6-alkyl-5-(2-isonicotinoylsulfohydrazoyl)uracil hydrochloride and pharmaceutical composition based on thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new 6-alkyl-5-(2-isonicotinoylsulfohydrazoyl)uracil hydrochlorides of the general formula (I) wherein R means alkyl comprising 1-4 carbon atom. Compounds possess an anti-mycobacterial and an immunotropic activity and can be used as an immunomodulating agent and an anti-mycobacterial agents. Also, invention relates to a pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of compounds.

4 cl, 10 tbl, 2 ex

 

The invention relates to the field set of biologically active dietary substances, in particular 6-alkyl-5-(2-isonicotinohydrazide)brazilianorigin that have antimycobacterial and immunotropic activity and can be used as immunomodulator and antimycobacterial funds, as well as to pharmaceutical compositions based on them.

Known alkali metal salts of N-(6-alkyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinylidene)-N'-isonicotinohydrazide formula (A) (Iodination)

where R is an alkyl with 1-4 carbon atoms and M is an alkaline metal, with a similar activity with toxicity 7000 mg/kg (see international patent application WO 01/32650). However, their activity is not high enough (see the following tables).

Also known N-(6-methyl-2.4-dioxo-1.2.3.4-tetrahydro-5-pyrimidinylidene)-N-isonicotinohydrazide hydrate (B), with antimycobacterial and immunomodulatory activities (patent RU 2141322). However, this compound (I) is not soluble in water, saline solution and other solvents has poor solubility in biological fluids, which testify to its low biological activity, low bioavailability.

The basis of the invention is to find new ones on the structure of compounds with more high is some activity.

The problem is solved proposed 6-alkyl-5-(2-isonicotinoyl-hydrosoil)brazilianorigin General formula (I)

where R is an alkyl with 1-4 carbon atoms.

6-Methyl-5-(2-isonicotinohydrazide)aracelytokarz formula (I) is a crystalline powder white to cream color with a melting point MP= 253-254°C.

The proposed connection is produced by the interaction of the hydrazide of isonicotinic acid with 6-methyluracil-5-sulfochloride in the solvent.

The compounds of formula (I) possess antimycobacterial and immunotropic activity.

The problem can be solved proposed pharmaceutical composition having antimycobacterial and immunotropic activity, including active substance and additives target, the difference of which is that as the active substances it contains 6-alkyl-5-(2-isonicotinohydrazide)aracelytokarz General formula (I) in an effective amount.

The dosage depends on age, condition and weight of the patient, and the type of injection. According to the invention, the proposed pharmaceutical composition contains the active substance in an amount of from 0.1 to 4 g

The proposed toxicity of the compounds was determined on outbred mice weighing 18-20 g in the acute experience in etodo of Litchfield-Wilcoxon signed and amounted to more than 7000 mg/kg

The claimed compounds have been tested in experiments on animals.

The definition of immunotropic activity proposed hydrochloride

a) Effect on humoral immunity was studied using the method of local hemolysis in gel. Mice of the F1 hybrids (NEA × C57BI6) were immunized with sheep erythrocytes in a dose of 5×106and immediately after this was introduced the substance as oral in starch suspensions, and parenteral. On the 5th day counted the number of antibody productive cells (AFC) in the spleen of mice and determined the index of stimulation of the immune response against the number of KLA in the experimental group to the number of the KLA in the control group.

The data presented in table 1.

Table 1.

