5-oxypyrimidine derivative possessing antineoplastic activity

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new antineoplastic drug representing 2-isobutyl-4,6-dimethyl-5-oxypyrimidine of the general formula I specified below. The drug may be used for an adjuvant antineoplastic immune therapy. The invention also refers to a method for preparing 2-isobutyl-4,6-dimethyl-5-oxypyrimidine. According to the method, isocaproic acid amide reacts in ice-cold acetic acid with chloracetyl acetone to form the respective oxazole which reacts with aqueous ammonia which leads to preparation of the above compound.

EFFECT: what is disclosed is a manifested tumour growth inhibition with no signs of the toxic effect on somatic characteristics of tumour-carrier mice.

3 cl, 9 tbl, 6 ex

 

The invention relates to a new derivative of 5-oxopyrimidine, which can be used in the treatment of cancer for adjuvant antitumor immunotherapy and recovery of bone marrow hematopoiesis after application of radiation therapy.

Modern medicine has a wide range of drugs for the treatment of cancer. The introduction into clinical practice of antitumor monoclonal antibodies (MAB) and low molecular weight inhibitors tyrosinekinase was an important step towards the creation of target-directed (targeted) means [Yang EV, Guo Y.J., Zhang, K. et al. Butein, a specific protein tyrosine kinase inhibitor // Biochem. Biophys. Res. Commun. - 1998. - Vol.245. No. 2. - P.435-438. Yang E.B., Guo Y.J., Zhang K. et al. Inhibition of epidermal growth factor receptor tyrosine kinase by chalcone derivatives // Biochem. Biophys. Acta. - 2001. - Vol.1550. No. 2. - P.144-152.].

The use of "targeted" funds in clinical Oncology has been a breakthrough in the treatment of certain tumors (e.g., Hematology), but in many cases, their efficiency is lower than expected, in addition, monoclonal antibodies have a wide range of serious side effects (Corman D. fundamentals of cancer chemotherapy. - M. 2006, p.9-359; Protsenko S.A. ways to individualize cancer therapy. Practical Oncology. 2007, Vol.8, No. 4, s-181). The introduction of new drugs has not solved the problem of drug resistance of tumors. In recent years, in addition to target, actively develop modern methods of immunotherapy in Oncology is to fight against various tumors and relieve side effects of using drugs.

In patients with cancer the growth of most malignant tumors is accompanied by severe disturbances of the immune response. In this regard, one of the most important areas is the development of new drugs for immunotherapy of cancer.

The main tasks of modern immunotherapy of tumors:

1) the reduction of side effects of traditional cancer therapy (mielo - and immunosuppression);

2) prevention of the recurrence of the tumor;

3) direct antitumor effect.

Currently, the proven efficacy of cytokines [interferon-alpha, interleukin-2 (Roncoleukin), tumor necrosis factor] in various malignant tumors as monotherapy and in combination with chemotherapy. However, small doses are often insufficient, and the high - toxic. In particular, recombinant human interleukin-2 (Roncoleukin), produced using recombinant DNA technology, using a strain of E. coli containing the modified gene of the human IL-2. (The mechanism of action of RNA-411 such Roncq is Leikin). Roncoleukin stimulates endogenous immune protection, activates T-lymphocytes and natural killer cells, promotes the production of antibodies by b-cells, stimulates cellular secretion of secondary cytokines, runs the mechanisms of the release of hormones. Evidence - hyperdiploidy kidney cancer, metastatic melanoma. However, high-dose immunotherapy with IL-2 is mostly of historical value and is almost never used because of possible complications caused by the toxicity of the drug (chemotherapy of neoplastic diseases. Edited by NI Perevozchikova. - M. 2013, p.49-54).

Finding new means for the treatment of neoplastic diseases, their synthesis and use is an important task.

The present invention relates to novel means adjuvant antitumor immunotherapy, representing a derivative of 5-oxopyrimidine, in particular 2-isobutyl-4,6-dimethyl-5-oxopyrimidine (1, SNK-411) the following structural formula:

Previously the specified connection was registered as a connection with RN890641-03-9 in DB ACS on STN REGISTRY. The method of obtaining this compound and its use has not been known. 2-Isobutyl-4,6-dimethyl-5-oxopyrimidine (1, SNK-411) synthesized in the Department of chemistry NII pharmacology behalf of nine CENTURIES RAMS. Antitumor what effect the connection of the specified formula and activating effect on bone marrow hematopoiesis suggest the use of this compound for anticancer immunotherapy in medicine.

