Derivatives of glycosides of indolo[2,3-a]-pyrrolo[3,4-c]carbazol-5,7-diones eliciting cytotoxic and antitumor activity

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to new glycosides of indolo[2,3-a]-pyrrolo[3,4-c]carbazol-5,7-diones of the general formula (1)

wherein: -R1 means residue of mono- or disaccharide in pyranose form taken among the group: D-Rib, L-Ara, D-Xyl, D-Gal, D-Glc, D-Lac; -R2 means hydrogen atom, methyl group or residue of mono- or disaccharide; -R3 means hydrogen atom, hydroxyl group, amino-group or formamido-group; each -X1 and -X2 means independently of one another hydrogen atom or bromine atom under condition that they can't mean hydrogen atom simultaneously and under condition also that if R1 means disaccharide residue then R2 differs from hydrogen atom. Prepared derivatives show, in particular, cytotoxic and antitumor activity against melanoma B16 and Ehrlich tumor.

EFFECT: valuable medicinal properties of derivatives.

3 cl, 3 tbl, 2 dwg, 8 ex


The invention relates to the field of chemistry, medicine and biology and concerns glycosides derived indolocarbazole and, in particular, L-arabinopyranoside of indolocarbazoles exhibiting cytotoxic and antitumor activity.

In a number of glycosides indolocarbazoles with anticancer properties are known, for example, the antitumor antibiotic rebeccamycin (U.S. patent 4487925 and 4552842), having a natural origin, and its modified water-soluble analogue of (U.S. patent 4785085), antitumor compounds, which are a derivative of indeliberately with monosaccharide residues (PCT 95/30682 A1). Described glycosidic derivatives of indeliberately (PCT 98/07433 A1)containing the carbohydrate residues of the amino sugars. Also known derivatives indeliberately, containing a carbohydrate residue of the disaccharide and exhibiting antitumor properties (PCT 96/04293 A1).

Known methods of introduction of glycosidic residue in the molecule indolocarbazole can be divided into two groups. The first group consists of microbiological methods described in U.S. patent 5468849; 5668271, in the European patent 0602597 A2 and in PCT application 96/04293 A1. However, these methods allow to enter only a few sugars, mainly glucose. This group may include methods chem is over modification obtained by microbiological method rebeccamycin (U.S. patent 4785085). The second group consists of methods of chemical glycosylation using the reaction of Mitsunobu (U.S. patent 5804564 and 5922860, PCT application 95/30682 A1) and the salts of mercury, silver, and other (U.S. patent 5668271 and 5591842 and PCT application 96/04293 A1). These methods are rather time-consuming, as they require the introduction of protective groups in indolocarbazole and their subsequent removal, as well as multi-stage synthesis derived carbohydrate used in glycosylation reactions.

The present invention is to provide new compounds similar patterns, showing significant efficacy against various tumors.

The task is implemented proposed new derivatives glycosides, indolo[2,3-a]pyrrolo[3,4-C]carbazole-5,7-diones of General formula (I)


R1means the residue of a mono - or disaccharide in pyranose form, preferably D-Rib, L-Ara, D-Xyl, D-Gal, D-Glc, D-Lac;

R2means a hydrogen atom, methyl group or the residue of a mono - or disaccharide;

R3means hydrogen, hydroxyl group, amino group or formamido-group;

X1and X2means, each independently from each other, a hydrogen atom or a bromine atom,

provided that they may not mean simultaneously a hydrogen atom, and provided that if R1Osnach the em disaccharide glycosides of the rest, R2different from hydrogen.

The claimed compounds can be obtained in a known manner (Miller SJ, Bachledova A.A. and other Bioorgan. chemistry, 22, 458-467, 1996; Miller, SJ, Bachledova A.A. and other Bioorgan. chemistry, 22, 832-837, 1996; Bachledova A.A., Garaeva L.D. and other Bioorgan. chemistry, 23, 667-674, 1997), as well as an alternative way by the interaction of glycoside indole-3-luxusni acid with an indole or N-methylindole in dichloroethane when heated. To obtain glycosides indole-3-luxusni acid as starting compounds used per-O-acetylated glycosides indole, obtained with the help of indolin-indole method” (Preobrazhenskaya M.N., Korbukh I.A. in: "Chemistry Nucleosides and Nucleotides". Ed. L.B. Townsend, Plenum Press, NY, 1993, p.1-105). Thus obtained N-glycosides indole is treated sequentially with oxalylamino and water with formation not previously described glycosides indole-3-illikkalam acid in the form of per-O-acetate. Selective recovery β -carbonyl group in the remainder of Glyoxylic acid leads to not opisannym previously glycosides indole-3-luxusni acid in the form of per-O-acetates.

