Antioxidant, possessing hepatoprotective and hemostimulating activity

FIELD: chemistry.

SUBSTANCE: invention relates to novel compound, namely to (1'S,5'S,9'S,10'R)-methyl-5-[2-(3-benzyl-6-carboxy-4-oxo-10-oxa-3-azatricyclo[5.2.1.01.5]deca-8-ene-9-yl)ethyl]-1,10-dimethyl-6-methylene-decahydronaphtylene-1-carboxylate of formula (I) .

EFFECT: possesses anti-oxidant, hepatoprotective and hemostimulating activity, has low toxicity, and can be applied in medicine.

1 cl, 4 tbl, 4 ex

 

The invention relates to new chemical compound, specifically to (1'S,5'S,9'S,10'R)-methyl-5-[2-(3-benzyl-6-carboxy-4-oxo-10-oxa-3-azatricyclo [5.2.1.01,5]Dec-8-EN-9-yl)ethyl]-1,10-dimethyl-6-methylene-decahydronaphthalene-1-carboxylate of the formula (I),

with antioxidant, hepatoprotective and haemostimulating activity.

This property suggests the possibility of using the compounds in medicine as a pharmaceutical drug.

In modern medical practice, used synthetic antioxidants and natural (plant) origin. Among the antioxidants of plant origin application found mainly flavonoids, such as rutin, quercetin [1, 2], dihydroquercetin [3]. Similar to the pharmacological properties of the claimed compounds is dihydroquercetin [(2R,3R)-3,5,7,3',4'-pentahydroxyflavanone] formula (II).

Dihydroquercetin is a major bioflavonoid (90% and above) of the drug decortin, the production of which is made of larch wood established in recent years. Dihydroquercetin has antiradical and antioxidant activity, anti-inflammatory, capillarisation, gastro - and hepatoprotective properties [3]. These effects ensure that the connection status of the basic substance to create on its basis the combined preparations expanding the range of its biological activity. The main disadvantage of drugs on the basis of flavonoids is the possible side effects on the gastrointestinal tract, manifested mainly in the form of nausea, heartburn [1, 2].

The task to be solved by the invention is the creation on the basis of domestic herbal antioxidant of a new structural type with a high hepatoprotective activity. An important element of the task is to obtain an agent with improved pharmacological properties, aimed at correcting systemic side effects resulting from the use of highly toxic drugs, such as cytostatics. This group of drugs commonly used in cancer therapy, cause severe disorders in the form of mielo and emodepside, immunological disorders, functional and morphological damage of various organs and so on [4, 5]. The analysis of literature data shows that the synthesis of new compounds from vegetable raw materials with a view to expanding the range of non-toxic antioxidants with additional (in addition to antioxidant activity) protective properties, is an important task.

The problem is solved a new chemical compound - (1'S,5'S,9'S,10'R)-methyl-5-[2-(3-benzyl-6-CT is hydroxy-4-oxo-10-oxa-3-azatricyclo [5.2.1.0 1,5]Dec-8-EN-9-yl)ethyl]-1,10-dimethyl-6-methylene-decahydronaphthalene-1-carboxylate of the formula (I)having hepatoprotective and haemostimulating activity, including the background of the introduction into the organism of the cytotoxic drugs.

The similar structure of these compounds is methyl-5-[2-(4-benzyl-3,5-dioxo-10-oxa-4-azatricyclo[5.2.1.02,6]Dec-8-EN-9-yl)ethyl]-1,10-dimethyl-6-methylene-decahydronaphthalene-1-carboxylate of formula (III)having antidepressant activity [6].

The method of obtaining the compound (I)containing in the structure labdanoids frame connected with a fragment of 10-oxa-3-azatricyclo [5.2.1.01,5]Dec-8-ene, is implemented as shown in the diagram 1. The acylation 16-[(N-benzyl)aminomethyl]-methylamphetamine (IV)obtained by the reaction of aminomethylpyridine methylaspartate by the method of [7], maleic anhydride proceeds under mild conditions (chloroform, 20°C) and leads to the formation of substituted 10-oxa-3-azatricyclo[5.2.1.01,5]-6-carboxy-Dec-8-EN-4-it (I). The connection is formed in the form of a mixture of (1R,5S,6R,7R)- and (1S,5R,6S,7S)-diastereoisomers (1:1) (data range1H NMR) (yield 84%).

Scheme 1

The biological activity of the compound (I) was studied by determination of antioxidant and hepatoprotective activity on the model of toxic CCl4g is petite in mice and with the defeat of rats caused by the introduction of cyclophosphamide. As the comparison drug used antioxidant dihydroquercetin (II).

Previously in experiments on outbred mice weighing 18-23 g was determined acute toxicity after a single intragastric route of administration. Found that LD50the compound (I) exceeds the maximum possible for a single administration of a dose of 1000 mg/kg

For the study of the antioxidant and hepatoprotective effects was used a standard experimental model of toxic CCL4hepatitis in mice. The model was reproduced according to the methodical recommendations [8]. The solution CCL4in vegetable oil (25%) was administered intragastrically to mice-males. The compound (I) was introduced into the stomach in a dose of 100 mg/kg in the form of water-tween suspension for 1 hour before hepatotoxin. Reference connection - dihydroquercetin (DQC) is introduced in a similar way. A day in the serum of mice was determined by the activity of alanine aminotransferase (ALT), aspartate aminotransferase (ACT), alkaline phosphatase (apase) and the concentration of malondialdehyde (MDA) standard methods [9]. It is established that the compound (I) in terms of hepatotoxicity provides reliable anticatalytically effect, reducing the activity of ALT and ACT in the blood, respectively, 1.5 and 1.9 times compared to what stralem. The effect on the level of ALT agent (I) does not yield, and the impact on the ACT exceeds the reference connection 1.6 times. The expression of anticholesterol effect of compound (I) is not inferior to DQC (table 1).