The synthesis is based on the fact that amide ISO-Caproic acid vzaimodeistvie in glacial acetic acid with chloroacetylation with the formation of the corresponding oxazole. Interaction oxazole with a water solution of ammonia in an autoclave leads to the formation of the claimed compounds.

Example 1. 11.4 g (0,063 mol) of 2-isobutyl-4-methyl-5-acetyl oxazole heated on an oil bath with a tenfold excess of 33% aqueous ammonia solution in an autoclave at a temperature of 170°-180°C for 10 hours, cooled the reaction mass is then poured the solution into a flask and evaporated in a water-jet pump vacuum and recrystallized from water. Obtain 7.0 g (62%) of 2-isobutyl-4,6-dimethyl-5-oxopyrimidine with a melting point of 118-120°C.

Found, %: C To 66.3; H 8,90; N 15,42. C10H16N2O1.

Calculated, %: C 66,67%; N 8,87%; N 15,56; PMR spectrum (DMSO - d6), BMD: 0,84 (6N, g, J 6,6 (CH3)2); 2,10 (1H, S, CH); 2,31 (6N, S, CH3); 2,53 (2N, g, J 7,0 CH2); OF 8.90 (1H, S, OH).

Pharmacological study of the compounds obtained

When learning connection 1 (SNK-411) were identified various properties, in particular as a result of drug therapy 1 mice bearing grafts carcinoma of the lung Lewis found a pronounced inhibition of tumor growth with no signs of toxic effects on somatic indicators of masaofurusawa. The antitumor effect of the drug was confirmed by the modulation of the activity of natural killer cells of humans and mice. An important feature of the drug is its activating effect on the proliferation and migration of hematopoietic stem cells (HSCs). Increased proliferation CCM under action 1 can be used in medical practice when restoring lymphohemopoietic from radiation, chemotherapy effects, and when immunosuppression in cancer. These properties connection 1 indicate the availability of its investigation as anti-cancer agents and for recovery of bone marrow hematopoiesis after application of radiation therapy.

Example 2. Acute toxicity of the compound I defined in the experience of 50 outbred male mice weighing 18-20 g intraperitoneal injection. LD5About amounted to 474 (416-540) mg/kg calculated according to Litchfield and Wilcoxon signed. Classification Sidorov, K.K. connection 1 refers to low-toxic pharmacologically effective substances.

Example 3. We studied the effect of compound 1 on somatic indicators, the number of cells and the growth of experimental tumor strain carcinoma of the lung Lewis (obtained from laboratory strains of WANTS them. N.N. Blokhin) in mice F1(CBA×C57B1/b), and anti-tumor efficacy is ü domestic ftorpirimidinu ftorafura, used in medical practice for the treatment of solid tumors. Tumors from C57BL/6 mice in the experiment were inoculated subcutaneously to mice F1(CBA×C57B1/b) in the region of the armpit 0.5 ml tumor suspensions. The antitumor effect was detected on tumor size at the time of slaughter. The effect of compound 1 on the state of the mice-carriers of tumour (C57BL/6) and tumor growth was assessed after an early (2-8 days), deferred therapy (9-15 days), fractional introduction to a/b connection 1 at a dose of 50 mg/kg once daily for 7 days (total dose equal to 3/4 LD5O) and a single injection of a total dose on the 8th day after inoculation of the tumor (tables 1 and 2).

When all modes of introduction connections 1 mice-tumor-bearing registered significant inhibition of tumor growth.

Action connection2-8 daysday 89-15 days
Braking leukocytosis43% P<0,0129% P<0,014% P>0,05
The inhibition of tumor growth39% P<0,0123% P<0,0527% P<0,05

Lymphotropic potential is soedineniya 1, as measured by the increase in weight of the thymus of mice-carriers of tumour, also most pronounced when this mode and early therapy of tumors.

Connection 1 partially corrects leukemoid reaction induced by tumor growth, reducing the number of kariolou in peripheral blood and tumor growth. Correction leukocytosis and tumor growth by compound 1 is most pronounced during early therapy. Connection 1 has no effect on body weight and condition of the reticuloendothelial organs (spleen, liver) mice-carriers of tumour. Given the available literature data on the existence of enhanced antitumor efficacy ftorafura when combined with the natural pyrimidine uracil metabolite, studied the combination of compound 1 with Ftorafur order potentiation and enhance its antitumor efficacy (table). Therapy Ftorafur at a dose of 400 mg/kg once spent 8 days after inoculation of the tumor when reaching the calculated masses of 1.5-2.5% of body weight. Compound 1 (50 mg/kg, once a day W/in 7 days) was administered to (2-8 days) and after (9-15 days) therapy Ftorafur or once at the same total dose simultaneously with Ftorafur on the 8th day after inoculation of the tumor. However, when one of the used modes not detected a significant reduction in toxicity and potentiation of the anti-Christ. opujoleva efficiency ftorafura. Thus, in the monotherapy connection 1 mice bearing syngeneic grafts carcinoma of the lung Lewis found a pronounced inhibition of tumor growth with no signs of toxic effects on somatic indicators mice-carriers of tumour. Not revealed a significant reduction in toxicity and potentiation of antitumor efficacy of cytostatic ftorpirimidinov series - ftorafura when combined with the application connection 1.

