Semi-synthetic analogues of aureolic acid olivomycin a antibiotic, having anti-tumour activity, and synthesis method thereof

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of the anti-tumour antibiotic of the aureolic acid olivomycin A group, having anti-tumour activity and low toxicity, and synthesis method thereof. The invention also relates to a method of producing derivatives of the antibiotic of the aureolic acid olivomycin A group, involving selective oxidation of the side chain of olivomycin A aglycone through reaction with sodium periodate, followed by amidation of the obtained key intermediate 1'-des-(2,3-dihydroxy-n-butyroyl)-1'-carboxyolivomycin A with corresponding amines in the presence of a condensing agent.

EFFECT: disclosed compounds have marked anti-tumour activity and low toxicity compared with the original olivomycin A.

2 cl, 9 ex, 1 dwg, 6 tbl

 

The invention relates to pharmaceutical industry and relates to new derivatives of antitumor antibiotic group aureolus acid olivomitsina and the way they are received.

Antibiotics group aureolus acids are highly effective natural anticancer drugs, some of which are permitted for use as antineoplastic agents for the treatment of several neoplastic diseases. The most important representatives of this group are: olivomycin And (olivomycin 1) (formula 1, R1=COCH3, R2=CH3, R3=COCH(CH3)2, R4=H), olivomycin With (formula 1, R1=H, R2=CH3, R3=COCH(CH3)2, R4=H), chromomycin A2 (formula 1, R1=COCH3, R2=CH3, R3=COCH(CH3)2, R4=(CH3), chromomycin A3 (formula 1, R1=COCH3, R2=CH3, R3=COCH3, R4=CH3), mithramycin.

The mechanism of action of antibiotics group aureolus acids based on their interaction with GC-pairs in the minor groove of DNA and the damage to the structure and function of nucleic acids including gene transcription [Simonov B.C., Samusenko AV, N.A. Filippova, Levashova A.N., Lyniv PS, Kulik GI, Chekhun V.F., Calm A.A. "Olivomycin causes apoptosis of tumor cells and suppresses p53-induced transcription is s", Bulletin of experimental biology and medicine, 2005, vol 139, No. 4, str-455]. Antibiotics group aureolus acid along with valuable properties have several disadvantages, the main of which are high toxicity, mutagenicity, Carcinogenicity, mielo and immunosuppressive effect.

The present invention aims to obtain a semi-synthetic analogues of a new type of antibiotic group aureolus acid olivomitsina And high antitumor activity and reduced toxicity. The invention includes compounds corresponding to formula 2:

where R5represents hydroxyl, NH2, 2-amino-2-deoxyhexose, C3-C10aminosilanes or C1-C5-aminoalkyl with a straight or branched hydrocarbon chain, optionally substituted by one or more hydroxyl or amino groups, benzyl, optionally having substituents in the aromatic ring.

Although chemical modification of natural antibiotics, including antitumor is the most important method of obtaining new drugs have advantages over the original antibiotic, chemical modification of the antibiotic group aureolus acid is practically not carried out.

The path of the biosynthesis of the antibiotic olivomitsina And strain-producer described in [W.R. Roush, Hartz R.A., Gustin D.. "Total synthesis of olivomycin A", Journal of American Chemical Society, 1999, vol. 121, pp.1990-1991]. Describes approaches to chemical modification olivomitsina And 2'-carbonyl group and the aromatic part of the aglycone [Kumar V., W.A. Remers, "Preparation and antitumor activity of olivomycin A analogues". Journal of Medicinal chemistry, 1980, vol.23, pp.376-379]. The authors made the following chemical transformation olivomitsina And 2'-carbonyl group and received Imin, oxime, hydrazone, semicarbazone. All known derivatives olivomitsina And a carbonyl group possess cytotoxicity comparable with the original olivomycin A. Previously, we have described a method of obtaining derivatives of the antibiotic group aureolus acid olivomitsina And consists in the selective modification of the 2'-carbonyl group olivomitsina And reaction with aminooxyacetic acid, followed by the amidation reaction of the obtained key intermediate 2'-(carboxymethoxy) olivomitsina 1 (2'-(carboxymethoxy)olivomitsina A) with the corresponding amines in the presence of a condensing agent [the Patent for invention №2350621 "Derivative of the antibiotic group aureolus acid olivomitsina 1 with antitumor activity, and the way their production"]. The described modification resulted in a decrease of the cytotoxic activity of derivatives by at least one order of magnitude compared with the original olivomycin A. based On data EN is proliferative activity and inhibition derived olivomitsina And work topoisomerase I had made the assumption, the elongation and an increase in the side chain of the aglycone derivatives olivomitsina And hindered the formation of the complex antibiotic-DNA due to steric factors [Diankov L.G. Dissertation on competition of a scientific degree of candidate of chemical Sciences, "Communication structure-activity in the range of antitumor antibiotics, derivatives and analogs of new inhibitors topoisomerase I", Moscow, 2008].