Study of the protective action of compound (I) in terms of the defeat of cyclophosphamide (CP) was studied on rats female Wistar. The fit was administered once intraperitoneally at a dose of 125 mg/kg in a solution of 0.9% NaCl to all the animals. The compound (I) in the form of water-tween suspension was injected rats (12 PCs) in the stomach in a dose of 50 mg/kg for three days after administration of CP. Reference connection - dihydroquercetin (DQC) - was administered in the same dose in the same way a separate group of rats (10 PCs). The control group was injected only cyclophosphamide (10 PCs). At the end of the experiment determined the composition of peripheral blood and leukocyte formula. In serum using a standard reagent kits investigated the activity of alanine aminotransferase (ALT), aspartate aminotransferase (ACT), alkaline phosphatase (apase), the concentration of total protein, glucose. The concentration of malondialdehyde (MDA) investigated the conventional method [9].

The results of the study of biological activity are given in table 2-4. It is established that the compound (I) after intragastric administration at a dose of 50 mg/kg on the background ciclofosfamida defeat inferior DQC on anticatholicism properties, but exceeds e is about antiholetsaticeski and antioxidant effect. Found that the combination of (I) tends to decrease cytopenia caused by cyclophosphamide, increasing the number of leukocytes and platelets relative to control, respectively, 1.4 and 1.2 times, the number of neutrophils 1.8, and monocytes - 2.5 times. It is shown that gemostimuliruyuschee the effect of compound (I) is superior to that for DQC.

Thus, the present invention has the following advantages.

The compound (I) has a high antioxidant and hepatoprotective activity, as well as gemostimuliruyuschee effect on the background of the introduction of the cytostatic cyclophosphamide.

- Use for its synthesis of the original obtained from the available raw materials, pine needles or resin Siberian cedar (Pinus sibirica R. Mayr.

The invention is illustrated by the following examples.

Example 1. Synthesis of (1R,5S,6R,7R)- and (1S,5R,6S,7S)-(1'S,5'S,9'S,10'R)-Methyl-5-[2-(3-benzyl-6-carboxy-4-oxo-10-oxa-3-azatricyclo[5.2.1.01,5]DECA-8-ene-9-yl)ethyl]-1,10-dimethyl-6-methylene-decahydronaphthalene-1-carboxylates (I).

To a stirred solution of 0.87 g (1.96 mmol) of furfurylamine (IV) [7] in 30 ml of benzene was added 0.19 g (1.96 mmol) of maleic anhydride. The reaction mixture was stirred at 20°C 48 hours the Solvent is evaporated in vacuo, the residue was chromatographically on silica gel (eluent - chloroform). Got 0.90 g (84%) of a mixture of (1R,5S,6R,7R)- and (1S,5R,6S,7S)-diastereoisomeric 10-oxa-3-azatricyclo[5.2.1.0 ]DECA-8-ene (I) in the form of a colorless oil. UV-spectrum, λmaxnm (lg ε) 258 (1.71), 264 (1.67). The infrared spectrum, cm-1: 692 (C=C); 1132, 1229, 1723 (C=O). An NMR spectrum1N (δ, ppm, J, Hz): 0.45 (6N,16'H3), 0.97 m (2N, N4'), 1.00 m (2N, N2'), 1.14 (6N,15'H3), 1.24 m (2N, N9'), 1.45 m (2N, N3',11'), 1.52 m (4N, N5',11'), 1.73 m (4N, N4',8'), 1.81 m (6N, N3',7',12'), 1.95 m (2N, N8), 2.14 D.M. (2N, N2'I , Jheme13.1), 2.22 m (2N, N12'),

2.35 m (2N, N7'), 2.83 ush. C (2N, N6), 2.87 ush. C (2N, N5), 3.50 d, 3.53 (2H, N.2, J 13), 3.58 (6N, co3), 3.66 d, 3.68 (2H, N.2, J 13), 4.33, 4.36 (2H, N.13'), 4.40 d, 4.60 d

