Application of triindolyl methane derivatives as anticancer drugs

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine and concerns triindolyl methane derivatives of formula

and as anticancer drugs showing cytotoxic, apoptotic action on tumour cells, and also blocking NFkB transcription factor activity.

EFFECT: compounds exhibit high anticancer activity.

4 dwg, 3 tbl, 4 ex

 

The invention relates to medicine, in particular to cancer, and with derivative triandayllidou as anticancer agents with cytotoxic, apoptotic effect on tumor cells and block the activity of transcriptional factor NFkB.

Currently, the main methods of cancer treatment remains surgical and chemotherapy. The effectiveness of cancer treatment, especially in patients with III-IV stage disease, low. There is a need to develop new highly effective anticancer drugs original action with low toxicity. Currently conducting active research in the field of creation of new highly effective anti-tumor agents, especially the so-called "targeted" drugs that block specific protein targets in tumor cells, the use of which may reduce cancer mortality and improve quality of life. Drug resistance of the tumor to traditional chemotherapy drugs may occur when the inhibition of the start of programmed cell death - apoptosis. Development of a novel class of antitumor substances, reducing the sensitivity of tumor cells to induction of apoptosis, or search for other targets for which upucka cell death are relevant approaches.

Close to the claimed substances on the mechanism of action are triphenylmethane (TRMA) - derived triphenylarsine acid, which significantly reduces the level of active nuclear factor NFkB, causes inhibition of melanoma cells in the G1phase of the cell cycle and apoptosis. TRMA little toxic for cells in the bone marrow of healthy donors, and high doses are well tolerated when administered to mice (Robin S. Dothager, Karson S. Putt, Brittany J. Allen, Benjamin J. Leslie, Vitaliy Nesterenko, and Paul J. Hergenrother. // Synthesis and Identification of Small Molecules that Potently Induce Apoptosis in Melanoma Cells through G1 Cell Cycle Arrest J. Am. Chem. Soc, 2005, 127, 8686-8696). The disadvantage of TRMA is their low activity.

The closest to the claimed substances on the structure are their full structural analogues derivatives trihalomethanes formulas I and II as antimicrobial and antifungal agents (patent RU 2388749).

The present invention is to evaluate the possibility of using derivatives triandayllidou as anticancer agents.

With this purpose it is proposed the use of derivatives triandayllidou corresponding to formulas I and II with the specified radicals as anticancer agents.

where R1; R7; R13are independently hydrogen, alkyl, substituted alkyl, ar is l, heteroaryl;

R2; R8; R14are independently hydrogen, alkyl, substituted alkyl. The provision and quantity of any substituents can vary. Any of the substituents may in turn be substituted;

R3-R6; R9-R12; R15-R18are independently hydrogen, alkyl, substituted alkyl, aryl, halogen, -OH, -OR, where R is an alkyl or substituted alkyl. The provision and quantity of any substituents can vary. Any of the substituents may in turn be substituted;

Y-represents the anion of any pharmaceutically acceptable organic or inorganic acids;

R19represents hydrogen or alkyl.

The above formula include any stereoisomers - enantiomers or diastereoisomers (individual, racemates, enriched in one of the forms etc.) if the existence of such possible.

The above formula include any aggregate state of these compounds, including amorphous form, crystalline form, solvate.

The above formula include any pharmaceutically acceptable salt forms of the above, if the existence of such possible.

"Pharmaceutically acceptable salt" is a salt that is safe is generated in biological or other respects, non-toxic and acceptable in veterinary medicine and in the pharmaceutical industry and have the necessary pharmacological activity of the parent compound. Pharmaceutically acceptable salts are salts of inorganic acids such as hydrochloric acid, Hydrobromic acid, itestosterone acid, sulfuric acid, nitric acid, phosphoric acid, etc. or salts of organic acids such as formic, acetic, propionic, benzoic, benzolsulfonat, toluensulfonate, econsultancy, methansulfonate, camphorsulfonate, succinic, fumaric, maleic, lactic, malic, almond, tartaric, citric, gluconic, glucuronic, glycolic, salicylic, trimethyllysine, etc. Assumes that all pharmaceutically acceptable salts include solvate or crystalline form of the specified salt

"Solvate" - solvated form, containing stoichiometric or non-stoichiometric amount of solvent.