Proposed by applicants method differs from the previously described that provides a given configuration of the glycosidic bonds, allows you to use a wide range of carbohydrates, including disaccharides, does not require pre-synthesis proizvodnogo, suitable for glycosylation, and protection of the aglycone and, thus, allows to obtain a series of compounds that differ not only by the nature of the carbohydrate residue and heterocyclic substituents in the aglycone and of interest to biology and medicine.

Synthesized glycosides characterized data thin-layer chromatography (TLC),1H-NMR and mass spectra of high resolution. Spectra1H-NMR of the synthesized compounds recorded on the instrument Bruker WH-360 (Germany), the internal standard tetramethylsilane was; for the assignment of signals in the spectra and the adjustment of the constants of spin-spin interaction used in the dual resonance at different power levels of suppression of the spin-spin communication; when describing waveforms the following abbreviations: s - singlet, d - doublet, t - triplet, m = multiplet, DD - doublet of doublets, DDD - doublet of doublet of doublets, ush. with a broadened singlet, the values of the constants of spin-spin interaction (J) are given in Hz, aromatic protons3J=8.2-8.3. Mass spectra were recorded on a mass spectrometer Finnigan MAT 8430 (Germany) with the data processing system SS-300 at an accelerating voltage of 3 kV, the energy of ionizing electrons of 70 eV, a source temperature of ions 250° C, the evaporation temperature of the sample 170-250° applying the direct input of the substance into the area and the organization; the values given m/z. TLC was carried out on Silufol UV254, preparative chromatography on plates (20× 20 cm) with silica gel LSL254, 5-40 microns (Chemapol, Czech Republic) with a layer thickness of 1 mm.

Brief description of drawings

Figure 1. The kinetics of development of melanoma In 16 animals treated with compound (Ia) in a number of doses, in comparison with control (mouse BDF1). The horizontal axis shows the time after inoculation of the tumor in days, y-axis is the mass of the tumor,

1-70 mg/kg once daily, in b/W; 2 - 40 mg/kg, five times, in b/W; 3 - 30 mg/kg five times, in b/W; 4 - 20 mg/kg, five times, in b/W.

Figure 2. Change indicators ratingaverage effect of compound (Ia) in time on the model of melanoma In 16 (mouse BDF1).

A - dependence of the rate of inhibition of tumor growth (SRW, %) from the time of exposure to the drug. B - dependence of kinetic activity criteriontime after exposure to the drug.

1 - 70 mg/kg, once daily, in b/W; 2 - 40 mg/kg, five times, in b/W; 3 - 30 mg/kg five times, in b/W; 4 - 20 mg/kg, five times, in b/W.

Examples of carrying out the invention

Example 1. Synthesis of 9-bromo-13-methyl-12-(α-L-arabinopyranosyl)indolo-[2,3-a]pyrrolo-[3,4-C]carbazole-5,7-ion (Ia)

a) To a solution of 1.2 mmol of 1-(2,3,4-tri-O-acetyl-α-L-arabinopyranosyl)-5-bromoindole (HFG, 13(6), 47, 1979)) in 10 ml of methylene chloride under stirring and cooling gap is the situation to-5-0° C was added a solution of 1.8 mmol of oxalicacid in 6 ml of methylene chloride. The reaction mixture was stirred for 18 h at 20-22° C, then evaporated to dryness. To the residue dissolved in 12 ml of dichloroethane at 0° With added 1.2 mmol of 1-methylindol-3-luxusni acid and 2.4 mmol of triethylamine. The reaction mixture was heated at boiling for 6 hours, the Solvent was evaporated in vacuo, the residue was purified preparative TLC in the system benzene - acetone, 4:1. Received 3-(1-methylindol-3-yl)-4-[1-(2,3,4-tri-O-acetyl-α -L-arabinopyranosyl)-5-bromoindole-3-yl]-furan-2,5-dione, yield 61%. Mass spectrum (m/z): 678.0917 (M+), 420, 422, 376, 378, 348, 350, 269, 268, 259, 199, 157, 139, 97, 43.1H-NMR (CDCl3): 7.96 (s, 1H), 7.84 (s, 1H), 7.42 (d, 1H), 7.32 (d, 1H), 7.20-7.05 (m, 2H), 6.85-6.70 (m, MN), 3.92 (s, 3H, CH3), 5.43 (d, 1H, H1', J1',2'8.9), 5.70 (DD, 1H, H2', J2',3'10.2), 5.27 (DD, 1H, H3', J3',4'3.4), 5.47 (DDD, 1H, H4', J4', 5A'2.1, J4',5B'0), 4.20 (DD, 1H, N and Jheme.13.6), 3.98 (d, 1H, N b), 2.26 (s, 3H, AC), 2.03 (s, 3H, AC), 1.81 (s, 3H, AC).