Compared to these derivative compounds of the present invention contain a shorter side chain, which, presumably, will not prevent the interaction of the antibiotic with the target. The compounds possess cytotoxicity close to that of the original antibiotic. The invention also includes a method of obtaining a new semi-synthetic analogues of the antibiotic group aureolus acid olivomitsina And (formula 2), which consists in the selective oxidation of the side chain of the aglycone olivomitsina And in position 3 by reaction with periodate sodium (Scheme 1), followed by the amidation reaction of the obtained key intermediate 1'-des-(2,3-dihydroxy-n-buterol)-1'-carboxylicacid And (formula 3) with amines in the presence of a condensing agent.

The amidation reaction of 1'-des-(2,3-dihydroxy-n-buterol)-1'-carboxylicacid And (formula 3) with the amine to obtain the compound of formula 2 is carried out in at outstay condensing agents, known from the prior art and used for the formation of amide linkages, for example diphenylphosphinite (DPPA) or condensing agents postoyalogo and Orangevale types, mainly postoyalogo type, mainly, benzotriazol-1-yl-oxy-despiralization of hexaflurophosphate (PyBOP). The amidation reaction of 1'-des-(2,3-dihydroxy-n-buterol)-1'-carboxylicacid And (formula 3) with the amine to obtain the compound of formula 2 is carried out in a solvent selected from methanol, ethanol, N,N-dimethylformamide, dimethyl sulfoxide, toluene, xylene and chloroform/dichloromethane, or a mixture thereof. Selected conditions amidation 1'-des-(2,3-dihydroxy-n-buterol)-1'-carboxylicacid And (formula 3) in the presence of a condensing agent allow you to enter in the reaction of primary amines with different structures, including 2-amino-2-deoxyhexose, C3-C10cycloalkenyl, C1-C5-alkylamines followed with a straight or branched hydrocarbon chain, optionally substituted by one or more hydroxyl or amino groups, benzylamine, optionally having substituents in the aromatic ring.

The compounds of formula 2 have a pronounced antitumor activity and reduced toxicity compared with the original olivomycin (see Examples 6-9) and can be used to treat cancer the disease.

AIDS:

Periodate sodium, benzotriazol-1-yl-oxy-despiralization hexaflurophosphate (Rubor), diphenylphosphoryl (DPPA) were commercial products of the company Acros. Hydrochloride of 2-adamantylamine, methyl ester of L-alanine, D-galactosamine, 4-forbindelsen, triethylamine, were commercial products of the firm Aldrich (USA).

Thin-layer chromatography was performed on plates of silica gel G60 (Merck) in mixtures of solvents: chloroform-methanol-acetic acid 10:1:0.01 (I), chloroform-methanol-acetic acid 7:1:0.01 (II). For preparative purification used column chromatography on silica gel Merck G60 with a particle size 0.040-0.063 μm.

HPLC was carried out on the instrument Shimadzu HPLC LC 10 column Kromasil-110A-C18, No. 2671, 4×250 mm, eluent: n. H3PO4(pH 2.6) - MeCN, gradient of acetonitrile from 40% to 80% (system A) or 30% to 90% (system B), flow rate 1 ml/min or on column Gemini-C-C18, No. 542, 6×250 mm, eluent: n. H3PO4(pH 2.6) - MeCN, gradient of acetonitrile from 20% to 80%, flow rate 1 ml/min (system B). Registration was conducted at a wavelength of 270 nm at a temperature of 20°C.

1H NMR and13With NMR spectra were recorded on a spectrometer Varian VXR-400 (USA) at 400 MHz.

Mass spectra when ionization elektrorazpredelenie (ESI) were obtained using the device Finnigan MAT 900S (Germany) and on the device "micrOTOF-Q II" ("Bruker Daltonics GmbH, Germany).

the reamers interaction 1'-des-(2,3-dihydroxy-n-buterol)-1'-carboxylicacid And with primary amines, belonging to different classes of organic compounds, in the presence of a condensing agent to obtain derivatives of the antibiotic group aureolus acid olivomitsina And according to the present invention and investigation of their anticancer activity:

Example 1. Obtain 1'-des-(2,3-dihydroxy-n-buterol)-1'-carboxylicacid A (LCTA 1498) (Formula 3)

To a solution of olivomitsina A (500 mg, 0.418 mmol) in Meon (5 ml) solution was added periodate sodium (200 mg, 0.935 mmol) in H2O (0.5 ml). The reaction mixture was stirred at room temperature for 24 h the Reaction mixture was diluted with ethyl acetate (50 ml), washed with water (3×30 ml), dried over Na2SO4and was evaporated. The residue was applied onto a column of silica gel, was suirable a mixture of CHCl3-Meon-CH3COOH (15:1:0.1). The fractions containing the target substance were combined, solvent was removed on a rotary vacuum evaporator to a minimum volume and hexane was added. The precipitation was filtered, washed with hexane, and dried.