The influence of the studied compounds on the accumulation of antibody productive cells (AFC) in the spleen of mice (difference significantly (p less than 0.01) compared to normal).
Drug nameRoute of administrationDose m kg/mouseThe number of AFC in the spleenQty animalsThe stimulation index of immune response
Controloral0.5 ml of grahm. suspension500±50121,0
oral5002850±150125,3±0,5
Iodinationoral5002360±250124,6±0,7
Controlparenteral0.2 ml of Physiol. solution510±50121,0
Hydrochlorideparenteral1001800±10012403±0,6
Iodinationparenteral1001650±280123,20±0,6

Indexes stimulation of the immune response hydrochloride and iodination with the introduction of drugs inside significantly indistinguishable among themselves. This suggests that the studied drugs have immediate effect on humoral immunity, under test in response to the accumulation of AFC in the spleen of mice.

b) influence of the studied drugs on the proliferation of T-lymphocytes was studied on a model in vitro. For this preliminary 3-hour incubation of mononuclear cells in the presence of different concentrations of each analyte. Studied a wide range of concentrations of each analyte: from 0.01 to 5 μg/L. as a negative the main control was added to a physiological solution of 0.9% NaCI.

The effects of new compounds on the intensity of the proliferation of T-lymphocytes person in the culture of cells in vitro are presented in table 2.

Table 2.

The effect hydrochloride on the proliferation of T-lymphocytes in vitro culture.
MedicationDose, mg/mlThe intensity of the incorporation of 3H-thymidine DNA of cultured cells (pulse/min)
SpontaneousActivated PHA
Saline80020002
Hydrochloride590020132
1127525400
0,1130138000
0,03198031150
0,01153029990
Iodination562019142
181222068
0,1114428145
0,03176234284
0,01149629586

Thus, the proposed hydrochloride and iodination has as its own mitogenic activity, and in response to phytohemagglutinin, but this shows the activity when added in a smaller dose.

C) the Effect of study drug on the phagocytic activity of macrophages was studied by clearance carcasses in the blood taken from retroorbital sinus of mice treated with oral drugs. The results were evaluated by phagocytic index (table 3).

Table 3.

The influence of the studied drugs on the phagocytic activity of macrophages (the difference was significantly (p less than 0.01) compared to normal).
MedicationRoute of administrationDose, μg/mousePhagocytic indexQty animals
Starch, susp.oral0.5 ml4,2±0,0612
Hydrochlorideoral5007,1±0,0312
Iodinationoral5006,64±0,1212
Salineparenteral.0.2 ml 4,1±0,0712
Hydrochlorideparenteral.1007,5±0,0612
Iodinationparenteral.1007,12±0,0912

The results in the table suggest that hydrochloride stimulates the phagocytic activity of macrophages to a greater extent than iodination at any way of introduction.

g) Immunomodulating ability hydrochloride was determined on the model of immunodeficiency caused by irradiation of mice F1(CBA x57BI6) at a dose of 4 gray.

It is shown that the irradiation of mice at a dose of 4 gray reduces the immune response in 15-20 times, his recovery begins at 6-8 day and ends at 30 days (Yarylo A.A., Polushkina AF, Filatov P.P. Effect of ionizing radiation on the ratio of populations of lymphoid cells in mice, Radiobiology, 1976, so 16, No. 3, pp. 451-454). When using this model, the experimental animals were treated with tested drugs in doses of 500 μg/mouse administered orally in 0.5 ml of starch suspension and 100 µg/mouse injecting 0.2 ml of saline. The drugs were injected three times at 6,7,8 day after irradiation. Control group animals received 0.5 ml of starch suspension or 0.2 ml saline. By day 15 in these animals was determined by the number of KLA in which elegance method local hemolysis in gel.

The obtained data are presented in table 4.

Table 4.

The effect hydrochloride on the recovery process of the formation of antibody productive of spleen cells in irradiated animals.
MedicationRoute of administrationDose μg/mouseQty animalsThe KLA on the spleenThe stimulation index
Irradiated control12309±36
HydrochlorideOral500121080±393,5±0,4
IodinationOral50012995±123,2±0,5
Control physiologic solutionParenteral0.2 ml12312±40
HydrochlorideParenteral100121200±544,0±0,2
IodinationParenteral100121074±12 83,5±0,5

On the basis of the received data restore the structure of the immune response after exposure we can conclude, the hydrochloride is very immunokorrigiruyuschuyu activity than the Comparators.

The definition of anti-TB activity hydrochloride.