Example 4. To confirm the anticancer activity of compound 1 was studied its effect on the activity of natural killer cells (ECC). Cytotoxic activity of ECC was determined using radiometric techniques against labeled3N-uridine cells of human erythromyeloleukemia K-562 line in suspension of mononuclear cells from peripheral blood. Thus was obtained a suspension of mononuclear cells heparinized peripheral blood of normal healthy donors, making it the drug at various concentrations for 1 hour, after which the drug was removed by centrifugation. Found that compound 1 possesses dose-dependent modulatory effect on the activity of ECC (table 3).

Identified immunomodulating activity. The strongest stimulating effect (an increase of 50%) had a dose of 2 μg/ml, a dose of 0.2 is 20 µg/ml stimulated ECC 20%, and the dose of 200 µg/ml did not work. Thus, compound 1 has a strong modulating effect on the activity of ECC person.

Example 5. The effect of compound 1 on the proliferation of hematopoietic stem cells (HSCs) in the bone marrow and the formation of endogenous colonies in the spleen of mice

The F1 mice (C57B1/hswa) was administered intraperitoneally compound 1 at doses of 0.1-100 μg/mouse. After 1 day, the mice were irradiated in a sublethal dose of 6.0 Gy, after which survives about 1% of hematopoietic stem cells. After another 8 days, the mice were scored, recorded spleen in a solution of Bush and counted the number of macroscopically visible endogenous colonies under a magnifying glass. In the result set (table 4)that at doses of 0.1-100 μg/mouse the drug exerted a stimulating effect on the formation of endogenous colonies after 8 days after irradiation. The stimulating effect is most pronounced at doses of 0.1 and 10 μg/mouse (0.005 and 0.5 mg/kg).

To determine the proliferation CCM bone marrow in mice after 1 day after administration of compound 1 was extracted femur, washed bone marrow and cultured cells 1.5 hours in the presence of 1 mg/ml hydroxyurea, inactivating proliferating cells. After incubation, the cells treated with oximosilane and untreated (control)was injected at 5×104/0.5 ml of medium syngeneic recipients irradiated in flew the Noah dose (table 5). After 8 days, the mice were scored, recorded spleen and counted the number of colonies, as above. The content of the CCM 8-phase of the cell cycle was calculated by the formula:

where a is the number of CCMS in S-phase (%)

and the number of colonies from bone marrow, inkubirovanie without hydroxyurea,

b - the number of colonies from bone marrow cells, inkubirovanie with oximosilane.

The study established (table 5)that the connection 1 has a dose-dependent ability to stimulate the proliferation of SCC.

Thus, compound 1 induces pronounced proliferation CCM bone marrow (tested on suicide oximosilane) at doses of 0.1 and 1 μg/mouse (0.005 and 0.05 mg/kg, the proliferation rate were, respectively, 51%and 35%, in control - 13%). Doses of 10 and 100 µg/mouse did not increase the proliferation of SCC.

Example 6. The effect of compound 1 on the migration of the CCM.

At different times after administration of compound 1 in mice was determined by the content of the CCM in the peripheral blood, which reflects the level of migration of the CCM. To this end heparinised blood was diluted 2 times with saline and were injected in 0.2 ml intravenously syngeneic mice exposed to a lethal dose.

In the result set (table 6)that the compound 1 at a dose of 1 μg/mouse (0.05 mg/kg) possesses a strong ability to induce the release of CCM in accessories the historical blood, especially after 3 days. After 1 day the contents of the CCM was 72,2/ml (control 17,8), and after 3 days - 233/ml (control - 13,3).

For immunotherapy of tumors the most important indicators are the activation of antitumor immune response NK cells and cytotoxic T-killer cells. Assessment was conducted population composition of blood lymphocytes, spleen and thymus of C57BL/6 mice by the method of four-color cytometrical analysis on flow-laser cytometer EPICS XL 4 color (Beckman Coulter, USA).