(4H, CH2RH, J 12), 4.78 (2H, N.13'), 5.14 ush. C (2N, N7), 5.94 (1H, H8, J 1.3), 5.96 (1H, H8, J 1.4), 7.21 m (4N, N2",6"), 7.26 m (2N, N4"), 7.30 m (2N, N3",5"). An NMR spectrum13S, δ, ppm: 12.31, 12.38 (With16'), 19.70 t (3'), 20.79 t, 21.10 t (11'), 25.54 t (12'), 25.99 t (8'), 28.56, at 28.58 (With15'), At 37.92 t (2'), 38.41 t (7'), 38.98 t (4'), 40.10, 40.15 (With1'), 44.07 (With10'), At 46.81 t, 46.82 t (CH2), 46.93 t, 47.00 t (2), 47.19 d (6), 50.66 d, 50.72 d (5), 50.98 (och3), 55.28 d, 55.59 d (5'), 56.01 (With9'), At 81.66 d, 81.70 d (7), 89.60, 89.68 (With1), 106.20 t, 106.24 t (13'), 127.58

d (4"), 127.77 d, 127.82 d (2",6"), 127.99 d, 128.29 d (8), 128.69 (With3",5"), 135.16, 135.18 (With1" ), 147.42, 147.63 (With6'), 149.60, 149.81 (With9), 172.02, 172.09 (With4), 173.57 (CO2N), 177.42 (With14). Found, %: C 72.79; N, 7.40; N, 2.55. C33H46NO6. Calculated, %: C 72.53; N, 7.33; N, 2.56.

Example 2. Investigation of hepatoprotective properties in a model of acute toxic hepatitis.

Acute toxic hepatitis caused offspring of male mice by a single intragastric administration of a 25% solution of CCL4in sunflower oil at the rate of 0.1 ml per 10 g of body weight. The compound (I) was administered intragastrically at a dose of 100 mg/kg in the form of water-tween suspension for 1 hour before play hepatitis. The control animals similarly injected water tenovuo suspended in an equivalent volume, the comparison group - dihydroquercetin in the dose of 100 mg/kg a day in the serum of mice was determined using a standard reagent kits ("Biocon", "olivex Diagnosticum") the activity of alanine aminotransferase (ALT), aspartate aminotransferase (ACT) and alkaline phosphatase (apase). The results were processed statistically using the software package "STATISTIKA 6".

It is established that the compound (I) in terms of hepatotoxicity provides reliable anticatalytically effect, reducing the activity of ALT and ACT in the blood, respectively, 1.5 and 1.9 times in comparison with control. The effect on the level of ALT agent (I) does not yield, and the effect on the ACT - excellent the t reference connection in 1.6 times. Found that under the action of compound (I) significantly reduced the level of alkaline phosphatase (1.5-fold compared with control), indicating that anticholesterol the action of the agent. The expression of anticholesterol effect of compound (I) is not inferior to DQC. Both of the agent in terms of this experience showed no influence on the intensity of peroxidation processes: the concentration of MDA in the respective groups had no significant differences with the control (table 1).

Table 1
The effect of compound (I) on biochemical parameters of blood serum of mice with induced CCL4hepatitis
GroupBiochemical parameters
ALT, µkat/lACT, µkat/lAlkaline phosphatase, µkat/lHMM, umol/l
Control880,80±37,12554,00±48,342,91±0,263,56±0,35
(I)592,47±40,76***301,46±29, 36 the**1,97±0,27*389±0,22 #
DQC577,24±25,81***480,47±41,142,18±0,14*3,28±0,11
*P<0,05; **P<0,01; ***P<0,001 - differences from control are reliable;
#P<0,05 differences with DQC authentic

Thus, it is shown that compound (I) after intragastric administration in a dose of 100 mg/kg has a hepatoprotective effect, reducing the severity of cytolytic and cholestatic processes on the background of toxic hepatitis.

Example 3. Investigation of hepatoprotective and antioxidant properties on the background of toxic lesions in rats with cyclophosphamide

The experiment was performed on rats female Wistar, which was administered once intraperitoneally cyclophosphamide at a dose of 125 mg/kg (solution 0.9% NaCl). The compound (I) was injected into the stomach 12 to rats at a dose of 50 mg/kg for three days after administration of CP (in the form of water-tween mist). Reference connection - dihydroquercetin (DQC) - was administered in the same dose in the same way a separate group of rats (10 PCs). Control animals were with the introduction of only ZF (10 PCs). At the end of the experience in serum was investigated using standard reagent kits ("Biocon", "olivex Diagnosticum") the activity of alanine aminotransferase (ALT), Apartamentos erase (ACT), alkaline phosphatase (apase), the concentration of total protein and glucose. The concentration of malondialdehyde (MDA) was determined by standard method [9].

The results are presented in table 2. It is established that under these conditions as the compound (I)and the reference drug had no significant effect on ALT activity. In relation to the ACT, the compound (I) showed only a trend of decreasing activity (1.3-fold compared with control), whereas the DQC has caused a small but significant decrease in activity of this enzyme in the blood (1.4 times). The compound (I) found a marked trend towards anticholesterol action: the activity of alkaline phosphatase under the influence of compound (I) was decreased relative to control and DQC, respectively, 1.3 and 1.4 times. The reference agent antiholetsaticeski effect is not detected. The concentration of MDA in animals with the introduction of the agent (I) was 1.3 times lower than in the group with the introduction of the DQC, which in terms of this experience strengthened the intensity of lipid peroxidation. The effects of these two agents on the overall metabolism (protein, glucose) is not marked.

From the table it is seen that the compound (I) after intragastric administration at a dose of 50 mg/kg on the background ciclofosfamida defeat inferior DQC on anticatholicism properties, but surpasses it in antiholetsaticeski and antioxidant effect.