Yield: 410 mg (86%). Rf(I) 0.58, Rt(A) 15.41.

TPL170-172°C (decomposition).

13C-NMR (DMSO-d6) spectrum of 1'-des-(2,3-dihydroxy-n-buterol)-1'-carboxylicacid And fully complies with13C-NMR spectrum of the source olivomitsina (DMSO-d6) [assignment signals, see Yoshimura Y., Koenuma M., Matsumoto K., Tori K., Tend Y. "NMR studies of Chromomycins, olivomycin and their derivatives", The Journal of Antibiotics, 1988, vol. XLI, No. 1, pp.53-67], with the following exceptions:

- there are no signals: 211.81 ppm (corresponding 2'-carbonyl group olivomycin As);

- in the field 65.00-80.00 ppm, corresponding to the signal groups SNON, present in the two signals is smaller than in the original antibiotic;

- no signal 19.47 ppm (corresponding to 5'-CH3group);

- a signal: 173.05 (-COOH).

ESI MS MW calculated for C55H7O251138.48 found.: 1137 (M-N)-1.

Example 2. General methods of amidation 1'-des-(2,3-dihydroxy-n-buterol)-1'-carboxylicacid A.

To a solution of 1'-des-(2,3-dihydroxy-n-buterol)-1'-carboxylicacid And (0.131 mmol) in DMSO (3 ml) was added amine hydrochloride (0.395 mmol). The pH of the reaction mixture was brought to 7.5-8 by the addition of triethylamine. Several portions were added by condensing reagent (0.263 mmol), controlling the pH of the reaction mixture by the addition of triethylamine. The reaction mixture was stirred for 40-60 min, then was added ether, and the mixture was shaken with ether, removing the upper colored layer. The obtained viscous oil was dissolved in ethyl acetate. Precipitated white precipitate was filtered, the mother liquor was evaporated to a small volume, was added petroleum ether. The precipitation was filtered and dried. If necessary, further purification (purity according to HPLC <90%) was obtained amide of rest rely in CHCl 3and put on a column of silica gel. Substance suirable first CHCl3and then with a mixture of CHCl3-Meon-CH3COOH (7:1:0.1). The fractions containing the target substance were combined, solvent was removed on a rotary vacuum evaporator to a minimum volume and added to petroleum ether. The precipitation was filtered, washed with petroleum ether, and dried.

The purity of the obtained compounds were studied by TLC and HPLC. The structure of the obtained compounds was confirmed by mass spectrometry.

Example 3. The amidation 1'-des-(2,3-dihydroxy-n-buterol)-1'-carboxylicacid A (LCTA 1498) (Formula 3) alkylamino branched hydrocarbon chain carrying additional tertiary amino group, for example, obtain the N,N-diethylaminoethylamine 1'-des-(2,3-dihydroxy-n-buterol)-1'-carboxylicacid AND (LCTA-1599)

To a solution of 1'-des-(2,3-dihydroxy-n-buterol)-1'-carboxylicacid A (150 mg, 0.131 mmol) in DMSO (3 ml) was added the hydrochloride of N,N-diethylaminoethylamine (49 mg, 0.395 mmol). The pH of the reaction mixture was brought to 7.5-8 by the addition of triethylamine. Several portions were added Rumor (103 mg, 0.263 mmol), controlling the pH of the reaction mixture by the addition of triethylamine. The reaction mixture was stirred for 40 min, then was added ether (20 ml), the mixture was shaken with ether, removing the upper colored layer. Received askoe oil was dissolved in ethyl acetate (20 ml). Precipitated white precipitate was filtered, the mother liquor was evaporated to a small volume (~1 ml), was added petroleum ether. The precipitation was filtered and dried.

Yield: 130 mg (82%). Rf(II) 0.33, Rt(A) 6.21.

TPL175-177°C (decomposition).

ESI MS: MW calculated for C59H88N2O241208.57, 1209.58 (M+H)+1.

Example 4. The amidation 1'-des-(2,3-dihydroxy-n-buterol)-1'-carboxylicacid A (LCTA 1498) (Formula 3) benzylamino having a substituent in the aromatic nucleus, for example 4-formanilide 1'-des-(2,3-dihydroxy-n-buterol)-1'-carboxylicacid AND (LCTA 1974)

To a solution of 1'-des-(2,3-dihydroxy-n-buterol)-1'-carboxylicacid A (10 mg, 0.01 mmol) in DMF (0.5 ml) were added hydrochloride 4-forbindelsen (8 mg, 0.03 mmol). The pH of the reaction mixture was brought to 7.5-8 by the addition of triethylamine (~0.005 ml, 0.03 mmol). Then added DPPA 0.012 ml (0.06 mmol). The reaction mixture was stirred for 2 hours, then was added ether (2 ml), the mixture was repeatedly shaken with ether, removing the upper colored layer. The obtained viscous oil solidified upon addition of petroleum ether. The precipitation ottagonale in a centrifuge and dried.