In examining the impact of TNC-411 on the number of NK cells in the blood and organs from mice of C57/BL6 were obtained the following results:

CD335+(NKp46) is the main marker of NK-cells in mice, NKp46 is expressed on the surface of the activated NK cells, and the lytic activity of NK cells, mainly associated with this receptor.

Introduction only SNK-411 dose of 50 mg/kg, most significantly stimulated NK cells in 2.9, and 1.9, 2.5 times in the blood, spleen and liver, respectively, in comparison with the control. Joint introduction of the fit and the compounds caused only in the blood of a significant stimulation of NK 3.9 times compared to the group that received CP (table 7).

In examining the impact of TNC-411 on the contents of cytotoxic T-lymphocytes in the blood and organs from mice of C57/BL6 introduction SNK-411 at a dose of 25 mg/kg, most significantly stimulated T-killers 2.3 RA is in the blood and decreased 2.7 times in the spleen compared with control, and in the thymus and liver were observed trend of increasing T-killers. Introduction RNA-411 dose of 50 mg/kg significantly stimulated the content of T-killers 3.3, 1.4 times in the liver and thymus, respectively, compared with control. In the blood and spleen was observed a tendency to increase the T-killer cells (table 8).

When using the MTT-test initiated the study of the cytotoxic effect of the compounds SNK-411 in vitro.

The estimate of the direct cytotoxic effect of the compounds SNK-411 was performed MTT-test using human eritromicina K-562 line in comparison with doxorubicin hydrochloride and tecaform (Ftorafur). Compounds were tested in 4 parallel measurements at 4 concentrations of 10-8M, 10-7M, 10-6M, 10-5M. Evaluation of the results was performed colorimetrically. The optical density was measured on a spectrophotometer to advance tablets at λ=545 nm when λcomparison=630 nm. Next, to calculate the % survival of cells compared to control. Statistical analysis of obtained data was performed using Statistica 6.0 for t-criterion of student. The differences were considered statistically significant at p<0,05.

The most pronounced cytotoxic effects connection SNK-411 demonstrated at a concentration of 10-5M, which is comparable with the effect of doxorubicin g/HL at a concentration of 10-8M and tegafur is in a concentration of 10 -7M Thus, according initiated research connection SNK-411 has a mild cytotoxic effect on human eritromicina line K-562.

Thus, when studying the connection 1 (SNK-411) were identified various properties, in particular as a result of treatment with compound 1 mice bearing grafts carcinoma of the lung Lewis found a pronounced inhibition of tumor growth with no signs of toxic effects on somatic indicators mice-carriers of tumour. The antitumor effect of the drug was confirmed by the modulation of the activity of natural killer cells of humans and mice. An important feature of the drug is its activating effect on the proliferation and migration of hematopoietic stem cells (HSCs) and antitumor activity. Increased proliferation CCM under action 1 can be used in medical practice when restoring lymphohemopoietic from radiation, chemotherapy effects, and when immunosuppression in cancer. These properties connection 1 indicate the availability of its use as antitumor agents for recovery of bone marrow hematopoiesis. Compound 1 can also be used to enhance the protective functions of the body after the application of radiation therapy.

Table 1
The effect of compound I on somatic indices and growth of lung carcinoma Lewis with different modes of administration (M+m)
Groups of animalsThe number of animalsWeightLeukocytes, thousand in mm3Liver, gThe spleen mgThe thymus mgThe tumor weight, g
before therapyafter therapy
control of tumor growth1924,03±0,7122,90±0,4924,0±1,851,50±0,05337±16,235,60±2,202,71±0,22
the connection I, 50 mg/kg (2-8 days)1023,29±0,8523,97±0,9213,70±0,54 P<0,011,42±0,07329±14,4 42,50±2,831,65±0,26 P<0,01
the connection I, 50 mg/kg (9-15 days)1023,73±0,63results were 23.08±0,6723,10±2,081,47±0,04310±18,230,70±1,561,99±0,17 P<0,05
the connection I, 360 mg/kg (1 time per day 8)10results were 23.08±0,4322,63±0,4317,05±1.31 P<0,011,42±0,03310±14,537,10±1,412,10±0,20 P<0,05
Note: 1 day experience - inoculation of tumor strain