Example 4. The study gemostimuliruyuschee actions on the background of toxic lesions in rats with cyclophosphamide

The experiment was performed on rats female Wistar, which was administered once intraperitoneally cyclophosphamide at a dose of 125 mg/kg (solution 0.9% NaCl). The compound (I) was injected into the stomach 12 to rats at a dose of 50 mg/kg for three days after administration of CP (in the form of water-tween mist). The product comparison - dihydroquercetin (DQC) - was administered in the same dose in the same way a separate group of rats (10 PCs). Control animals were with the introduction of only ZF (10 PCs). At the end of the experience with the help of geoanalytical MEDONIC defined morphological composition of peripheral blood. Leukocyte counts were counted under the microscope in the blood smears, stained with hematoxylineosin.

The results are presented in table 3. It is established that the compound (I) tends to decrease cytopenia caused by cyclophosphamide, increasing the number of leukocytes and platelets relative to control, respectively, 1.4 and 1.2 times. Gemostimuliruyuschee effect of dihydroquercetin was manifested in the form of increased 1.6 times the number of cells. Both compounds are characterized by a small reliable increase in the quantity of hemoglobin in erythrocytes (sit, ICSU). At the same time under the action of the DQC was observed a small reliable reduced the e number of erythrocytes and hematocrit.

Table 2
The effect of compound (I) on the average values of biochemical parameters of blood serum of rats on the background of intoxication cyclophosphamide
GroupALT, mkat/g proteinACT, mkat/g proteinAlkaline phosphatase, mkat/g proteinHMM, umol/lTotal protein, g/lGlucose, mol/l
control54,3±6,873,9±7,9129,0±9,51,93±0,0963,1±2,3416,43±1,02
(I)58,4±7,258,4±5,5102,6±15,81,93±0,0865,27±4,1214,29±0,91
DQC55,2±5,253,7±3,9*146,3±13,6to 2.57±0,09*63,14±1,5214,19±0,70
*P<0,05 - differences with control reliable
Table 3
The effect of compound (I) on the average values of the peripheral blood of rats on the background of intoxication cyclophosphamide
GroupRBCPCTWBCGPLTMCVRDW%MPVSitICSU
control5,06±0,2128,0±1,20,9±0,115,5±0,8for 93.9±8,455,3±1,010,2±0,48,8±0,0130,6±0,655,5±0,6
(I)4,77±0,1926,2±1,01,3±0,1the 15.6±0,7to 109.6±11,954,9±0,610,3±0,28,3±0,03*32,8±0,5* 59,7±1,0*
DQC4,19±0,20*22,6±0,9*1,4±0,214,2±0,6to 88.3±8,955,3±0,810,2±0,68,3±0,1*33,9±0,3*61,3±0,8*
Norma6,87±0,1438,7±0,717,0±0,919,7±0,6to 257.0±21,257,1±0,913,3±0,79,0±0,129,7±0,552,0±0,4
*P<0,05 - differences with control reliable
RBC - the number of red blood cells, HCT - hematocrit, WBC - white blood cell count, G - hemoglobin, PLT - platelets, MCV is the average volume of erythrocytes, RDW% - percentage distribution of the absolute weight of the red blood MPV - volume of platelets, sit - average haemoglobin content in an erythrocyte, ICSU - average concentration of hemoglobin.

On the background of neutropenia caused by cyclophosphamide, under the action of compound (I) was observed trend of increasing amounts of the granulocytic cells: the number of segmented neutrophils increased in 1.8 times compared with the control, appeared young neutrophils. In this group of animals showed a relative monocytosis, which was expressed in a 2.5-fold increase in the number of monocytes compared with control. A tendency to stimulation of cells with leukocyte number under the action of compound (I) was more pronounced than in DQC (table 4).

4,71±0,47
Table 4
The effect of compound (I) on average values leukocyte blood of rats on the background of intoxication cyclophosphamide
Groupeosinophilsp/nuclearwith/nuclearMonocytesLymphocytes
control001,43±0,482,43±0,8196,14±0,51
(I)00,14±0,14to 2.57±0,846,0±1,091,29±1,02
DQC000,71±0,2994,57±0,48
Norma0,86±0,46019,29±1,447,14±1,0672,61±1,44

Thus, it is shown that compound (I) after intragastric administration at a dose of 50 mg/kg on the background of emodepside caused by the introduction of cyclophosphamide, exceeds DQC on gemostimuliruyuschee action.

Sources of information

1. Medmaravis. Medicinal product. 2 so Kharkov: "Torching", 1998, so 2, p.55.

2. Drugs approved for use in the USSR. Ed. by M.A. Klyuyev, Aaabaa. M, Medicine, 1979, p.61-65.

3. Mberotica, Naukasana, Templatica. Medicines on the basis of divertida. Tomsk: Publishing house of Tomsk University, 2005, 228 S.

4. Mlechanovci, Wailau, Maxim Akimov, Ago. Introduction to pharmacotherapy of malignant tumors. St. Petersburg: satis, 1999, 152 S.

5. Vasodilan, Map, Luellen, Wmini, Laivnieki, Bulletin of experimental biology and medicine. 2003, T. 136, No. 12, s.

6. Tgolemanov, Iavarone, Mpoly, Uwharrie, Svernov, Eel, Gaellic. Chemical and pharmaceutical journal. 2004, T. 38, No. 10, s-15.