Yield: 7 mg (70%). Rt(B) 19.51.

Similarly were obtained including the following compounds: LCTA 1597 (methylamide 1'-des-(2,3-dihydroxy-n-buterol)-1'-carbox the olivomitsina A), LCTA 1598 (amide 1'-des-(2,3-dihydroxy-n-buterol)-1'-carboxylicacid A), LCTA 1600 (3-hydroxypropylamino 1'-des-(2,3-dihydroxy-n-buterol)-1'-carboxylicacid A), LCTA 1601 (adamantylamine 1'-des-(2,3-dihydroxy-n-buterol)-1'-carboxylicacid A), LCTA 1964 (methyl ester of L-alanine 1'-des-(2,3-dihydroxy-n-buterol)-1'carboxylicacid A), LCTA 1973 (D-galactosamide 1'-des-(2,3-dihydroxy-n-buterol)-1'-carboxylicacid AND LCTA 1974 (4-forbindelse 1'-des-(2,3-dihydroxy-n-buterol)-1'-carboxylicacid). These compounds correspond to the Formula 2, where the values of R5presented in table 1.

Table 1
Data HPLC and mass spectrometry
ConnectionR5Rt(system)Mass spectrum (ESI MS)Class of amine introduced into the reaction
Calculated [M]Found [M+Na]+1
LCTA 1498HE15.41 (A)C55H78O251138.481137.49* -
LCTA 1597NHCH316.60 (A)C56H81NO241151.511174.54Alkylamine
LCTA1598NH213.94 (A)C55H79NO241137.501160.34NH2
LCTA 15996.21 (A)C59H88N2O241208.571231.47Substituted alkylamine with the amino group
LCTA160012.90 (A)C58H85NO251195.541218.57Substituted alkylamine with a hydroxyl group
LCTA 160130.11 (B)With65H93NO241271.611294.64Cycloalkylation
LCTA 196419.51 (B)C59H85NO261223.541246.55Substituted alkylamine (amino acid)
LCTA 197313.27 (B)C61H89NO291299.551298.55*2-Amino-2-methoxybenzoate
LCTA 197416.38C62H84NO241245.321268.53Benzylamine with a substituent in the aromatic nucleus
*[M-N]-1

Example 5. Obtaining L-glutamate N,N-diethylaminoethylamine 1'-des-(2,3-dihydroxy-n-buterol)-1'-carboxylicacid A (LCTA-1852)

To a solution of N,N-diethylaminoethylamine 1'-des-(2,3-dihydroxy-n-buterol)-1'-carboxylicacid AND (LCTA 1599) (100 mg, 0.083 mmol) in Meon (3 ml) was added a solution of L-glutamic acid in water (0.5 ml). The mixture was stirred for 15 minutes at room temperature, acetone was added (10 ml), concentrated in vacuo to small is the volume (~0.5 ml). Acetone was added (1 ml), ethyl acetate (1 ml), petroleum ether (10 ml). The precipitation was filtered, washed with petroleum ether, and dried.

Yield: 100 mg (90%).

Example 6.

The study of the antiproliferative activity of the claimed new semi-synthetic analogues olivomitsina And was conducted on the culture of tumor cells of large intestine cancer NTS. Data on the antiproliferative activity of the studied derivatives olivomitsina And presented in table 3

Table 3
Antiproliferative activity olivomitsina and new semi-synthetic analogues olivomitsina And against tumor cell adenomas of the colon line NTS and human leukemia K-562 line (MTT-test, 72 h, 37°C, shows the average results of the two measurements).
ConnectionIC50*(µM)
HCT-116K-562
Olivomycin And0.020.045
LCTA 149822.2
LCTA 1597 0.12-
LCTA 15980.1-
LCTA 15990.020.045
LCTA 18520.040.05
LCTA 16000.16-
LCTA 16010.18-
LCTA 19640.020.055
LCTA 19740.3-
IC50- the concentration of a compound that causes death of 50% of cells

Example 7.

The study of antitumor activity of the drug LCTA 1599 when multiple daily injection in comparison with oligomycin were performed on mice with lymphoma R. Female B6D2F1 mice, weighing 20 to 25 g, inoculated intraperitoneally to 106ascitic tumor cell lymphoma R on day 0. The drugs were injected intravenously 1 times a day, every day from 3 to 7 (table 4).