In table 1 and table 2 shows examples of the biological activity of substances derived triandayllidou corresponding to formulas I and II.

Inhibition of growth of tumor cells is an indicator of antitumor activity, is widely used to describe the antitumor properties of new drugs. Cytotoxic activity of the joint is tested on a panel of cell lines of human tumors of different histogenesis (Example 1, Table. 1, Figure 1). The maximum inhibition of tumor growth was observed for cell lines of metastatic melanoma Mel Kor. It is shown that cell death cell line Jurkat under the action of the compounds occurs by apoptosis (Example 2, Table. 2, Figure 2). Assessment of apoptosis was performed by immunofluorescence method by staining of Jurkat cells dye Annexin V-FITC after 48 hours incubation of the cells with the compounds under evaluation on a flow cytometer. One of the mechanisms of action derived triandayllidou on tumor cells is blocking level activation of NFkB protein (Example 3, Fig 3). Shown anticancer activity of derivatives of triandayllidou in B6D2F1 mice with transplantable melanoma B16 (Example 4, Figure 4).

Example 1. Cytotoxic effect of derivative triandayllidou on cell lines of human tumors in vitro

Antitumor activity of compounds was evaluated on seven cell lines of human tumors using MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) test. In the study we used the following cell lines of human tumors: NST (rectal cancer); C (erythromelalgia leukemia); Jurkat (T-cell lymphoblastic leukemia); mel Kor (disseminated melanoma of the skin); SKOV-3 (ovarian cancer); MCF-7 (breast cancer) and SK-BR-3 (breast cancer). Soy is inane were tested in the concentration range from 10 μm to 1 nm.

Tumor cells in an amount of 105-106cells/ml were introduced into the wells of flat-bottomed 96-well plate in a medium RPMI-1640 containing 10% fetal serum, 2 mm glutamine. After 24 hours, the wells were added to the claimed substances in various concentrations. As control was used tumor cells, to which was added a solvent. Incubation with the preparation was carried out 48 hours, then MTT was added at a final concentration of 0.5 mg/ml Cells were incubated for 4 hours, then the medium was collected and cells were dissolved in DMSO. The optical density (OD) was evaluated on the analyzer BioTek ELx808 at 520 nm using DMSO as the zero control. The studies were repeated at least 3 times.

The cytotoxic effect of substances in various concentrations expressed in number of viable cells relative to control (%). The number of viable cells was determined as [(OD of treated cells)/(OD of untreated cells)]×100. Defined parameter cytotoxic action of the drug - IC50(inhibitory dose, which blocks the viability of 50% of the cells).

Cytotoxic effect of compounds on cell lines of human cancers (colorectal cancer NST; erythromelalgia leukemia K; T-cell lymphoblastic leukemia Jurkat; disseminated melanoma skin Mel Kor; ovarian cancer SKOV-3 and breast cancer MCF-7 and SK-BR-3) CR is dostavleno values IC 50(expressed in micromol) of some compounds of the invention (Table 1). Figure 1 shows the typical survival curves of tumor cells lines under the influence of various concentrations of the drugs on the example of the inventive substances LCTA 1575.

From the data presented in table 1 and figure 1 shows that the claimed compounds have a meaningful and accurate antitumor activity against various cell lines of human cancers in the concentration range from 10 to 0.01 μm. The highest cytotoxic activity of substances show LCTA 1574, LCTA 1578, LCTA 1950, LCTA 1589, for them IC50is the dose range from 0.1 to 0.01 μm. Derivatives triandayllidou corresponding to formulas I and II have a higher antitumor activity against tumor cells of melanoma line Mel Kor.

Example 2. Apoptotic activity of derivatives of triandayllidou in vitro

Testing was performed on cell lines of T-cell leukemia Jurkat. The cells were cultured in medium RPMI 1640 containing 10% fetal bovine serum, 2 mm glutamine, antibiotics (100 IU/mL penicillin and 100 mg/ml streptomycin).

Assessment of apoptosis was performed by staining for Annexin V using the test set FITC Annexin V Apoptosis Detection kit (BD Pharmingen).