7. Svernov, Eel, May, Gaellic. Journal of organic is chemistry. 2000, T.36. No. 8. s-1498.

8. Manual on experimental (preclinical) study of new pharmacological substances. Moscow: Medicine, 2000, s.

9. Kamyshnikov B.C. Handbook of clinical-chemical laboratory diagnostics. Minsk: Belarus, 2000, Vol.2, s.

(1'S,5'S,9'S,10'R)-methyl-5-[2-(3-benzyl-6-carboxy-4-oxo-10-oxa-3-azatricyclo [5.2.1.01,5]DECA-8-ene-9-yl)ethyl]-1,10-dimethyl-6-methylene-decahydronaphthalene-1-carboxylate of the formula (I),

with antioxidant, hepatoprotective and haemostimulating activity.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention pertains to new compounds with general formula: , where R is -(CH2)n-A, where A: where each of B and C independently represent phenyl or phenyl substituted with 1-3 substitutes, independently chosen from a halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl) and -NO2; or n equals an integer from 0 to 3; n1 equals an integer from 1 to 3; n2 equals an integer from 0 to 4; n3 equals an integer from 0 to 3; n4 equals an integer from 0 to 2; X1 is chosen from a chemical bond -S-, -S(O)2-, -NH-, -NHC(O)- and -C=C-, R1 is chosen from C1-C6alkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, tetrahydropyranyl, CN, -N(C1-C6alkyl)2, phenyl, pyridinyl, pyrimidinyl, furyl, thienyl, naphtyl, morpholinyl, triazolyl, pyrazolyl, piperidinyl, pyrrolidinyl, imidazolyl, piperizinyl, thiazolydinyl, thiomopholinyl, tetrazolyl, benzoxazolyl, imidazolidine-2-thionyl, 7,7-dimethylbicyclo[2.2.1]heptane-2-onyl, benzo[1.2.5]oxadiazolyl, 2-oxa-5-azabicyclo[2.2.1]heptyl and pyrrolyl, each of which can be optionally substituted with 1-3 substitutes, independently chosen from a halogen, -CN, -CHO, -CF3, OCF3, -OH, -C1-C6alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NO2, -SO2(C1-C3alkyl), -SO2NH2, -SO2N(C1-C3alkyl)2, -COOH, -CH2-COOH, pyridyl, 2-methylazolyl, morpholino, 1-chloro-2-methylpropyl, phenyl, (optionally substituted with one or more halogens), benzyloxy, and , X2 selected from -O-, -CH2-, -S-, -SO-, -SO2-, -NH- and , R2 represents a ring group, chosen from a phenyl or thienyl group. Each ring group is substituted with a group with formula -(CH2)n4-CO2H; and besides that, the ring group can optionally be substituted with 1 or 2 extra substitutes, independently chosen from halogen, - C1-C6alkyl and -C1-C6alkoxy; R3 is chosen from H, halogen and -NO2; R4 is chosen from H, halogen and morpholino; or its salt form, used in pharmaceuticals. The invention also relates to pharmaceutical compositions, to methods of treatment, and to compounds with formula (A).

EFFECT: obtaining new biologically active compounds and pharmaceutical compositions based on them, which have inhibiting effect on cytosolic phospholipase A2.

45 cl, 300 ex

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to condensed heterocyclic succinamide compounds of the formula (I): , their pharmaceutically acceptable salts, solvates or isomers wherein G represents mono- or polycyclic aryl or heterocyclic group substituted possibly at one or more positions; L represents a bond, -(CR7R7')n (wherein n = 1; R7 and R7' represents independently hydrogen atom (H), alkyl or substituted alkyl) or -CH2-NH-; Z1 represents oxygen atom (O); Z2 represents O; A1 and A2 represent -CR7 or in common with R7 from group W is a heterocyclic ring wherein oxygen represents a heteroatom; Y represents -O-, -SO-, -N(V2)-, -CH2-N(V2)-, -CO-N-(alkyl)-, -CH2-S-, -CH2-SO2-; V2 represents hydrogen atom, alkyl, arylalkyl, -CO-alkyl, -CO-O-aryl, -CO-O-arylalkyl; W represents -CR7R7'-CR7R7'-, -CR7R7'-C=O, -NR9-, -CR7R7'-, -N=CR8-, -N=N, -NR9-NR9'-, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo- or substituted heterocyclo-group, aryl or substituted aryl wherein if W doesn't mean -NR9-CR7R7'-, -N=CR8-, -N=N, -NR9-NR9'- or heterocyclo- or substituted heterocyclo-group then Y must mean -O-, -CH2-S-, -SO-, -CH2-SO2-, -N-(V2)- or -CH2-N-(V2)-; Q1 and Q2 represent hydrogen atom (H). Also, invention describes a method for synthesis of intermediate compounds in synthesis of compounds of the formula (I), using the latter for preparing agents modeling function of the nuclear hormone receptors. Compounds of the formula (I) can be used in treatment of prostate cancer.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds.

8 cl, 11 tbl, 463 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel derivatives of 2,6-dihydro-7H- pyrazolo[3,4-d]pyradazin-7-one, 1,4-dihydropyrazolo[3,4-b]thiazin-5(6H)-one; N-acylated 4-imidazo[1,2-a]pyridin-2-yl- and 4-imidazo[1,2-a]pyrimidin-2-yl- anilines; amides of [(4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]pyperidin-4-carboxylic acid; amides of 2-(4-carbamoylpyperidin-1-yl)isonicotinic acid; amides of N-sulfonyl-1,2,3,4-tetrahydrochinolin-6-carboxylic acid; as well as to N-acylated 3-azolyl derivatives of 2-amino-4,5,6,7-tetrahydtithieno[2,3-c]pyridine possessing properties of Hh-signal cascade inhibitors.