Table 2
The effect of compound I and ftorafura on somatic indices and growth of lung carcinoma Lewis with different modes of administration (M+m)
Groups of animalsThe number of animalsWeightLeukocytes, thousand in mm3 Liver, gThe spleen mgThe thymus mgThe tumor weight, g
before therapyafter therapy
control of tumor growth1924,03±0,7122,90±0,7924,0±1,851,50±0,05337±1635,60±2,202,71±0,22
the connection I, 50 mg/kg+Ftorafur, 400 mg/kg (2-8 days)1023,29±0,621,90±0,74of 14.12±0,85 P<0,011,42±0,08365±262I,30±1,011,54±0,16 P<0,05
the connection I, 50 mg/kg+Ftorafur, 400 mg/kg (9-15 days)1023,80±0,3322,74±0,4517,93±1,391,42±0,06345±2616,56±1,06is 1.81±0.17 P<0,05
Phys. solution+Ftorafur, 400 mg/kg
(2-8 days)
1023,05±0,7821,63±0,9115,96±1,51 P<0,051,51±0,08393±5526,44±1,762,33±0,24
the connection I, 300 mg/kg+Ftorafur, 400 mg/kg (1 time per day 8)1024,10±0,423,88±0,4221,17±2,141,59±0,05422±13,633,60±1,422,69±0,28

Table 3
The effect of compound 1 on the activity of ECC man
Dose 1 (mg/ml)Stimulation of the activity of ECC (%) P
0,221,4*<0,05
2,050,4*<0,05
20,019,8>0,05
200,00

table width="90%" border="1" cellpadding="0" cellspacing="0" frame="all"> Table 4The effect of compound 1 on the formation of endogenous colonies in the spleenthe dose of compound 1 (μg/mouse)the number of coloniesthe stimulation index-2,9±1,01,00,19,8±2,73,41,04,3±1,21,510,08,6+3,13,0100,04,5±1,01,6

td align="left"> -
Table 5
The effect of compound 1 on the proliferation of CCM bone marrow after 1 day after injection
The dose of compound 1 (μg/mouse)the number of colonies in the spleenthe number of CCM 8-phase %
without hydroxyureawith oximosilane
9,718,42
0,114,57,051,7
1,09,0of 5.8435,2
10,08,437,69,9
100,010,410,50

Table 6
The effect of compound 1 on the content of the CCM in peripheral blood
The dose of compound 1 (μg/mouse)number of CCMS in 1 ml of blood
after 1 dayin 3 days
-17,813,3
0,152,523,3
1,0722233,0
10,0 35,720,0
100,0of 45.720,0

Table 7
CD335+(NKp46)BloodSpleenLiver
Control7,7±1,112,4±3,811,6±1,0
Fits 200 mg/kg10,3±1,010,6±3,936,9±1,7**↑3.2 p
SNK-411, 25 mg/kg3,5±0,2**↓2.2 p10,1±0,418,2±2,4*↑1.6 p
SNK-411, 50 mg/kg23,4±2,2**↑2.9 p24,0±1,9**↑1.928,7±2,8**↑2,5 p
ZF+SNK, 25 mg/kg33,2±3,3**↑4.3 p12,4±1,023,7±2,6**↑B2,0 R
ZF+RNA, 50 mg/kg39,0±2,3**↑5.0 p14,4±0,939,3±3,0** ↑ 3,4 p

Table 8
CD8+BloodSpleenLiverThe thymus
Control6,4±0,714,8±3,46,5±1,14,3±0,5
Fits 200 mg/kg23,0±1,4**↑3.6 p18,2±1,830,1±1,9**↑of 4.620,7±0,9**↑4.8 p
SNK-411, 25 mg/kg14,4±0,9**↑2.3 p5,5±0,7**↓2,7 p11,5±2,1 (P=0.07)5,8±0,6
SNK-411, 50 mg/kg8,6±0,8 (p=0.06)12,4±0,921,2±2,2**↑3,3 p6,2±0,4**↑1.4 p
ZF+SNK, 25 mg/kg18,1±2,7**↑2.8 p19,1±1,824,0±2,5**↑3,7 p18,1±0,5**↑4.2 p
ZF+RNA, 50 mg/kg23,8±1,4**↑3.7 p 14,9±0,611,3±2,6 (p=0.15)19,8±1,2**↑4.6 p

1. Antitumor agent representing 2-isobutyl-4,6-dimethyl-5-oxopyrimidine

2. The method of obtaining 2-isobutyl-4,6-dimethyl-5-oxopyrimidine, based on the fact that amide ISO-Caproic acid interacts in glacial acetic acid with chloroacetylation with the formation of the corresponding oxazole, that communicates with an aqueous solution of ammonia leads to the formation of the claimed compounds.