The Jurkat cells in the amount of 1.25×105cells/ml were introduced into the wells of flat-bottomed what about the 96-well plate in a medium RPMI-1640, containing 10% fetal serum, 2 mm glutamine, and incubated with the substances within 48 hours. Cells were washed in cold phosphate-buffered saline (FSB) and was added to the cells in 100 μl of Annexin V-binding buffer. Added 5 μl of Annexin V and 5 μl of propedy iodide and incubated for 15 minutes at room temperature in the dark. Fluorescent activity of the cells was determined using flow cytometer Becton Dickenson FacsCallibur at 525 nm (green channel, FL1, Annexin V) and 675 nm (red channel, FL2, propedy iodide). Analyzed at least 10 thousand cells. The studies were repeated at least 3 times.

Apoptotic activity of derivatives of triandayllidou expressed in the number of apoptotic cells relative to the total number of cells in the sample (in %). The number of apoptotic cells was determined as [(number of cells stained with Annexin V)/(total number of cells)]×100.

The claimed substances induce apoptotic cell death line T-cell lymphoblastic leukemia Jurkat depending on the dose of the substance (Table 2). From the presented data in Table 2 shows that the majority of substances in a concentration of 1 μm significantly increased the number of apoptotic cells. High apoptotic activity are substances LCTA 1574, LCTA 1575, LCTA 1340, LCTA 1950. Figure 2 presents a typical dotplot painted on the Annexation V CL the current line Jurkat under the influence of substances LCTA 1575 (0.1 ám) (A - control Jurkat cells without treatment substance; B) Jurkat cells after 48 hours incubation with LCTA 1575 (0.1 ám)). There was an increase in the number of cells stained with Annexin V compared to control.

Example 3. The inhibition activity of NFkB protein under the action of the derivative triandayllidou in vitro

Protein NFkB regulates the expression of various genes (including some of the many proto-oncogenes, involved in inhibition of apoptosis, enhancement of the survival of the cells and their proliferative activity, stimulation of angiogenesis and metastasis is the major processes involved in the development and progression of tumors. Activated NFkB translocases to the nucleus and initiates the transcription of various genes, including anti-apoptotic. Protein NFkB is a promising target for the actions of modern anticancer drugs targeted mechanism of action.

A study of the effect of the claimed compounds in recitations concentration on the level of the activated subunit of NFkB p65. Evaluation of the inhibition activity of NFkB protein was performed using fluorescent immunocytochemical method for the incubation with the primary antibody against the activated subunit P65 NFkB.

The Jurkat cells in the amount of 1.25×105cells/ml were introduced into the wells of flat-bottomed 96-well plate in a medium RPMI-1640 containing 10% embryo is the real serum 2 mm glutamine, and incubated with drugs in recitations doses within 48 hours. Cells were washed 2 times in cold FSB and two systems on glass using cytocentrifuge, then the cells were fixed in alcohol for 5 minutes and the acetone for 3 minutes, then treated in a solution of the FSB, containing 1% Triton X-100 for 5 minutes. Then the glasses were incubated for 10 minutes in the FSB, containing 5% BSA to block nonspecific binding. Primary antibodies against the active subunit of NFkB p65 (MAB3026, Chemicon) was applied for 1 hour. As secondary antibodies used antibody conjugated with the dye Alexa Fluor 594 (A, Invitrogen). The drugs they finished painting areas Hoechst-33258 (2 μg/ml). The sections were analyzed using a fluorescent microscope (Nikon 80i at magnification 400x.

The claimed substance reduces the level of expression of the activated subunit P65 in Jurkat cells, as well as blocking its translocation into the nucleus (PL. 3).

Figure 3 shows that the substance LCTA 1575 reduces the activity of the NFkB protein. Untreated Jurkat cells expressed significant levels of activated NFkB. There is staining of the cytoplasm and nuclei of tumor cells by antibody to an activated form of NFkB fluorescent dye red color, which is combined with blue staining of cell nuclei (Figure 3,A). During the incubation of Jurkat cells with a substance LCTA 155 (10 -8M) within 48 hours there was a significant decrease in the level of activated NFkB. In the colored cells there is no fluorescent staining with antibodies to the activated form of NFkB (Fig 3,B). Similar results were obtained for the other substances of the group.