EFFECT: compounds can be applied for use in pharmaceutical compositions and medications for treating diseases induced by abberant activity of Hedgehog (Hh) signal system, in particular, oncological diseases, for instance, for pancreatic carcinoma treatment.

23 cl, 13 dwg, 11 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to application of derivatives of 5-amino-2,4,7-trioxo-3,4,7,8-tetrahydro-2H-pyrido[2,3-d]pyrimidine of formula [I] as active ingredient for preparation of medication possessing anti-tumor activity, as well as to novel compounds of formula [I'], their pharmaceutically acceptable salts, hydrates and solvates. In formula[I] or [I'] values X1 and X2 are respectively selected from nitrogen atom and carbon atom, group is respectively selected from or . Other radical values are given in invention formula.

EFFECT: compounds can be applied for treatment and prevention of diseases induced by undesirable cell proliferation, such as cancer, rheumatism, etc.

32 cl, 11 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to formula I compounds and their pharmaceutically acceptable salts. Compounds of claimed invention can be applied as medication for treating disorders induced by cell proliferation or mediated by nucleus receptors. In general formula , A represents phenyl or unsaturated monocyclic 6-member group, containing nitrogen atom as heteroatom; B represents phenyl group; Z represents bond; Y represents group -CO-NH-CH2-; R1, R2, R3 independently represent hydrogen; R4 represents aminogroup; and one of X1, X2 , X3 or X4 represents halogen atom, while other ones of X1, X2, X3 or X4 independently represent hydrogen atom.

EFFECT: invention also relates to method of obtaining, pharmaceutical compositions, to application of invention compounds, as well as to formula IV compound.

22 cl, 1 dwg, 2 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to oncology and can be used for treatment of the patients suffering from IIIB-stage Hodgkin's lymphoma (IIIB HL). Method is implemented as follows. A specific patient is examined to estimate degree of regression of the measured lesion foci of Hodgkin's lymphoma at relieving intoxication symptoms after 2-4 cycles of the combined chemotherapy. After regression of the measured lesion foci is not less than 75%, radiation therapy is applied in extent of total or subtotal irradiation of lymph nodes in a dose 36-40 Gy.

EFFECT: method allows improving clinical effectiveness of chemoradiation therapy due to individualised detection of IIIB HL patients with indications for radiation therapy following the combined chemotherapy.

2 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely oncology and can be used for treatment of inflammatory breast cancer. The therapy is implemented as follows. The preoperative therapy is combined with hypodermical introduction of prescribed recombinant tumour necrosis α-factor thymosin-α1 in a dose 200000 ME on the day of chemotherapy 30 minutes prior to introduction of cytostatic agents and 4 days after chemotherapy.

EFFECT: application of the invention allows ensuring tumour regress and reducing therapeutic toxicity due to combined cytostatic agents and recombinant tumour necrosis α-factor thymosin-α1.

2 ex

FIELD: medicine.

SUBSTANCE: group of inventions concerns biology and medicine. There is disclosed method of biotreatment blood serum production involving electrostimulation of an animal, other than a human, blood drawing of specified animal, serum separation from specified blood and gamma irradiation in a dose 10 to 40 kGy. There is offered blood serum product and pharmaceutical composition containing said blood serum product, and also their application for treatment of various diseases.

EFFECT: invention provides production of biotreatment animal's blood serum applied for treatment of wide range of diseases, including epileptic attacks and apoplexy.

24 cl, 4 ex, 7 tbl, 11 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to oncology and can be used for therapy of patients suffering from hepatic metastases of gastric carcinoma. The mode is implemented as follows. Celiac trunk is catheterised through femoral artery by Seldinger approach. That is followed with selective catheterisation of common hepatic artery wherein Cisplatin is injected within 24 hours, and Fluorouracil - within the next 72 hours. Therapeutic course includes 4-6 procedures every 4 weeks.

EFFECT: invention use allows downsizing the metastatic foci, extending life span and improving life quality of said patients.

1 ex

FIELD: medicine.

SUBSTANCE: invention concerns immunology area. Versions of the artificial fused protein consisting of an antibody (or its fragment) and cytokine, fused through a link peptide are offered. The antibody or its fragment is chosen from an antibody 225, 425, KS 1/4, 14.18, anti-CDx-antibody where x has the whole value 1-25. Each of versions of the fused protein has lowered quantity T-epitopes, at least, in the component of the fused protein presented by an antibody, and as consequence, possesses the lowered adjuvanticity, in comparison with an initial molecule. Identification of T-lymphocyte epitopes is performed by the automated calculation of sizes for the binding centres of class II MHC molecules with the subsequent experimental test of the obtained versions of protein for presence of the lowered adjuvanticity. The automated way of T-epitopes calculation is based on use of the Bjom's function modified in such manner that contribution of Van-der-vaals repulsion and lipophilic interaction in pairs between all lipophilic atoms of the chosen segments of the fused protein and a binding groove of a MHC P molecule is taken into account. Also a way of protein construction on the basis of the modified function Bjom's function with the subsequent experimental test of the received versions for presence of the lowered adjuvanticity is revealed, and also application of the fused protein for preparation of a pharmaceutical composition for tumour treatment is in addition considered.