3. Use as antineoplastic compound according to claim 1 for adjuvant antitumor immunotherapy.



 

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18 cl, 147 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new pyrimidine of the general formula (I), which possess properties of the inhibitor of CDK-kinase. In the general formula (I) R1 designates hydrogen, halogen, C1-C6alkyl, R2 designates C1-C10alkyl, C1-C10alkenyl, or C3-C10cycloalkyl which can be mono-, bi- or tricyclic or denotes one- or polysubstituted by identical or different substitutes from the number of hydroxy-group, halogen, C1-C6alkoxygroup, C1-C6kalkylthiogroup, -NH-(CH2)n-C3-C10cycloalkyl, C3-C10 cycloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy-C1-C6alkyl, C1-C6alkoxy-C1-C6alkoxy-C1-C6alkyl, -NHC1-C6alkyl, -N(C1-C6alkyl)2, C1-C6alkanoil, -CONR3R4, -COR5, C1-C6alkylOAc, where Ac indicates C1-C4alkylCO-group, carboxygroups, phenyl, 5-6-member heteroaryl, containing 1-2-heteroatom in the ring, selected from nitrogen, -(CH2)n- phenyl, -(CH2)n-5-6-member heteroaryl containing 1-2-heteroatom in a ring, selected from nitrogen, phenyl-(CH2)n-R5, -(CH2)nPO3(R5)2 and -R6 and -NR3R4C1-C10alkyl, or C3-C10cycloalkyl, in this case phenyl, C3-C10 cycloalkyl, heteroaryl, -(CH2)n-phenyl and -(CH2)n heteroaryl can be one or polysubstituted by identical or different substitutes from halogens, hydroxygroup, C1-C6alkyl, C1-C6alkoxygroup, benzoxy-group and -CF3 groups, and ring of C3-C10 cycloalkyl and C1-C10alkyl can be separated by one or several nitrogen atoms, oxygen and/or sulfur and/or the said ring can be interrupted by one or two groups of =C=O or R2 designates the group X designates oxygen or group-NH-, and one of A and B independently indicates hydrogen, and the other indicates hydrogen, hydroxygroup, C1-C3alkyl, C1-C6alkyoxy,group SR7, SO2R7, CO(OH)R7, CR7(OH)R7, C1-C6alkyl-P(O)OR3OR4, COR7 or A and B together form C3-6-cycloalkyl ring which does not necessarily have to be interrupted by 1-3 atoms of nitrogen, oxygen and/or sulfur and/or can be interrupted by =C=O or =SO2 groups, and/or does not necessarily have to contain one or several double bonds, X designates oxygen or group-NH-, either one from A and B independently indicates hydrogen, and the other indicates hydrogen, hydroxygroup, C1-C3alkyl, C1-C6alkyoxy,group SR7, SO2R7, CO(OH)R7, CR7(OH)R7, C1-C6alkyl-P(O)OR3OR4, COR7 or A and B together form C3-6-cycloalkyl ring which does not necessarily have to be interrupted by 1-3 atoms of nitrogen, oxygen and/or sulfur and/or can be interrupted by =C=O or =SO2 groups, and/or does not necessarily have to contain one or several double bonds, values of R3 -R10 are specified in the formula of the invention.

EFFECT: connections can be used for the treatment of cancer, autoimmune diseases caused by chemotherapeutic means of alopecia and inflammations of mucous membrane, cardiovascular diseases, infectious diseases, chronic neurodegenerative and viral infections.

13 cl, 1 tbl, 540 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel methods (variants) for synthesis of 2-(N-methyl-N-methanesulfonylamino)-pyrimidine of the formula (3) and aminopyrimidine compound of the formula (8) that can be used in synthesis of the known medicinal preparation - rosuvastatin. In compounds of formulae (3) and (8) R represents lower alkyl; each of R1 and R2 represents independently hydrogen atom, alkyl group, alkylsulfonyl group or arylsulfonyl group. Method for synthesis of compound of the formula (3) involves the following steps: (I) isobutyrylacetate ester of compound of the formula (5): wherein R represents lower alkyl is subjected for interaction with 4-fluorobenzaldehyde and urea in the presence of proton compound and metal salt; (II) compound synthesized in reaction at step (I) is oxidized; (III) obtained product after oxidation from stage (II) is subjected for interaction with organic sulfonyl halide of the formula (2): R'-SO2-X wherein R' represents lower alkyl substituted possibly with halogen atoms, phenyl substituted possibly with 1-3 groups chosen from nitro-group, halogen atoms, branched or direct lower alkyl, lower alkoxy-group; X represents halogen atom or organic sulfonic anhydride of the formula (2a): (R'-SO2)-O wherein R' has a value given above in the presence of a base; (IV) product of reaction at step (III) is subjected for interaction with N-methyl-N-methanesulfonamide in the presence of a base. Method for synthesis of compound of the formula (8) involves a step for interaction of corresponding 2-halide- or 2-substituted sulfonylpyrimidine with corresponding amino-compound. Also, invention relates to novel intermediate compounds and methods for their synthesis. Proposed methods provide avoiding toxic compounds and to obtain compounds of high purity and with the high yield.