Example 4. Anticancer activity of derivatives of triandayllidou in vivo

The antitumor activity of substances LCTA 1578 studied in vivo by inhibition of the growth of the grafted mice B16 melanoma.

Melanoma B16 was inoculated on 106cell B6D2F1 male mice subcutaneously. Substance LCTA 1578 was administered in doses of 7.5 and 12.5 mg/kg nine every three days (day of vaccination of tumor - 0) intraperitoneally. Measurement of tumor size was started after the appearance of palpable tumors. Further, the measurement was performed every 3-4 days. We measured the length, width and height of the tumor (mm).

Antitumor effect on inhibition of tumor growth (SRAW) was measured by the conventional indicator, calculated as the ratio of the average volume of tumors in the treated and control groups (in %). TRO was calculated by the formula (VK-VO)/VK×100, where VK-the average tumor volume in the control group (mm3); VOthe average tumor volume in the experimental group (mm3). The volume of tumors in mice was calculated by the formula: V(mm3)=L×S×N, where L, S, N - the length, width and height of the tumor (mm).

Re ulitity research is shown in Figure 4. From Figure 4 it follows that the growth inhibition of B16 melanoma for substance LCTA 1578, introduced in doses of 7.5 and 12.5 mg/kg, 100% on the 14th day of observation and 60-70% on the 25th day of observation.

The technical result of the invention is that the derivatives of triandayllidou corresponding to formulas I and II, have antitumor activity: have a cytotoxic effect, enhance the apoptotic activity and inhibit the activity of NFkB protein in tumor cells.

Table 1
The use of derivatives triandayllidou as anticancer agents
ConnectionThe concentration of a substance, IC50(µm)+SD
STCJurkatMel KorSKOV-3MCF-7SK-BR-3
LCTA 1292
2,3±0,21,6±0,4N.D*NoNoNoNo
Tris(1H-indol-3-yl)matilija methanesulfonate
LCTA 1320
3,2±0,33,2±0,3NoNoNoNoNo
Tris(1-methyl-1H-indol-3-yl)matilija methanesulfonate
LCTA 1293
1,3±0,30,2±0,10,5±0,20,22±0,04of 2.26±0,421,31±0,162,17±0,95
Tris(1-ethyl-1H-indol-3-yl)matilija methanesulfonate
LCTA 1319
1,0±0,30,2±0,1027±0,01 0,24±0,070,81±0,031,84±0,661,76±0,01
Tris(1-propyl-1H-indol-3-yl)matilija methanesulfonate
LCTA 1574
0,3±0,10,09±0,040,22±0,040,07±0,010,26±0,040,65±0,250,27±0,12
Tris(1-butyl-1H-indol-3-yl)matilija methanesulfonate
LCTA 1575
15,0±2,29,3±2,10,04±0,010,06±0,020,33±0,060,49±0,152,47±0,09
Tris{1-benzyl-1H-indol-3-yl)matilija methanesulfonate
LCTA 1578
0,15±0,040,05±0,030,2±0,060,05±0,010,28±0,07 0,78±0,120,44±0,19
Tris(1-pentyl-1H-indol-3-yl)matilija methanesulfonate
LCTA 1340
0,3±0,10,07±0,030,49±0,010,62±0,183,81±2,64>10>10
Tris(1-hexyl-1H-indol-3-yl)matilija methanesulfonate
LCTA 1874
NoNo1,13±0,160,42±0,084,11±2,184,66±1,126,39±1,85
Tris(1-heptyl-1H-indol-3-yl)matilija methanesulfonate
LCTA 1576
16,4±2,312,4±2,1NoNoNoNoNo
Tris(1-decyl-1H-Indo) - Rev.-3-yl)matilija methanesulfonate
LCTA 1950
NoNo0,14±0,020,36±0,080,4±0,081,33±0,520,42±0,03
Tris(1-isopentyl-1H-indol-3-yl)matilija methanesulfonate
LCTA 1949
NoNoNo>10>10>10>10
Tris(1-pentyl-5-bromo-1H-indol-3-yl)matilija methanesulfonate
LCTA 1875
H.oH.o>100,95±0,064,58±1,64>10>10
Tris(1-pentyl-5-methoxy-1H-indol-3-yl)matilija acetate
LCTA 1984
H.oH.oH.o>10>10>10>10
Tris(1-(4'-chlorobutyl)-1H-indol-3-yl)matilija methanesulfonate
LCTA 1978
H.oH.oH.o0,51±0,130,88±0,33,24±0,260,87±0,02
Tris(1-phenyl-1H-indol-3-yl)matilija methanesulfonate
LCTA 1401
1,3±0,21,1±0,4H.oH.oH.oH.oH.o
Tris(2-methyl-1H-indol-3-yl)matilija methanesulfonate
LCTA 1376
0,10,1NoNoNoNoNo
3,3'-((1H-indol-3-yl)methylene)bis(2-methyl-1-propyl-1H-indole)methanesulfonate
LCTA 2011
Tris(5-methyl-1H-indol-3-yl)matilija methanesulfonate1,5±0,31,3±0,2NoNoNoNoNo
LCTA 1590
0,24±0,040,12±0,030,34±0,050,12±0,030,42±0,070,98±0,250,58±0,2
Tris(1-pentyl-1H-indol-3-yl)methanolthe
LCTA 1589
0,4±0,10,11±0,040,32±0,050,15±0,020,35±0,050,83±0,310,04±0,15
Tris(1-butyl-1H-indol-3-yl)methanol
*Was not determined.