Table 4
Comparison of activity olivomitsina, LHT-1599 model ascitic lymphoma R.
No. of gr.OlivomycinLHTA 1599Δ0→7Δ0→11ALE (range)WPGLH
mg/kg/smg/kg/s%%%l/n (%)
1the intact100±3*102±2*0/5 (0)
2--119±2119±29,1 (7-12)0/15 (0)
3485±2*71±1*12,0 (5-17)3 13/15 (87)
42104±2*114±312,3 (10-14)350/10 (0)
51117±3123±211,3 (8-13)240/10(0)
64103±1*104±5*13,9 (12-18)520/9 (0)
72114±2111±311,7 (10-14)280/10 (0)
81122±2122±210,4 (8-13)140/10(0)
Notes intact - mice without tumors and treatment. Δ0→7and Δ0→11- change of body weight for 7 and 11, the body weight at day 0 is taken as 100%. ALE - life expectancy. UPG - increasing life expectancy. LH - drug deaths. l/n in the numerator the number of mice died in the lethal toxicity of the drug, in the denominator - the total number of mice in the group. * - significant difference from control tumor growth (gr).

As can be seen from the presented data, olivomycin at a dose of 4 mg/kg highly toxic (dramatic weight loss all mice, LH=87%). Preparation of LHT-1599 in the studied conditions is not toxic and causes a strong antitumor effect in a dose of 4 mg/kg, At this dose can be increased. The lifespan of mice with lymphoma R, which injected drug LHTA 1599, was higher compared with the control group (UPG to 52%). The introduction of the drug LCTA 1599 inhibited the accumulation of ascites, which was reflected in a highly reliable slow increase in body weight, body weight of control mice increased to 7 days to 119% due to the accumulation of ascites.

Example 8.

The study of antitumor activity of the drug LCTA 1599 with a repeated (every 4 days) in comparison with oligomycin were performed on mice with lymphoma R. Female B6D2F1 mice, weighing from 19 to 23 g, inoculated intraperitoneally to 106ascitic tumor cells is infamy R on day 0. The drugs were injected intravenously 1 time per day 1, 4, 7, 10 and 13 C. In group 3 - 3 mouse received 5 injections at 4 - 1 mouse, gr - 4 mouse (table 5).

Table 5
Comparison of activity olivomitsina, LHT-1599 model ascitic lymphoma R.
No. of grOlivomycinLHTA 1599Δ0→7Δ0→10Days of deathALEWPGLH
mg/kg/smg/kg/s%%%l/n (%)
1the intact100±2*99±2*Scored 170/5 (0)
2-127±2125±29, 9, 9, 10, 10, 11, 11, 11, 11, 1110,2 (9-11)0/10 (0)
34108±3*107±2*12, 13, 14, 15, 1513,5 (12-15)321/5 (20)
42118±2*120±211, 13, 13, 13, 1412,8 (11-14)250/5 (0)
54118±1*118±2*13, 14, 14,14,2 (13-16)390/5 (0)
14,16
Notes: intact mice without tumors and treatment. Δ0→7, Δ0→10- change of body weight for 7 and 10 days, the body weight at day 0 is taken as 100%. ALE - life expectancy. UPG - increasing life expectancy. LH - drug deaths. l/n in the numerator the number of mice died in the lethal toxicity of the drug, in the denominator - the total number of mice in the group. * - significant difference from control tumor growth (gr).

Changing the mode of administration of drugs has led to some of the best endurance olivomitsina. Olivomycin at a dose of 4 mg/kg caused weight loss and death after 5-second injection only 1 mouse (LH 20%). Preparation of LHTA 1599 in the studied conditions is not toxic and causes a strong antitumor effect in a dose of 4 mg/kg/S.

Example 9.

The study of antitumor activity of the drug LCTA 1852 with a repeated (every 4 days) in comparison with oligomycin were performed on mice with melanoma b-16. Female B6D2F1 mice inoculated subcutaneously with 106of B16 melanoma cells on day 0. Drugs introduced on days 1, 4, 7, 10, 13/(fivefold introduction) or in the days 1, 4, 7, 10, 13, 16, 19, 22 in/in (eightfold introduction). Mouse scored at day 28 (03.07.09) (table 6).

Because the activity Olivo did not depend on the number of introductions, sample merged.

Table 6
Comparison of activity olivomitsina, LHTA 1852 on the model of melanoma b-16
No. of gr.MedicationDoseThe options at the bottom (28):
MOTROMPMSMT-MORK (%)LH/n (%)
mg/kg/smg%mgmg% d
1the intact--1178±3577±4uu108±1uu-0/10 (0)
2CROS02647±4641193±43243±31 93±35/8 (62,5)0/25 (0)
3Olivomycin2×51388±472481078±44183±2795±42/8 (25)0/8 (0)
4Olivomycin2×81465±581451126±52155±1597±52/10 (20)0/10 (0)
6LHTA-185210×5423±172uu731021±25uu188±2298±21/10 (10)0/10 (0)
8LHTA-18525×81283±458u521070±36i,u203±3395±2 3/10 (30)0/10 (0)
9LHTA-185210×8410±109uu851088±82171±2194±45/10 (50)0/10 (0)
Notes: the AOC control of tumor growth. TRO - inhibition of tumor growth. MO, MP, MS, MT is the mass of the tumor, liver, spleen, body. MT-MO - body weight without
tumor (mass housing). Tumors developed in all mice. RK - cancer cachexia is a strong weight loss in end-stage malignant disease. LH - drug deaths, n is the number of mice. In the group of mice not treated with the drugs (CROS) to the time of slaughter, fell in the development of neoplastic disease 4 out of 25 mice. * in this group introduction olivomitsina led to a strong weight loss 3 out of 5 mice, the u - P<0,05; uu - P<0,01 compared to gr CROS.