EFFECT: improved methods of synthesis.

35 cl, 27 ex

The invention relates to new derivatives of 4-phenylpyrimidine and their pharmaceutically acceptable acid additive salts, which possess the properties of receptor antagonists neirokinina(NK-1), and can be used to treat diseases, oposredstvovanii NK-1 receptor, for example, headache, Alzheimer's disease, multiple sclerosis, cardiovascular changes, oedema, chronic inflammatory diseases and so on

FIELD: medicine.

SUBSTANCE: what is presented is a method for simulating a delayed hyperresponsiveness to mycobacteria bovis. Avirulent mycobacteria bovis of the strain BCG are administered intracutaneously to albino guinea pigs produced by consanguineous mating of brother x sister (F2); that is followed by forming a group (groups) of animals showing various extents of an inflammatory response in reaction to the intracutaneous administration of mycobacteria bovis of the strain BCG 30-35 days later.

EFFECT: method is effective in studying the mechanisms of the delayed hyperresponsiveness and assessing the efficacy of antituberculosis agents.

2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: agent, having adaptogenic and immunomodulating activity, containing medicinal marigold flower heads; rhaponticum carthamoides root and rhizome; horse-heal rhizome; nutmeg fruit; cardamom fruit; calamus root; sweet weed root; ginger rhizome; knotgrass; cinnamon bark; pomegranate; long red pepper; juniper fruit; leather bergenia black leaves; chitosan, taken in a defined amount.

EFFECT: agent has marked adaptogenic and immunomodulating activity.

10 tbl

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine, in particular to gastroenterology, and deal with treatment of ulcerative colitis and Crohn's disease. Method of treatment includes introduction into organism of therapeutically efficient quantity of attaching cells from placenta, cultivated in such a way as not to differentiate into adipocytes or osteocytes. Also claimed is application of said cells for obtaining medication, intended for treatment of ulcerative colitis or Crohn's disease. Claimed produced product for treatment of ulcerative colitis or Crohn's disease includes in packing form pharmaceutically efficient quantity of said cells.

EFFECT: inventions ensure essential reduction of inflammatory process in colon in modelling of said diseases, as well as due to pathological mechanisms of treatment in addition to T-lymphocyte suppression.

31 cl, 5 ex, 12 tbl, 16 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to paediatrics and neonatology, and can be used for treating small premature infants at the hospital stage of developmental care. A therapeutic complex comprises administering a probiotic preparation into the newborns. The preparation is presented with a liquid probiotic containing E.faecium L3 109 CFU in 1 ml. If the enteral nutrition volume of the newborn is 5 ml or more, this preparation is orally administered in a dose of 0.5 ml 3 times a day for 14 days.

EFFECT: method is effective in children with a very low body weight, promotes normalising the intestinal microflora and reducing a rate of manifestations of infectious complications.

2 ex, 3 dwg, 3 tbl

FIELD: chemistry.

SUBSTANCE: group of inventions relates to biotechnology and medicine. Disclosed is a polysaccharide which is isolated from the Bifidobacterium infantis NCIMB 41003 strain and has the structure [-β(1,3)-D-GalpNAc-β(1,4)-D-Glcp-]n, where said disaccharide unit repeats n times, which yields a polysaccharide with molecular weight greater than 100000 Da. The polysaccharide exhibits immunomodulating activity and is used in preparing medicinal agents for treating or preventing undesirable inflammatory activity, undesirable gastrointestinal inflammatory activity, rheumatoid arthritis and autoimmune disorders.

EFFECT: pharmaceutical composition for treating and preventing inflammatory disorders and a food product containing the isolated polysaccharide are disclosed.

9 cl, 6 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound CL168 of general structural formula I where R is oxygen. The invention also relates to a method of producing a compound of formula I and use of the compound of formula I to produce a medicinal agent for preventing or treating tumorous and immunological diseases.