Table 2
The use of derivatives triandayllidou as anticancer agents
Drugs % of apoptotic cells (±SD) during incubation with substances in concentrations
1 micron0.1 ám
LCTA 157450,83±0,4721,21±5,14
LCTA 157866,27±with 4.64of 6.99±1,84
LCTA 1319of 30.48±7,555,71±1,52
LCTA 129319,64±7,825,27±1,39
LCTA 187424,89±2,415,7±1,87
LCTA 1875 24,51±2,517,8±0,45
LCTA 1575
84,64±6,245,71±1,67
LCTA 1340
52,54±6,8413,39±0,7
LCTA 1950
96,95±0,5622,53±4,06

Table 3
The use of derivatives triandayllidou as anticancer agents
DrugsDecrease the level of expression of the activated subunit of NFkB P65 in cells Jurkat/lock is of its translocation into the nucleus
0.1 ám
LCTA 1574Yes/Yes
LCTA 1578Yes/Yes
LCTA 1319Yes/Yes
LCTA 1293Yes/Yes
LCTA 1874Yes/Yes
LCTA 1875Yes/Yes
LCTA 1575
Yes/Yes
LCTA 1340
Yes/Yes
LCTA 1950
Yes/Yes

The use of derivatives triandayllidou formulas (I) and (II) as anticancer agents with cytotoxic, apoptotic activity and ability to inhibit the activity of NFkB protein:

or their pharmaceutically acceptable salts or compositions containing them,
where R1; R7; R13are independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl,
where R2; R8; R14are independently hydrogen, alkyl, substituted alkyl; the provision and quantity of any substituents can vary, any of the substituents may in turn be substituted;
R3-R6; R9-R12; R15-R18are independently hydrogen, alkyl, substituted alkyl, aryl, halogen, -OH, -OR, where R is alkyl or substituted alkyl; the provision and quantity of any substituents can vary, any of the substituents may in turn be substituted;
represents the anion of any pharmaceutically acceptable organic and the inorganic acid,
R19represents hydrogen or alkyl.



 