As can be seen from the presented data (table 6, Figure 1), for the preparation of LHT-1852 observed significant differences from the AOC 19 (P=0.02), 25 (P=0.007), 28 (P=0,0015). For olivomitsina significant differences from CROS are observed only at 28 (P=0.008). Thus, the antitumor effect of the preparation is LHTA 1852 significantly stronger what effect olivomitsina 21 with (almost significantly (P=0,055), 25 (P=0.02), 28 (P-0,03).

Thus, with the introduction of the LCTA connection 1599 (at doses of 2 and 4 mg/kg) or LHTA 1852 (10 mg/kg) at different modes of intravenous injection, a marked antitumor activity of these drugs and no toxic death of mice at different models of tumors in mice. The life span of the treated mice was higher than that in control mice (UPG to 52%). Introduction LCTA 1599 inhibited the accumulation of ascites, which was reflected in a highly reliable slow weight gain. When applying olivomitsina And in doses up to 4 mg/kg per day intraperitoneally was observed toxic destruction of the majority of mice.

Thus, the proposed new method of modification of the antibiotic group aureolus acid olivomitsina And allows to obtain new derivatives olivomitsina And possessing advantages over the original antibiotic oligomycin, namely high antitumor activity and low toxicity of the compounds.

1. Derivatives of the antibiotic group aureolus acid corresponding to the formula 2,

where R5represents hydroxyl, NH2, 2-amino-2-deoxyhexose, C3-C10aminosilanes or C1-C5-aminoalkyl with a straight or branched hydrocarbon chain optionally substituted by one or more hydroxyl, or amino groups, benzyl, optionally having substituents in the aromatic ring.

2. The method of obtaining derivatives of the antibiotic group aureolus acid olivomitsina And according to claim 1, which consists in the selective oxidation of the side chain of the aglycone olivomitsina And reaction with periodate sodium (Scheme 1), followed by the amidation reaction of the obtained key intermediate 1'-des-(2,3-dihydroxy-n-buterol)-1'-carboxylicacid And (formula 3)

with appropriate amines in the presence of a condensing agent.



 

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SUBSTANCE: invention relates to compounds of formula II: where R1 can be 1-β-D-glucopyranosyl or 2-(1-β-D-glucopyranosyl)-1-β-D-glucopyranosyl, and R2 can be hydrogen, 1-β-D-glucopyranosyl, 2-(1-β-D-glucopyranosyl)-1-β-D-glucopyranosyl, 2,3-bis(1-β-D-glucopyranosyl)-1-β-D-glucopyranosyl, 2-(1-α-L-rhamnopyranosyl)-1-β-D-glucopyranosyl, 2-(1-α-L-rhamnopyranosyl)-3-(1-β-D-glucopyranosyl)-1-β-D-glucopyranosyl, or 2-(1-β-D-xylopyranosyl)-3-(1-β-D-glucopyranosyl)-1-β-D-glucopyranosyl.

EFFECT: compounds can be used as sweetening agents which do not have nutritional qualities in food and drinks.

35 cl, 8 ex, 23 dwg

FIELD: chemistry; pharmacology.

SUBSTANCE: invention refers to derivatives of olivomycin I antibiotic of aureolic acid group with anticancer activity by structural formula as follows, where R5 represents hydrogen, C3-C10-cycloalkyl or C1-C4-alkyl with straight or branched hydrocarbon chain, optionally substituted with one or more hydroxyls. Additionally, invention concerns method of production of the specified derivatives, consisting in selective modification of 2'-carbonyl group of olivomycin 1 by reaction with aminooxyacetic acid, followed by amidation reaction of produced intermediate 2'-(carboxymethoxime)olivomycin 1 and related amines condensing agent added.

EFFECT: method of production of antibiotic derivatives with anticancer activity.

2 cl, 5 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: in derivatives of colchicine of general formula (I) X is oxygen or sulphur, particularly - to 3-O-β-D- xylopyronozyl-3-O-demethyltiocolchicine and 3-O-β-L- xylopyrano-zyl-3-O-demethyltiocolchicine.

EFFECT: efficient for preparation of miorelaxant medications, medications for treatment of inflammatory conditions, which influence muscular system, and antigout medications.

11 cl, 2 tbl, 6 ex

FIELD: medicine; pharmacology.

SUBSTANCE: crystal epirubicine hydrochloride of type II has diffraction pattern of X-ray powder scattering providing average diffraction angles (2θ) and relative intensities P(%), presented in the Table indicated below:

EFFECT: effective application of new crystal form for cancer treatment in people and animals.