b) a Solution of 0.41 mmol 3-(1-methylindol-3-yl)-4-[1-(2,3,4-tri-O-acetyl-α-L-arabinopyranosyl)-5-bromoindole-3-yl]furan-2,5-dione and 20 mg of iodine in 220 ml of benzene were placed in a quartz tube and when bubbling air was irradiated under Hg-lamp for 6 h (monitoring by TLC in the system benzene-acetone, 4:1). The solvent was evaporated in vacuo, the residue was chromatographically in the system benzene-acetone, 4:1. The floor is Ali 9-bromo-13-methyl-12-(2,3,4-tri-O-acetyl-α -L-arabinopyranosyl)indolo-[2,3-a]furano[3,4-C]carbazole-5,7-dione, yield 66%. Mass spectrum (m/z): 676.0774 (M+), 417, 419, 259, 199, 157, 139, 97, 69, 43.1H-NMR(Dl3): 9.12 (d, 1H), 9.00 (DD, 1H), 7.91 (d, 1H), 7.73 (t, 1H), 7.68 (DD, 1H), 7.63 (d, 1H), 7.40 (DDD, 1H), 4.24 (s, 3H, CH3), 5.88 (d, 1H, H1', J1',2'9.3), 5.56 (DD, 1H, H2', J2',3'10.3), 5.08 (DD, 1H, H3', J3',4'3.2), 5.47 (DD, 1H, H4', J4',5a'2.0, J4',5B'0.7), 4.48 (DD, 1H, N and Jheme.13.8), 4.07 (d, 1H, N b), 2.35 (s, 3H, Ac), 1.87 (s, 3H, Ac), 0.87 (s, 3H, AC).

C) the Mixture consisting of 0.33 mmol of 9-bromo-13-methyl-12-(2,3,4-tri-O-acetyl-α-L-arabinopyranosyl)indolo-[2,3-a]furano[3,4-C]carbazole-5,7-dione in 5 ml of DMF and 5 ml of 33%aqueous ammonia was heated for 4 h at 140° in the autoclave was left for 18 h at 20-22° C. the Solvent was evaporated in vacuum. The residue was chromatographically in the system chloroform-methanol 4:1. Received 9-bromo-13-methyl-12-(α-L-arabinopyranosyl)indolo-[2,3-a]pyrrolo[3,4-C]carbazole-5,7-dione (1A), yield 62%. Mass spectrum (m/z): 549.0476 (M+), 417, 419, 402, 04, 338, 267.1H-NMR (DMSO-d6): 9.27 (d, 1H), 9.09 (DD, 1H), 8.02 (d, 1H), 7.77 (DD, 1H), 7.72-7.65 (m, 2H), 7.44 (t, 1H), 4.20 (s, 3H, CH3), 5.62 (d, 1H, H1', J1',2'8.7), 4.32 (DD, 1H, H2', J2',3'10.0), 4.15-3.80 (m, 4H, H3', H4', NN'), 5.04, 4.76 (2-HE).

Example 2. Synthesis of 6-amino-9-bromo-13-methyl-12-(1-α-L-arabinopyranosyl)indolo-[2.3-a]pyrrolo[3,4-C]carbazole-5,7-dione (Ib, R3=NH2)