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21 cl, 44 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted heteroarylpiperidine derivatives of formula (I) and enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof, where R1 denotes -N(R10)-(C(R6)2)m-T, (C(R6)2)1-T or -O-(C(R6)2)m-T; R6 is independently selected from H, OCH3, C1-6-alkyl, possibly substituted with 1-3 substitutes which are halogen, and C3-6-cycloalkyl, possibly substituted with 1-3 substitutes which are halogen, T denotes NR7R8, , , , or ; R7 and R8 are independently selected from H, C1-6-alkyl; R9 is independently selected from OH, C1-6-alkyl, O-C1-6-alkyl, or NR12R13; R10 denotes H or C1-6-alkyl; R12 and R13 are independently selected from C1-6-alkyl, possibly substituted with OH, C2-6-alkylene-O-C1-6-alkyl and W denotes CH, O or NR10; B denotes CR2 or N; G denotes CR2 or N; D denotes CR2 or N; E denotes CR2 or N; provided that one or more of variables B, G, D and E must be N; R2 is independently selected from H, F, Cl, CH3, OCH3 and CF3; R3 denotes: H, CI, F or CH3; R4 denotes Cl, F or CH3, R5 denotes , morpholine, possibly substituted with 1-3 identical or different substitutes R14, a 4-7-member saturated or partially unsaturated heterocycle containing one nitrogen atom in the ring and possibly an additional heteroatom selected from O, N and S, where the heterocycle is possibly substituted with 1-4 identical or different substitutes R11, or NR12R13; R11 is indendently selected from halogen, OH, C1-6-alkyl, possibly substituted with 1-3 substitutes which are halogen, C2-6-alkynyl, -C0-6-alkyl-C3-6-cycloalkyl, -OC(O)C1-6-alkyl, -NH2, -NH(C1-6-alkyl) and -N(C1-6-alkyl)2; A denotes a 3-7-member saturated ring; R12 and R13 are independently selected from C1-6-alkyl, possibly substituted with OH, C2-6-alkylene-O-C1-6-alkyl; R14 denotes C1-6-alkyl; 1 equals 0, 1, 2, 3 or 4; m equals 0, 1, 2, 3 or 4; o equals 0, 1 or 2; p equals 0, 1, 2, 3 or 4; r equals 0, 1, 2, 3 or 4; s equals 1 or 2 and t equals 0 or 1. The invention also relates to use the compound of formula I to produce a drug for treating or preventing disorders, diseases or conditions responsible for inactivation or activation of the melanocortin-4 receptor in mammals, and to a pharmaceutical composition based on said compounds.

EFFECT: novel compounds which can be used as melanocortin-4 receptor modulators are obtained and described.

10 cl, 134 ex, 16 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to pharmacology and medicine and concerns a combination containing a compound of formula (1) and one or more pharmaceutically active agents for treating cancer, a pharmaceutical composition containing said combination, a method of treating, and a market pack containing said combination.

EFFECT: invention provides high clinical effectiveness.

9 cl, 6 dwg, 2 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a new chemical compound (2E)-2-[(2-ethoxy-1H-indol-3-yl)methylene] hydrazincarboximydamine hydrochloride with formula : that displays antihypertensive and antihypoxic action. A method its production is described.

EFFECT: production of a new compound that displays antihypertensive and antihypoxic action.

3 cl, 5 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula 1c

, where A, B, R1, R2 and n have values given in the description, and pharmaceutically acceptable salts thereof. The invention also relates to pharmaceutical compositions based on compounds of formula 1c, which are used as modulators of ATP-binding cassette ("ABC") transporters or fragments thereof, including cystic fibrosis transmembrane conductance regulator ("CFTR"). The present invention also relates to a method of modulating ABC-transporter activity and methods of treating ABC-transporter mediated diseases using compounds of formula 1c.

EFFECT: improved method.

32 cl, 3 tbl, 118 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted cyclohexylmethyl derivatives, having serotonin, noradrenaline or opioid receptor inhibiting activity, optionally in form of cis- or trans-diastereomers or mixture thereof in form of bases or salts with physiologically compatible acids. In formula (1): R2 denotes H or OH; R1 and R2 together denote or =N-OH, R3 denotes a phenyl residue which is unsubstituted or monosubstituted with a halogen atom or a heteroaryl residue selected from a five-member sulphur-containing heteroaryl such as a thienyl residue or an unsubstituted phenyl residue bonded through a C1-C4alkyl group, R4 and R5 independently denote an unsubstituted C1-C3alkyl or R4 and R5 together denote (CH2)3-6, R8 denotes a linear saturated C1-C4 alkyl group bonded with an aryl, which is unsubstituted or monosubstituted with halogen atoms, R9 denotes a saturated C1-C8alkyl; values of radicals R1, m, n, R6, R7, R10-R13 are given in the claim. The invention also relates to methods of producing compounds of formula (I), a medicinal agent containing said compounds, use of compounds of formula (I) to prepare a medicinal agent for anaesthetic treatment during sharp, neuropathic or chronic pain and for treating depression, urinary incontinence, diarrhoea and alcoholism.

EFFECT: high efficiency of using the compounds.

32 cl, 501 ex, 21 tbl

FIELD: medicine.