EFFECT: invention use allows obtaining the fused proteins with the lowered adjuvanticity and, basically, keeping identical biological activity in comparison with a parent molecule; it can be used in treatment of tumours.

4 cl, 6 dwg, 22 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the aminopyridin compound of general formula (I) or its salt wherein X1, X2, X3, Z, Y1, Y2 are carbon or nitrogen atom, R, R1, R5, R6 are hydrogen atom, alkyl group, further see formula of the invention, and R7 is hydrogen or halogen atom, nitro or cyano group, -CpH2(p-1)(Ra1)(Ra2)-O-Ra3, -C(=O)-Rd1, 5-or 6-membered saturated heterocycle group, aromatic heterocycle group, -N(Rh1)(Rh2), further see formula of the invention. The invention refers also to the pharmaceutic composition thereof intended for treatment or prevention of allergic diseases, autoimmune diseases caused by malignant tumour, to the Syk inhibitor containing the compound of formula I and to the therapeutic and/or preventive agent.

EFFECT: compounds which not only possess high Syk inhibition activity but are selective Syk inhibitors are obtained and described.

24 cl, 24 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: present invention refers to the new naphtylene derivative having general formula (I-A) and to their pharmaceutically acceptable salts having the property of inhibition of the cytochrome ferment P450RAI (Cyp26) activity, to the pharmaceutic composition thereof and to the method of inhibition of cytochrome ferment P450RAI (Cyp26). , wherein X is selected from imidasolyl or triasolyl; R2 and R3, independently represent H, C1-10-alkyl; G1 is -NR72R82 or G1 and R3 taken together with attached carbon atom form 3-10-membered saturated ring or heterocyclic saturated ring containing N as heteroatom which is optionally substituted with substituting group R72, Z, R4b, R5b, Q1, R72, n2, n3 and n4 values are indicated in the formula of the invention.

EFFECT: present invention refers to the intermediates for compounds with general formula (I-A) and to their pharmaceutic salts thereof.

37 cl, 30 dwg, 7 tbl

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel derivatives of 2,6-dihydro-7H- pyrazolo[3,4-d]pyradazin-7-one, 1,4-dihydropyrazolo[3,4-b]thiazin-5(6H)-one; N-acylated 4-imidazo[1,2-a]pyridin-2-yl- and 4-imidazo[1,2-a]pyrimidin-2-yl- anilines; amides of [(4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]pyperidin-4-carboxylic acid; amides of 2-(4-carbamoylpyperidin-1-yl)isonicotinic acid; amides of N-sulfonyl-1,2,3,4-tetrahydrochinolin-6-carboxylic acid; as well as to N-acylated 3-azolyl derivatives of 2-amino-4,5,6,7-tetrahydtithieno[2,3-c]pyridine possessing properties of Hh-signal cascade inhibitors.

EFFECT: compounds can be applied for use in pharmaceutical compositions and medications for treating diseases induced by abberant activity of Hedgehog (Hh) signal system, in particular, oncological diseases, for instance, for pancreatic carcinoma treatment.

23 cl, 13 dwg, 11 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compounds of formula (I): , where: R1 represents hydrogen atom, (C1-C4)-alkyl, group -(CH2)mOH, group -(CH2)mCN, group -(CH2)mNR9R10; R2 represents hydrogen atom or (C1-C4)-alkyl; R3 represents phenyl, substituted with radicals R6, R7, R8; R4 represents: group ; heterocyclic radical selected from radicals: ; ; ; R5 represents hydrogen atom or (C1-C4)-alkyl; R6, R7 and R8 represent independently on each other hydrogen atom, halogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxy, hydroxyl, cyanogroup, group -(CH2)nNR9R10, group -O-(CH2)mNR9R10; R9 and R10 represent independently on each other hydrogen atom or (C1-C4)-alkyl; or R9 and R10 together with nitrogen atom, to which they are bonded, form heterocyclic radical, selected from pyrrolidin-1-yl, pyperidin-1-yl, morpholin-4-yl or pyperasin-1-yl, substituted or non-substituted in position 4 with (C1-C4)-alkyl; R11 represents hydrogen atom or (C1-C4)-alkyl; R12 represents hydrogen atom, (C1-C4)-alkyl, group -(CH2)m-CO-R16; R13 represents hydrogen atom, (C1-C4)-alkyl, phenyl, group NR17R18, group ; R14 represents hydrogen atom, (C1-C4)-alkyl, group -NR17R18; R15 represents hydrogen atom, (C1-C4)-alkyl, group -NR19R20, -COO(C1-C4)-alkyl; R16 represents hydroxyl, (C1-C4)-alkoxy, group -NR9R10; R17 and R18 represent independently on each other hydrogen atom or (C1-C4)-alkyl; R18 can also represent group -COR21, group -SO2R22; R19 and R20 represent independently on each other hydrogen atom or (C1-C4)-alkyl; R20 can also represent (C3-C6)-cycloalkyl, (C3-C6)-cycloalkylmethyl, group -(CH2)mNR9R10; R21 represents (C1-C4)-alkyl, (C3-C6)-Cycloalkyl, group -(CH2)mNR9R10; R22 represents (C1-C4)-alkyl; m equals 1, 2 or 3; n equals 1, 2 or 3. As well as to medication and pharmaceutical composition, to method of obtaining it and its application in therapy.