A mixture of 0.43 m the ol 9-bromo-13-methyl-12-(2,3,4-tri-O-acetyl-α -L-arabinopyranosyl)indolo-[2,3-a]furano[3,4-C]carbazole-5,7-dione and 5 ml of hydrazine hydrate was heated for 6 h at 50° C. the Reaction mixture was evaporated in vacuo, the residue was rubbed out with water, a yellow precipitate was separated, dried over R2O5. Received the compound (Ib), yield 41%. Mass spectrum (m/z): 564, 566 (M+), 434, 432, 417, 419, 338, 339, 268, 267.1H-NMR (DMSO-d6): 9.27 (d,1H), 9.09 (DD, 1H), 8.0 (d, 1H), 7.40-7-80 (m, 3H), 7.42 (t, 1H), 4.93 (ush. s, 2H, NH2), 4.20 (s, 3H, CH3), 5.60 (d, 1H, H1', J1',2'8.6), 3.90-4.15 (m, 3H, H2', NN'), 3.53 (m, 1H, H3'), 3,85 (ush. s, 1H, H4'), 5.04, 4.76 (2-OH), 4.37 (d, 1H, 1-IT, Jhe h6.0).

Example 3. Synthesis of 6-hydroxy-9-bromo-13-methyl-12-(1-α-L-arabinopyranosyl)indolo-[2,3-a]pyrrolo[3,4-C]carbazole-5,7-dione (Ic, R3=OH)

A mixture of 0.15 mmol of 9-bromo-13-methyl-12-(2,3,4-tri-O-acetyl-α-L-arabinopyranosyl)indolo-[2,3-a]furano[3,4-C]carbazole-5,7-dione, a 13.9 mmol of hydroxylamine hydrochloride, a 13.9 mmol of triethylamine and 2 ml of DMF, was stirred 1 h at 70° C. the Reaction mixture was diluted with water, precipitated orange precipitate was filtered, was chromatographically on silica gel in the system chloroform-methanol, 5:1. Received the compound (I), yield 24%. Mass spectrum (m/z): - (M+), 550, 433, 432, 419, 418, 339, 338, 268, 267.1H-NMR (DMSO-d6): 10.52 (ush. s, 1H, N-h), 9.24 (d, 1H), 9.06 (d, 1H), 8.01 (DD, 1H). 7.60-7.80 (m, 3H), 7.43 (t, 1H), 4.19 (s, 3H, CH3), 5.60 (d, 1H, H1', J1',2'8.3), 3.80-4.25 (m, 5H, H2', H3', H4', NN'), 5.01, 4.73, 4.37 (3 ush. d, 3H, ON).

Example 4. Synthesis of 6-formamido-9-bromo-13-methyl-12-(1-α-L-arabinopyranosyl)indolo-[2,3-a]pyrrolo[3,4-C]carbazole-5,7-dione (Id)

A mixture of 0.12 mmol of 9-bromo-13-methyl-12-(2,3,4-tri-O-acetyl-α-L-arabinopyranosyl)indolo-[2,3-a]furano[3,4-C]carbazole-5,7-dione, 1 ml DMF and 0.017 ml of concentrated hydrochloric acid, heated for 12 h at 50° C. the Reaction mixture was evaporated in vacuo, the residue was chromatographically on silica gel in the system chloroform-methanol, 5:1. Received connection Id, exit 15%. Mass spectrum (m/z): - (M+), 566, 564,460, 434, 432,419, 417, 339, 338.1H-NMR (DMSO-d6): At 10.82 (s, 1H, NH), 8.44 (s, 1H, Cho), 9.21 (d, 1H), 9.04 (d, 1H), 8.04 (d, 1H), 7.80 (d, 1H), 7.73 (t, 1H), 7.71 (t, 1H), 7.47 (t, 1H), 4.23 (s, 3H, CH3), 5.64 (d, 1H, H1', J1',2'8.8), 3.96-4.21 (m, 5H, H2', H3', H4', NN'), 5.1 (d, 1H, 1-OH), 4.83 (d, 1H, 1-IT, Jhe h5.8), 4.41 (d,1H, 1-IT, Jhe h6.0).

Example 5. The results of the study of the cytotoxic activity in vitro of glycosides indolocarbazoles

The cytotoxic properties of the synthesized glycosides studied in vitro on cultures of melanoma cells lines MS (melanoma Simpson), l38 and ovarian cancer man line CaOv. The cytotoxic effect was evaluated using the MTT assay (Microculture Tetrazolium Assay) in the modification Alley, included in the Program of screening of antitumor substances of the National cancer Institute USA. The principle of the method is based on the conversion of MTT (non-toxic yellow salt tetrazole) dehydrogenase W is o cells in the crystal blue formazan, the amount of which is measured spectrophotometrically. The formed crystals formazan was dissolved with DMSO and measured the partial absorption at a scanning spectrophotometer (Titertec Multiskan MCC/340) at λ =540 nm. The cell suspension was placed in 96-well plates, cells in the exponential phase of growth were added to the analyte, and then incubated for 72 hours. The incubation time was sufficient for the realization of the metabolic effects of the compounds under investigation that resulted in cell death. The surviving fraction of the cells was determined as a percentage of the ratio of the value of the partial absorption in the experimental samples and the control (cells in the growth medium without drug). The results are shown in table 1.