EFFECT: compound of formula I for producing a medicinal agent for preventing or treating tumorous and immunological diseases.

4 cl, 11 tbl, 19 ex

Iimmunomodulator // 2504371

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely to an immunomodulator. An immunomodulator for the immunocorrection accompanying the integrated treatment of chronic non-specific pulmonary diseases, chronic obstructive pulmonary disease, bronchial obstruction syndrome, chronic bronchial pneumonia, pulmonary fibrosis, tracheobronchitis, chronic laryngitis, pulmonary, tracheal and pharyngeal cancer; the immunomodulator is prepared by mixing a water infusion of rose bay leaves and a water infusion of yellow melilot taken in equal proportions, with a cattle lung and larynx powder, settling the prepared mixture, keeping on a boiling water bath, cooling; further, the mixture is filtered; the prepared solution is added with cattle blood serum containing leukaemia oncovirus antibodies, hemlock infusion, ascorbic and sorbic acids until all the ingredients fully dissolved; the prepared solution is placed in the water bath, cooled, filtered, sterilised under certain conditions.

EFFECT: above preparation provides higher effectiveness and reduces the length of treating the above diseases, and ensures the higher immunobiological properties of the human body.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely to an extract of one or more bacterial strains Lactobacillus. The extract of one or more bacterial strains Lactobacillus representing a soluble extract, wherein the extract contains chemically modified bacterial molecules prepared by the action of an alkaline medium on one or more bacterial strains Lactobacillus; the extract is effective in treating diseases associated with the anti-inflammatory cytokine production imbalance. A method for preparing the extract of one or more bacterial strains Lactobacillus. A pharmaceutical composition effective for reducing at least one symptom associated with at least one condition specified in a respiratory disorder, an allergic condition, an urinary disorder and a gastric disorder, containing the extract. A nutritional composition. A pharmacological composition effective in treating the diseases associated with the anti-inflammatory cytokine production imbalance, containing the extract. A method of relieving the above symptoms. The extract prepared by the above method.

EFFECT: extract is effective in treating the diseases associated with the anti-inflammatory cytokine production imbalance.

21 cl, 7 dwg, 23 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, namely to using at least one immunomodulatory compound of general formula (1) or a pharmaceutically acceptable, solvate or isomer thereof for preparing a pharmaceutical composition for treating a disease or disorder specified in asthma, atopic dermatitis, allergic rhinitis, inflammatory intestinal disease, diabetes or rheumatoid arthritis in homoiothermal animal, including a human. What is also presented is using (5S,11R)-1-amino-5-[(R)-3-dodecanoyloxytetradecanoylamino]-6-oxo-7-aza-11-[(R)-3-hydroxytetradecanoylamino]dodecan-12-ol-12-dihydrophosphate (OM-294-BA-MP (S,R)) or a pharmaceutically acceptable salt, solvate or isomer thereof for preparing the pharmaceutical composition.

EFFECT: group of inventions provides treating the above diseases by modulating the TH1/TH2 cytokine balance by reducing TH2-cytokine release and enhancing TH2-cytokine production.

11 cl, 16 dwg, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biotechnology, more specifically to preparing interferonogenic antiviral agents of yeast RNA, and may be used in medicine. The IFN-γ inducer is presented by a soapy amphiphilic complex of high-polymer Saccharorayces cerevisiae RNA and oleic acid penetrating easily through biological membranes in the following proportions: high-polymer RNA - 80-90%, oleic acid - 10-20%.

EFFECT: invention enables inducing interferon γ (IFN-γ) production effectively with using available and low-cost ingredients.

2 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, namely immunology and may be used for preparing a composition for immune system stimulation. For this purpose, the composition contains: the first extract of immune modulator sources containing colostrum or egg extract and having an upper limit of molecular weight at 10000 Da, wherein the first extract contains a transfer factor and a nanofraction of immunomodulatory molecules having molecular weight of 3000 Da or less; and the second extract of immune modulator sources containing colostrum or egg extract and having the upper limit of molecular weight at 3000 Da, wherein the second extract contains no transfer factor, but the nanofraction of immunomodulatory molecules having molecular weight of 3000 Da or less. The group of inventions also refers to the versions of the above composition, and a method for immune system modulation.

EFFECT: using the given compositions containing the nanofractions of immunomodulatory molecules and the transfer factor enables a down-regulation of an undesired T-cell activity, thereby providing an increase or an up-regulation of T-helper cell, T-memory cell and EK cell activity on pathogens.

13 cl, 8 tbl, 7 ex, 4 dwg

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