SUBSTANCE: invention refers to a compound having the structure of formula (I), or its pharmaceutically acceptable salt, wherein specified radicals are presented in the description, and also concerns a compound representing or its pharmaceutically acceptable salt. The present invention declares a pharmaceutical composition possessing inhibitory activity in the relation to 20S proteasome containing a pharmaceutically acceptable carrier or a diluent and a therapeutically effective amount of the compound, and also the invention refers to methods of treating the immune diseases, such as inflammatory intestinal disease, to treating cancer, to treating infection, to treating proliferative diseases, to treating neurodegenerative disease or asthma.

EFFECT: higher clinical effectiveness.

34 cl, 21 ex, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula

wherein: m, n, R0, R1, R2, R3 and R4 have the values presented in clause 1 of the patent claim provided the compound of formula (I) cannot represent N-methyl-1-(phenylsulphonyl)-1H-indole-4-methanamine.

EFFECT: compounds show 5-NT6 receptor antagonist activity that that allows them being used in the pharmaceutical composition.

19 cl, 3 tbl, 192 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is offered a pharmaceutical composition for treating and/or preventing gastric and duodenal ulcer containing a proton pump inhibitor (PPI) and N-acetyl-5-methoxytriptamine (melatonin) in the following proportions: PPI - 10 mg - 30 mg; N-acetyl-5-methoxytriptamine (melatonin) - 2 mg - 8 mg; excipients - up to 100 mg with the PPI being presented by the compounds specified in a group: lansoprazole, rabeprazole, esomeprazole, pantoprazole The composition has been found to provide the efficacy equal or exceeding such ensured by common doses of the PPI with prolonged therapeutic action (i.e. specified PPI doses are single and daily).

EFFECT: pharmaceutical composition may be presented by a solid dosage form - tablets, film-coated tablets, softgel capsules, solid gel capsules, by a soft dosage form - rectal suppositories.

3 cl, 21 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is offered a pharmaceutical composition for treating and/or preventing arterial hypertension containing an angiotensin converting enzyme (ACE) inhibitor and N-acetyl-5-methoxytriptamine (melatonin) in the following proportions: ACE inhibitor - 2-4; N-acetyl-5-methoxytriptamine (melatonin) - 2-8; excipients - up to 100 mg with the ACE inhibitor being presented by the compounds specified in a group of enalapril, captopril, perindopril, lisinopril, fozinopril, quinapril, spirapril. The pharmaceutical composition may be presented by a solid dosage form - a tablet, a film-coated tablet, a softgel capsule, a solid gel capsule, by a soft dosage form - a rectal suppositorium.

EFFECT: providing a therapeutically significant effect (stable night-time blood pressure profile) and a lower risk of side effects due to using the doses low for the ACE inhibitors specified above have been shown.

3 cl, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, and concerns a pharmaceutical composition in the form of capsules, containing as active substances 3,31-diindolylmethane and epicatechin-3-gallate, and a method for making this composition. A method consists in mixing 3,31-diindolylmethane and epicatechin-3-gallate with a liquid fatty excipient and adding a wedding agent. In mixing, the prepared mixture is heated to 35-45°C to prepare a solution. Then the prepared solution is cooled to 22-25°C to fill gelatine capsules in the following proportions, g/capsule: 3,3'-diindolylmethane - 0.01-0.1, epicatechin-3-gallate - 0.02-0.04, liquid fatty excipient - 0.05-0.1, wedding agent - 0.4-0.45. The prepared drug in the form of soft gelatine capsules containing 3,31-diindolylmethane and epicatechin-3-gallate in the form of a solution, enables increasing bioavailability of the active substances.

EFFECT: prepared drug is non-toxic, safe in prolonged introduction, has no local irritant action, no toxic effect on the immune and reproductive systems.