Characteristics of the used models: culture of human melanoma cell lines MS and l38 (doubling time of 36 hours) and ovarian cancer man line CaOv (doubling time of 48 hours) were grown as monolayer in the growth medium RPMI-1640 with the addition of 10% FBS, 2 mm glutamine, 40 μg/ml of gentamicin in an atmosphere of 5% CO3and 95% air, at 37° C.

This shows that all proposed connections indicator of cytotoxicity IC5010-5meets the selection criterion for the study of antitumor activity in vivo.

Antitumor activity of glycosides studied in mice colon and SK, mice-the first generation hybrids BDF1(C57B1/DBA2)weighing 18-20 g, breeding kennel “Pole”. Experimental models have served leukemia L1210 and R (mouse BDF1), Ehrlich tumor (colony SHK), transplantable in ascitic form vnutribruchinno (b) 5× 106tumor cells and solid tumor melanoma 16, subcutaneously transplantable crushed fragments of tumor tissue according to standard methods (Experimental evaluation of anticancer drugs in the USA and the USSR // Ed. Sofina Z.P., Syrkin A.B., F. Goldin, I. Klein // M.: Medicine, 1980). The drug was administered in the form of an aqueous-alcohol solution (10% ethanol). The concentration of the injected solution was 1 mg/ml Toxicity of the preparation was studied in the acute experience after a single dose intraperitoneally in a number of doses of intact mice colony SHK. The period of observation of the animals was 1 month. The median lethal dose (LD5o) was calculated according to the method of Cerberus. (Belenky, M. elements of a quantitative evaluation of the pharmacological effect. Riga: Publishing house of Academy of Sciences of Latesr, 1952). Antitumor activity of the drug was tested on animals-carriers of tumour intraperitoneal injection in a wide range of doses under different schemes applied once or multiple times during a 4, 5 or 6 nights daily, starting from the following day after inoculation SDA is Oli. Each dose of drug was administered 6 mice (10 animals in the control) when two-, three-fold repetition of the experiments. Criteria antitumor activity were as follows: the increase in the average life span of the treated animals (τop) compared to control (τto), expressed as a percentage:


The inhibition of tumor growth (TRO) in treated animals (Pop) compared to control (Pto), expressed as a percentage:

Kinetic criterion ratingaverage activitythat allows you to compare the relative speed of tumor growth in treated (ϕop) and control (ϕtoanimals:

Example 6. The antitumor activity of compounds of formula (Ia) model of leukemia L1210 (mouse BDF1)

The drug was administered, starting from the following day after inoculation of the tumor. The results of the test drug in a wide range of doses after single and multiple applications are presented in table 2.

As can be seen from the above data, the drug has certain antileykemicheskoy effect and depending on the applied dose increases the lifetime of the animals at 12-25% compared with control. N. the highest increase in life expectancy of animals observed in the use of the drug single dose of 80 mg/kg (τ 25%) or six to 20 mg/kg / day (τ20%)

Example 7. The antitumor activity of compounds of formula (Ia) model ascitic Ehrlich tumor (mouse colony SHK)

The drug was started the following day after inoculation of the tumor. The effect was evaluated 12 days after inoculation of the tumor. The results are shown in table 3.

According to these data, the compound (Ia) shows extremely high antitumor activity, completely inhibiting the development of this tumor in the application at all tested doses, including a low dose of 10 mg/kg per day, introduced six. Revision of the abdominal cavity of the treated animals for 12 hours after inoculation of the tumor revealed a lack of ascitic fluid in the standard development of tumors in control animals, which had for a specified period at an average of about 9 ml of ascites in the abdominal cavity. therapeutic index (TI100) compounds (Ia), calculated as the ratio of the MTD (maximum tolerated dose) for U100(dose inhibiting tumor growth in 100%), amounted to this model, an amount equal to 8.

Example 8. The antitumor activity of compound (Ia) on the model of B16 melanoma

The kinetics of development of B16 melanoma in mice treated with varying doses of the drug (once 70 mg/kg or pyatibrat the 40, 30, 20 µg/kg per day), as well as the control animals presented in figure 1.