6 cl, 7 dwg, 4 tbl, 6 ex

Carrier of antigens // 2322259

FIELD: biotechnology, immunology.

SUBSTANCE: invention proposes a carrier of antigens as a lipid complex consisting of glycoside, cholesterol and lipid. As glycoside a carrier comprises holotoxin A1, and as lipid - monogalactosyldiacyl glycerides (MGDG) of sea macrophytes taken in the weight ratio 3 (holotoxin A1) : 2 (cholesterol) : (2-6) (MGDG). Prepared glycoside-cholesterol-lipid carrier shows stretched threadlike-tubular structure. Use of the prepared carrier of antigens allows enhancing the immunogenic activity of vaccine preparations, and to decrease or remove completely hemolytic toxicity of holotoxin A1, and to eliminate inflammatory, painful, toxic and hemolytic effects of vaccines.

EFFECT: improved and valuable medicinal properties of carrier and vaccines.

4 dwg, 11 ex

FIELD: biotechnology.

SUBSTANCE: invention relates to carriers of antigens. Proposed carrier represents lipid-saponin complex consisting of a mixture of triterpene glycoside, cholesterol and glyceroglycolipid. Cucumarioside A2-2 is used as triterpene glycosides, and monogalacosyldiacylglycerides of sea macrophites are used as glyceroglycolipids. Method involves mixing solutions of cholesterol and glyceroglycolipid in chloroform, evaporation of mixture until dry under vacuum, addition of 3 weight parts of 0.4% aqueous solution of cucumarioside. Then the mixture is solubilized and the total concentration of cholesterol and glyceroglycolipid is brought about to 2 mg in 1 ml of suspension with phosphate-saline buffer at pH 7.2 followed by sonication of the prepared suspension by ultrasonic oscillation device at frequency 20 kHz for 5 min. Method provides preparing the effective adjuvant form of the carrier.

EFFECT: improved preparing method of carrier.

6 cl, 8 dwg, 13 ex

The invention relates to new derivatives of colchicine that has antiproliferative, antineoplastic, anti-inflammatory and relaxing muscle activity, processes for their preparation and the pharmaceutical ready preparative forms

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), having histone deacetylase (HDAC) enzyme inhibiting action, stereoisomers, hydrates, solvates and pharmaceutically acceptable salts thereof, compounds of formula (II), compounds selected from a list, a method of producing compounds of formula (I), a pharmaceutical composition, an inhibition method and methods of treating using compounds of formula (I). In formulae

and

R denotes substituted or unsubstituted groups selected from (C6-C10)aryl, (C3-C12)cycloalkyl, heteroaryl, (C6-C10)aryl (C1-C6)alkyl and heterocyclyl; where the heterocyclyl hereinafter is a 5-10-member ring radical which consists of carbon atoms and 1-5 heteroatoms selected from nitrogen, oxygen and sulphur, and heteroaryl hereinafter is an aromatic heterocyclyl, and each aryl, cycloalkyl, heteroaryl, arylalkyl and heterocyclyl can be substituted with one or more substitutes selected from halogens, including fluorine, chlorine, bromine, iodine, (C1-C6)alkyl, (C1-C6)alkoxy, (C6-C10)aryl, halogen(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkoxy, -O-(C3-C12)cycloalkyl, -O-CH2-(C3-C12)cycloalkyl, hydroxyl, NRaRb and ORa, where Ra and Rb independently denote (C1-C6)alkyl and aryl; R1 denotes (C6-C10)aryl; R2 and R3 independently denote hydrogen, (C1-C6)alkyl, -COOR5, -CONR5R6, -CH2NR5R6, -CH2CH2NR5R6, -CH2CH2OH or -CH2OH; provided that one of R5 or R6 is hydrogen or unsubstituted alkyl, the other is neither hydrogen nor unsubstituted alkyl; R5 and R6 independently denote hydrogen, (C1-C6)alkyl, (C3-C12)cycloalkyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl, heteroaryl or heteroaryl(C1-C6)alkyl, which can be unsubstituted or substituted; or R5 and R6 can be combined to form a saturated or unsaturated 3-8-member ring having 0-2 heteroatoms, including N, O or S; where the heteroaryl hereinafter is a 5-10-member ring radical consisting of carbon atoms and 1-5 heteroatoms selected from nitrogen, oxygen and sulphur, and each alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl can be substituted with one or more substitutes selected from halogen, including chlorine, fluorine, bromine or iodine,(C1-C6)alkoxy and NRaRb; R4 denotes OH, (C6-C10)aryl, ortho-substituted aniline or amino (C6-C10) aryl, which can be optionally substituted with one or more groups selected from halogens, including fluorine, chlorine, bromine, iodine, hydroxyl, amino groups or (C6-C10)aryl; X denotes -NR7-, -CONR7- or -N R7CO; R7 denotes hydrogen or (C1-C6)alkyl; Y denotes (C6-C10)aryl or (C6-C10)aryl(C2-C6)alkenyl; m is an integer from 0 to 1; n is an integer from 0 to 1; o is an integer from 0 to 7; and p is an integer from 0 to 1.