5 cl, 6 ex, 7 tbl, 4 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a novel clathrate complex of β-cyclodextrin with 1-{[6-bromo-1-methyl-5-methoxy-2-phehylthiomethyl-1-H-indol-3-yl]carbonyl}-4-benzylpiperazine of formula : with molar ratio 1-{[6-bromo-1-methyl-5-methoxy-2-phehylthiomethyl-1-H-indol-3-yl]carbonyl}-4-benzylpiperazine: β-cyclodextrin from 1:1 to 1:10, synthesis method and use thereof as an antiviral agent for treating influenza. The disclosed method involves mixing solutions of β-cyclodextrin and 1-{[6-bromo-1-methyl-5-methoxy-2-phehylthiomethyl-1-H-indol-3-yl]carbonyl}-4-benzylpiperazine in molar ratio from 1:1 to 1:10 while stirring and heating to temperature not higher than 70°C and then maintaining said conditions until a homogeneous solution is obtained and extraction of the obtained complex.

EFFECT: clathrate complex is a novel effective anti-influenza virus agent which is obtained using a novel efficient method.

13 cl, 2 ex, 3 tbl, 11 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula I

and/or to all isomer forms of a compound of formula I and/or to mixtures of these forms in any proportions, and/or to physiologically acceptable salts of the compound of formula I, wherein R1 represents 1) -(C6-C14)-aryl-Z, wherein Z represents aminomethylene, 2) Het-Z, wherein Z represents amino group, and wherein Het is unsubstituted or additionally monosubstituted by group T, R2 represents 1) -(C0)-alkylene-(C6-C14)aryl, wherein aryl is unsubstituted or mono- or disubstituted by group T or 2) -(C0)-alkylene-Het, wherein Het is unsubstituted or monosubstituted by group T, R3 represents 1) -(C0)-alkylene-(C6-C14)-aryl, wherein aryl is unsubstituted or mono- or disubstituted by group T, 2) -O-(C6-C14)-alkylene(C6-C14)-aryl, wherein aryl is unsubstituted or monosubstituted by group T, 3) -(C0)-alkylene-Het, wherein Het is unsubstituted or mono-, di- or trisubstituted by group T, 4) -(C0)-alkylene-(C6-C14)-aryl-Q-(C6-C14)-aryl, wherein both aryl radicals are unsubstituted, 5) -(C0)-alkylene-(C6-C14)-aryl-Q)-Het, wherein aryl and Het in each case are independently unsubstituted or disubstituted by group T, 6) -(C0)-alkylene-Het-Q-Het, wherein both radicals Het are unsubstituted, Q represents a covalent bond, -(C1-C4)-alkylene, -N((C1-C4)-alkyl)- or -O-, T represents 1) halogen, 2) -(C1-C6)-alkyl, wherein alkyl is unsubstituted disubstituted by group -(C1-C3)-fluoralkyl or -N-C(O)-(C1-C4)-alkyl, 3) -(C1-C3)-fluoralkyl, 4) -(C3-C8)-cycloalkyl, 5) -O-(C1-C4)-alkyl, 6) -O-(C1-C3)-fluoralkyl, 7) -N(R10)(R11), wherein R(10) and R(11) independently represent hydrogen atom or -(C1-C6)-alkyl, 8) -C(O)-NH-R10, 9) -SO2-(C1-C4)-alkyl, 10) -SO2-(C1-C3)-fluoralkyl, R4 and R5 are identical and represent hydrogen atom, and R6 represent hydrogen atom with said Het being 5-10-member ring system consisting of 1 or 2 coupled ring systems, and wherein one or two identical or different heteroatoms are selected from oxygen, nitrogen and sulphur. Also, the invention refers to the use of the compound of formula I for preparing a drug.

EFFECT: there are prepared new compounds exhibiting antithrombotic activity, which particularly inhibit blood coagulation factor lXa.

6 cl, 2 tbl, 9 ex

FIELD: medicine, pharmacology, pharmacy, medicinal biochemistry.

SUBSTANCE: invention proposes a pharmaceutical composition that comprises, in particular, N-(1-octyl-5-carboxymethyl-dimethylindolin-7-yl)-2,2-dimethylpropaneamid or its pharmacologically acceptable salts as inhibitor of enzyme ACAT and inhibitor of HMG-CoA-reductase that represents pravastatin, lovastatin, simvaststin, fluvastatin, rivastatin, atorvastatin, rosuvastatin or pitavastatin used as active component of the composition. The combination of active substances shows the expressed synergistic effect. Invention provides enhancing activity of the composition in clinical applying.

EFFECT: valuable medicinal properties of composition.

71 cl, 2 tbl, 3 ex

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