The dependences indicate significant ratingaverage efficacy of the drug in the tumor. Thus, the inhibition of tumor growth when assessing the effect on the third day after the end of treatment up to 100%, 90% and 80%, respectively, in a single (70 mg/kg) and five times (40 or 30 mg/kg per day) administration of the drug. The use of the drug in a relatively low dose of 20 mg/kg per day five times leads to inhibition of tumor growth by 45-50% (the first day after the end of treatment).

therapeutic index (TI50) drug, defined for this model as the ratio LD50to the ED50is an amount equal to 4.

Comparison of the kinetics of tumor growth in treated and control animals allows us to estimate the duration of the preservation ratingaverage effect of the drug.

As is seen in figure 2 dependencies, the inhibition of tumor growth remains at a level not less than 70% for 7 days after administration of the drug at a dose of 70 mg/kg once and for 4 days after fivefold injection 40 mg/kg per day.

Even in the more remote periods - within 10 days after use of the drug in the dose - inhibition of tumor growth is not less than 50% of p is compared to control (figa).

The nature of the time variation of the kinetic criterion(figb) also shows that after application of the drug at a dose of 70 mg/kg once values of this indicator for 7 days after administration of the compound (1A) remain in the field values corresponding to significant ratingaverage effect (>0.4). Kinetic evaluation of the antitumor effect of the drug in different modes of introduction suggests that the optimal schemes use are a single injection at a dose of 70 mg/kg or five times the use of 40 mg/kg per day (figure 2).

Thus, for example, compounds (Ia) shown significant antitumor efficacy against B16 melanoma (inhibition of tumor growth depending on the mode of administration of the drug is 70-90%), as well as against Ehrlich tumor, which was completely inhibited. Similar results were obtained for the other compounds described.

The obtained results allow to make a conclusion about the prospects of further testing of the claimed compounds to create new anticancer drugs.

Table 1
No. Conn. X1X2R2R2R3Cell lineIC50M
IaBrHL-araCH3NMS3× 10-6
IbBrHL-araCH3NH2CaOv0.8× 10-6
IbBrHL-araCH3NH2Colo386× 10-6
IcBrHL-araCH3HE Colo38>10-5
IdBrHL-araCH3NHCHOCaOv2× 10-5
Table 2
Dose, mg/kg per dayScheme introductionThe average life expectancy of animals dayThe increase in the average life expectancy of animals compared to the control
80*Once the13.2±1.823.4
60once the10.2±1.117.6
*The average life expectancy of animals in the control for the specified experience amounted to 10.7±1.2 days.
Table 3
Dose, mg/kg per dayScheme introductionThe volume of ascitic fluid is ti, mlThe inhibition of tumor growth, %
60once the0100

1. Derivatives glycosides, indolo[2,3-a]pyrrolo[3,4-C]carbazole-5,7-diones of General formula

where R1means the residue of a mono - or disaccharide in pyranose form selected from the group of D-Rib, L-Ara, D-Xyl, D-Gal, D-Glc, D-Lac;

R2means a hydrogen atom, a metal group or the residue of a mono - or disaccharide;

R3means hydrogen, hydroxyl group, amino group or formamido;

X1and X3denote each, independently of one another a hydrogen atom or a bromine atom, provided that they are not on the to start simultaneously a hydrogen atom, and provided that if R1means disaccharide glycosides of the remainder, R2different from hydrogen.

2. The compound according to claim 1, having cytotoxic activity against melanoma cells MS, Colo38 and ovarian cancer man CaOv.

3. The compound according to claim 1, which has antitumor activity against leukemia L1210, ascitic Ehrlich tumor and solid tumor-melanoma B16.


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The invention relates to the derivatives of introperative General formula

< / BR>
in which R1and R2each independently H, lower alkyl, lower alkenyl, phenyl, phenylalkyl, pyridyl or imidazolyl, and each of the groups lower alkyl, lower alkenyl, phenyl, phenylalkyl is optional from 1 to 5 substituents selected from carboxy, carbamoyl, cyano and hydroxy-group; or the group-Y - R2where Y is a carbonyl, thiocarbonyl or sulfonyl, and R3- H, lower alkyl, trifluoromethyl, phenyl, lower alkoxy, hydrazino, amino, phenylamino, carbarnoyl or Peregrina group, the lower alkyl or phenyl group are optionally 1 to 4 substituents such as hydroxy-group adjacent to the hydroxy-group-protected alkalinous group, carboxy or cyano, or R1and R2taken together with the nitrogen atom to which they are attached, form a piperazinilnom or pyrrolidinyloxy the group may hydroxylamino lower alkyl group, G - pentasa or hexana group, X1and X2independently H or halogen, OH, lower alkoxy - or benzyloxy

FIELD: chemistry of peptides, medicine, oncology, pharmaceutical chemistry.