EFFECT: obtained and described are novel compounds which can be useful in medicine.

14 cl, 67 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to surgical ophthalmology and anaesthesiology and can be used as a prevention technique of postoperative nausea and vomiting, and also within postoperative depression. It is ensured as follows. Premedication is combined with introduction of nonsteroid antiinflammatory agent in an age-specific dose. Premedication then does not include introduction of Dimedrol, Droperidol and Metaclopramide.

EFFECT: method allows lowering frequency of postoperative nausea and vomiting in the operations associated with traction and irritation of muscular system of an eye, and also providing early recovery of consciousness without by-effects characteristic for neurotropic agents used in standard premedication regimens.

1 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: compound contacts with 15-lipoxygenase and tested for activity for 15-lipoxygenase inhibition.

EFFECT: extended range of medical products for treatment of diseases associated with bone loss.

7 cl, 6 ex, 4 tbl, 9 dwg

FIELD: chemistry.

SUBSTANCE: invention refers to new spirocyclic cyclohexane derivatives of general formula I , where: R1-R3, R5-R10, W, X are disclosed in the claim 1 of formula.

EFFECT: compounds exhibit analgesic activity to be applied for making a medical product for pain therapy.

20 cl, 1 tbl, 54 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to oncology. General combined anaesthesia is followed with visual estimation of cancer process dissemination in organs, including with using of intraoperative ultrasonic diagnostics to localise secondary cancerous lesions. Primary cancerous lesion is extracted. The diagnosed and visible secondary cancerous lesions are extracted in any sequence. Extended limphodissection is followed by lavage with irrigating solutions within 15-20 minutes after all surgery stages. Irrigating solution is removed to install suction drains made of polymeric material, namely of silicone. Polyethylene film crucially incised in the middle is attached to wound edges with filling the operative tank with dialytic-based or Ringer-Locke solution containing ground and supplementary chemicals. Herewith perfusion solution contains Mitomycin C dosed 20 mg/m2 of body area as a ground chemical, 5-Fluorouracil dosed 1 g/m2 of body area as a supplementary chemical. Perfusion solution is introduced through the suction drains into upper operational cavity, and evacuated therefrom at temperature 42.5°C or higher through the suction drains installed in lower operational cavity. The temperature of perfusion chemical solution is controlled by thermal sensors mounted in said suction drains. Intraoperative intracavitary hyperthermal chemotherapy involves closed circulation of perfusion chemical solution within 60-120 minutes in operational cavity at rate 500-2000 ml/min combined with simultaneous mechanical agitation of the chemical solution. Intraoperative intracavitary hyperthermal chemotherapy is followed with complete closure of operational cavity and introduction of chemotherapeutical dialytic-based or Ringer-Locke solution containing 5-Fluorouracil dosed 1 g/m2 of body area and exposed in operational cavity within 8-12 hours, in the postoperative period daily 1st to 5th days after operation through the suction drains. Then the suction drains are removed. Thus prior to the operation the patient is placed on a mattress warmed up to 37-39°C on a surgical table. After extended thoracotomy, secondary cancerous lesions are localised and sised on parietal and visceral pleura with using intraoperative ultrasonic diagnostics. Pneumonectomy is carried out, while diagnosed and visible secondary cancerous lesions sised 10 mm and more including once penetrated 5 mm and deeper into invaded tissues, are extracted in any sequence. Parietal pleural areas are removed by including subtotal or total pleurectomy with thoracic lavage with irrigating solutions thereafter removed from thoracic cavity wherein suction drains made of polymeric material are installed. Polyethylene film crucially incised in the middle is attached to the edges of formed thoracic reservoir. In hyperthermal chemotherapy preparation stage, the heating mattress is disabled, while in the beginning and during hyperthermal chemotherapy, occiput and great vessel neck area are artificially cooled. Also 5% glucose solution is used as perfusion solution for hyperthermal chemotherapy. Besides the ground chemical of perfusion solution is Oxaliplatine (Eloxatine) dosed 50-130 mg/m2 of body surface area. The temperature of perfusion solution for hyperthermal chemotherapy is 43-48°C. It is introduced through the suction drains into upper thoracic cavity and evacuated through the suction drains installed in lower thoracic cavity. Intrapleural chemotherapy of the postoperative period involves introduction of chemotherapeutic solution of temperature 37-38°C through the left suction drains, combined with additional introduction of perfusion solution of 5% glucose.

EFFECT: more reliable prevention of intraoperational tumour cell penetration into vascular and lymphatic bed, prevention of malignant cell distribution and growth.

3 cl, 3 ex

FIELD: medicine.

SUBSTANCE: present group of inventions concerns medicine, namely, psychiatry, and includes methods of treatment of schizophrenia at patients with superfluous mass of a body and application of azenapin for manufacturing of the medicine for treatment of this pathological condition.

EFFECT: effective treatment of schizophrenia in the absence of characteristic for other antipsychotic preparations of augmentation of mass of a body.

12 cl, 1 ex, 2 tbl

Up!