substituent, selected from C4-C6cycloalkyl; and has other values, given in the invention formula. Values R1a R1b R1c are given in the invention formula.

EFFECT: increased efficiency of application of compounds.

12 cl, 8 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, anti-cancer therapy, and concerns a method of treating lymphoma specified in diffuse large B-cell lymphoma, marginal zone lymphoma and nodular sclerosis Hodgkin lymphoma by means of an organic derivative of arsenic, such as darinaparsin (S-dimethylarsinoglutathione, SGLU-1):

or its pharmaceutically acceptable salt. The administration is performed once a day for five days every four weeks in a dose of 200-420 mg/m2, in particular intravenously. The invention also concerns using the above compound or its pharmaceutically acceptable salt for preparing the respective drug and pharmaceutical compositions.

EFFECT: group of inventions provides the effective treatment of the above group of diseases with similar or higher activity or lower toxicity as compared to arsenic oxide.

8 cl, 11 ex

FIELD: food industry.

SUBSTANCE: sea-buckthorns seeds based biologically active additive production method envisages seeds sprouting in a wet condition at a temperature of 13-18°C during 12-14 days, drying till moisture content is equal to 14% and milling.

EFFECT: method simplification and cheapening, the additive biological value enhancement, expansion of the range of preventive purpose products and the ready product organoleptic characteristics improvement.

2 tbl, 3 ex

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