SUBSTANCE: invention relates to the development of medicinal agent of peptide nature eliciting an antitumor effect and can be used in treatment of endocrine and hormone-dependent tumors. Agent represents peptide of the general formula: . Invention provides enhancement of the therapeutic effect and reducing toxicity.

EFFECT: valuable medicinal properties of agent.

3 cl, 4 tbl, 2 ex

FIELD: biochemistry, medicine, pharmacy.

SUBSTANCE: leaves of Mikania micrantha, Mikania scandens and Mikania cordata are milled and dries and a solvent - toluene, ethyl acetate, their mixture, mixture of toluene with acetone, mixture of ethyl acetate with heptane or mixture of heptane with acetone is added in the ratio (7:3)-(3:7), mixture is filtered and concentrated up to 2.5-10% as measure for dry extract. Then extract is contacted with a mixture containing 10-50% of methanol or ethanol in water, an aqueous-alcoholic phase is washed out with n-hexane or heptane and alcohol is removed. An aqueous phase is extracted with ethyl acetate, prepared phase is dried, solvents are evaporated and dry extracted is purified. Dry extract prepared from leaves is dissolved in ethyl acetate and hydrogenated at 10-35°C in the presence of hydrogenation catalyst under pressure 1-2 atm. After hydrogenation dihydromikanolid is crystallized. Mikanolid and dihydromikanolid are used for treatment proliferative diseases and parasitic diseases. Also, invention relates to a medicinal agent containing above indicated vegetable extract. Invention provides realization of indicated designation.

EFFECT: valuable properties of agents.

12 cl, 3 tbl, 3 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to pharmaceutical composition comprising the known antibiotic eliciting an antitumor activity and derivative of hydroxamic acid of the formula (1) wherein the weight ratio of two active agents is (1:50)-(50:1), respectively. The composition reduces adverse effects and elicits the enhanced antitumor effect.

EFFECT: improved valuable medicinal properties of composition.

4 cl, 1 tbl, 5 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to epothilones with modified thiazole substituent, methods for production thereof and pharmaceutical composition capable of cell growth inhibiting containing the same. Claimed compounds have general formula I , wherein P-Q represents double carbon bond or epoxy; R represents H, C1-C6-alkyl; G represents ; R1 represents and ; G1 and G2 represent hydrogen; G3 represents O, S, and NZ1; G4 represents H, optionally substituted C1-C6-alkyl, OZ2, Z2C=O and Z4SO2; G5 represents halogen, N3, CN, NC, heteroaryl containing nitrogen or oxygen, and heterocycle; G6 represents H, C1-C6-alkyl, or OZ5, wherein Z5 represents H, C1-C6-alkyl; G9 represents oxygen; Z1 represents H, optionally substituted C1-C6-alkyl, optionally substituted acyl; Z2 represents optionally substituted C1-C6-alkyl or aryl; Z4 represents optionally substituted aryl.

EFFECT: new epothilones capable of cell growth inhibiting.

19 cl, 39 ex

FIELD: medicine, oncology.

SUBSTANCE: the present innovation should be applied at adjuvant chemotherapy in case of tumors of central nervous system. Moreover, while carrying out lumbar puncture it is necessary to perform catheterization of subarachnoidal space. Moreover, one should daily sample liquor at the quantity of 10 ml to be incubated with chemopreparation in vitro for 30 min at 38 C. One should daily introduce chemopreparations upon autoliquor through catheter during the whole period of therapy course. The method enables to choose any mode and duration of endolumbar chemotherapy at its decreased toxicity.

EFFECT: higher efficiency of chemotherapy.

1 ex

Antitumor agent // 2253446

FIELD: drugs, medicine.

SUBSTANCE: invention relates to application of 2-METHYL-4-chlorophenoxyacetic acid tris-(2-hydroxyethyl)ammonia salt, which represents known microorganism living function stimulator, as antitumor agent and metastasis inhibitor. Present invention makes it possible to produce drugs for treatment cancers, in particular hepatoma, melanocytoma, lymphadenoma, etc.