EFFECT: improved method.

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely oncology, and is applicable for treating rectal cancer with synchronous remote metastases. That is ensured by radiation therapy together with radio modifiers and combined with chemotherapy followed by radical resection of a primary tumour and remote metastases. The radio modifiers are presented by the intrarectal introduction of metronidazole as a part of a composite mixture containing sodium alginate and 2% dimethylsulphoxide, and also local microwave hyperthermia. The chemotherapy is presented by a two-day intensive course of chemotherapy FOLFOX6 involving high doses of platinum and 5-fluorouracil in the form of the 48-hour infusion.

EFFECT: method allows reducing total length of treatment, enabling a complete course of effective preoperative radiation chemotherapy with minimum toxicity in a relatively short time, performing earlier sphincter-preserving operations with well-timed resection of the primary tumour, regional and remote metastases ensured by implementing mechanisms, chemosensitisation and synergic effect of said radio sensitising agents.

2 ex

FIELD: medicine.

SUBSTANCE: invention refers to cell biology. Dopamine and/or its synthetic analogues, particularly substituted 3,4-dihydro-2(1H)-pyrimidinthione is applied as a cytotoxic agent having an effect on human cancer cells in culture.

EFFECT: presented substances can find application in medicine as a base for developing dosage forms used for therapy of malignant growths.

5 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound having chemical structure of formula II , all salts and stereoisomers thereof, where the value of radicals D, A2 and B are as described in paragraph 1 of the claim. The invention also relates to a composition having activity as a c-kit and c-fms modulator, a method of treating a subject suffering from a disease or condition mediated by c-kit and c-fms and a kit for modulating c-kit and c-fms.

EFFECT: novel compounds which can be useful in treating c-kit-mediated diseases or conditions and/or c-fms-mediated diseases or conditions are obtained and described.

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: present invention refers to a pharmaceutical composition and to a drug of 1,3-diethylbenzimizadolium salts of general formula: wherein X is an anion.

EFFECT: there are produced the compositions exhibiting high anti-cancer activity.

2 cl, 3 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is application of an effective amount of the composition containing nanoparticles containing taxane and a carrier protein for preparing a drug for a proliferative disease in a combination with an effective amount of at least one other chemotherapeutic agent specified in a group consisting of antimetabolite, platinum agents, alkylating agents, tyrosine kinase inhibitors, anthracycline antibiotics, vinca alkaloids, proteasome inhibitors, macrolides, a therapeutic antibody, an antiangiogenic agent, geldanamycin, 17-AAG and topoisomerase inhibitors; a related composition and a kit.

EFFECT: shown higher clinical effectiveness in combined treatment of even hard-to-treat cancers, including cancer of lungs and pancreatic cancer with no new toxicity cases detected.

46 cl, 9 dwg, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to pharmacology and concerns liquid compounds intended for RAF kinase inhibition, angiogenesis inhibition and/or cancer treatment, as well as to methods for preparing liquid compounds. The compounds contain {1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)pyridine-4-yloxy]-1H-benzimidazol-2-yl}(4-trifluoromethylphenyl)amine (the compound of formula I), its pharmaceutically acceptable salt or a mixture of any of two or more of said compound or its salts, a hydrophilic solvent containing ethanol, polyethylene glycol or their mixture, a lipophilic solvent containing fatty acid and an emulsifier. A method for making the liquid compound involves mixing the components specified above.

EFFECT: group of inventions provides higher bioavailability of the compound of formula I.

39 cl, 7 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to biotechnology and immunology. One proposes: JAM-A protein antibody or functional fragment thereof, hybridoma secreting such antibody, nucleic acid, expression vector and host cell as well as a method for the antibody and composition production. One considers application of the JAM-A protein antibody or functional fragment thereof.

EFFECT: invention usage ensures creation of new JAM-A protein antibodies which may be further applied in treatment or prevention of diseases related to proliferation of tumour cells extracting JAM-A protein.

34 cl, 31 dwg, 5 tbl, 19 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely dermatovenerology and is applicable for treating chronic infectious urethritis complicated by prostatitis. That is ensured by taking azithromycin 1.0 g (sumamed) once a day in 1st-7th-14th days combined with the complex therapy. The complex therapy involves rectal suppositories Dalargex, 1 suppository daily at bedtime No.10, prostate massage, rectal laser therapy and daily application of fluoroquinolone - gemifloxacin (factive) 1 tab. (320 mg) a day for 14 days.

EFFECT: method enables prolonged remission of the disease, higher life quality of the patients, recovers the reproductive function due to improved eradication of the opportunistic flora in the prostate secretion contents.

4 ex

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