EFFECT: new drug for cancer treatment.

2 tbl, 2 ex

FIELD: pharmaceutical industry, in particular new bioactive chalcones.

SUBSTANCE: invention relates to new chalcones of formula I

, pharmaceutically acceptable salts or solvates thereof, wherein Ar is optionally substituted C5-C10-carbocycle group or 5- or 6-membered heterocycle group having sulfur atom in cycle, and Ar substituents are selected independently from Cl, Br, F, CN, SCH3 and OR10, wherein R10 is linear or branched C1-C6-hydrocarbon; R is OH or R10; R2 and R3 are independently phenyl, saturated linear or branched C1-C6-hydrocarbon, or R2 and R3 together with carbon atom attached thereto form 5- or 6-membered carbocycle group with the proviso, that in compounds where R is OH and both R2 and R3 are methyl, Ar is not phenyl, 4-chlorophenyl, 4-chlorophenyl, 4-methylphenyl, 2-chlorophenyl, 3,4-dimethoxyphenyl, or 4-methoxyphenyl. Also disclosed are drug component for treatment or prophylaxis of neoplasm and pharmaceutical compositions with antiproliferation effect based on compounds of formula I.

EFFECT: new chalcone derivatives with value bioactive action.

26 cl, 2 tbl, 22 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: the suggested composition includes compounds of natural ethers in cancer of mammalian soft tissues (including, the man), for example, in case of diseases of mammary gland. Both dosage and frequency of introduction depending upon a certain symptomatics could be decreased up to the level at which it is necessary to maintain improved level. At weakening the symptoms up to desired level one should stop therapy immediately. At any relapse of disease symptoms patients could need periodic therapy upon lasting basis.

EFFECT: higher efficiency of application.

2 cl, 3 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: the present innovation includes polychemotherapy and radiation therapy. Moreover, polychemotherapy should be carried out by the following scheme: on the 1st and the 8th d of the first and the third courses it is necessary to introduce doxorubicin, cyclophosphan, vincristine, and since the 1st to the 14th d - procarbazine and prednisolone; moreover, on the 1st and the 8th d of the second and the fourth courses one should introduce doxorubicin, bleomycin, vinblastine, dacarbazine. The method enables to decrease the quantity of late therapeutic complications, improves the results of relapse-free, total tumor-specific survival rate and decreases the number of polychemotherapeutic cycles.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating oncological diseases. It is suggested to apply bisdioxopiperazine (previously known as cardioprotector) to either treat or prevent tissue lesions caused due to sporadic transudation of cytotoxic poison for topoisomerase II (represented by anthracyclines, etoposide, teniposide, mitoxantrone daunorubicin, doxorubicin, etc.), medicinal remedies and pharmaceutical set of the same indication. It is, also, suggested to apply the method to treat or prevent tissue lesions caused by sporadic transudation of topoisomerase II poison. BisdioxopiperazineICRF-187 has impact due to catalytic inhibiting topo II. Signs for possible transudation of topoisomerase II poison (of local toxicity) usually include the availability of acute pain, erythema, development of ulcerations in area of transudation; due to the action of ICRF-187 the quantity of wounds is reduced, or the development of side effects is not observed.

EFFECT: higher efficiency of therapy.

59 cl, 12 dwg, 13 ex, 10 tbl

The invention relates to glucopyranosyloxy derivative of the formula (I), where R1represents a hydrogen atom or a lower alkyl group; one of Q1and T1represents a group of formula (II), while the other of them represents a lower alkyl group or a halo(lower alkyl) group; R2represents a hydrogen atom, a lower alkyl group, lower alkoxygroup, lower allylthiourea, halogen(lower alkyl) group or a halogen atom, or its pharmaceutically acceptable salts

-substituted derivatives of carboxylic acids" target="_blank">

The invention relates tosubstituted derivatives of carboxylic acids, characterized by the General formula (I), (II), (III) and (IV)

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or their pharmacologically acceptable (C1-C6)-alkyl esters, or their pharmacologically acceptable Amida, or their pharmacologically acceptable salts

The invention relates to the field of medicine and relates to pharmaceutical compositions with antibacterial activity
The invention relates to medicine, namely to surgery, and for the prevention and treatment of purulent-inflammatory complications in the pre - and postoperative periods