The activity was tested in comparison with iodination. For infection were used laboratory strains of Mycobacterium tuberculosis H37RV usual and rubaidulloev to 100 mg. 230 mice of CBA infected intravenous 0.25 mg culture tuberculosis in 0.5 ml of saline. The experience lasted 2 months. Under supervision there were 20 groups of animals 15 mice in each group, all animals were kept in the same vivarium conditions on a standard diet. The control group received during the entire experience through the probe 5 times per week 0.5 ml of starch suspension or 0.2 ml saline parenteral. The experimental group of animals received drugs orally in different doses in 0.5 ml of starch suspension or in 0.2 ml of saline parenteral. All animals, both the fallen and the downtrodden, at the end of the experience were weighed, also weighed their internal organs was determined by the extent of internal organ involvement, measured in "+"addition of the drug to be judged by life expectancy (ALE).

The results of the experiments are given in table 5.

Table 5.

the influence of the studied substances on anti-TB activity.
Drugs, dose, route of administrationH37RVH37RV-dubaidiscount
Mean life span, daysThe light weight, mgThe index lesionMean life span, daysThe light weight, mgThe index lesion
Control 0.5 ml of a crash.24,2619,22,4823,8632,42,42
suspension oral±2,7±50,4±0,22±0,22±70,2±0,19
Hydrochloride 1003,5500±10537,3450,51,7
μg/mouse oral±5,051,2±0,13±3,8±51,7±0,2
Iodination 100the 33.4526,12,0132,4492,81,96
μg/mouse oral±5,1±47,2±0,12±3,5±and 63.4±0,21
Control 0.2 ml22,8628,3 2,5224,1to 648.22,72
saline parenteral±2,2±61,4±0,21±4,0±71,4±0,21
Hydrochloride31,25301,7the 33.4590,31,9
50 μg/mouse of parenteral±2,1±21,5±0,03±3,2±75,5±0,1
Iodination30,5580,2±1,8031,6607,82,03
50 μg/mouse of parenteral±4,646,2±0,09*±3,1±59,2±0,21*
* Values significantly different from control, P<0,05

The above results show hydrochloride has a strong anti-TB activity as Mycobacterium sensitive to most anti-TB drugs and TB bacilli resistant to tubazide. According to the index of the lungs, infected animals, anti-TB activity hydrochloride is manifested to a greater extent than is the courthouse square comparison.

The definition of leprosy activity hydrochloride in comparison with iodination.

Leprosy activity hydrochloride in comparison with iodination was studied in mice male line of the IAS infected with a laboratory strain of Chickens-4 Mycobacterium leprosy, taken in quantities of 5000 and put intraplantar the method of Shepard. The experience lasted for 6 months. Under supervision there were 5 groups of 20 mice in each group. All mice were kept in the same vivarium conditions on a standard diet.

The first group - control: within 6 months of mice in this group received through the probe 5 times per week 0.5 ml of starch suspension. In another series of experiments, control animals parenterally in the analyzed period were administered 0.2 ml of saline, and experimental drugs, diluted in saline solution.

After 6 months, the animals were killed by cervical spine, organs were subjected to microscopy study, no pathological abnormalities characteristic of any group, not detected. In the reading space of infection (foot) was ground in 2 ml of 0.1% solution of albumin, 0.01 ml of the suspension was done smear was stained by Zn and counted the number of mycobacteria in 1 mouse in each group.

The results are shown in table 6.

Table 6.

The influence of the studied substances on leprosy activity (the difference was significantly (p less than 0.01) compared to normal).
GroupDose μg/mouseNumber of mice in groupThe number of mycobacteria in the foot X106% of infected animals
Control0.5 ml of the collapse. susp. peror.201,14±0,12100
Hydrochloride5020-0
Iodination5020-0
Control0.2 ml of saline parenteral201,27±0,14100
Hydrochloride2520-0
Iodination2520-0

As shown, the hydrochloride in all the tested doses and methods of application manifests expressed leprosy activity as well as iodination at a dose of 25 μg/mouse.

Study of the antimicrobial action hydrochloride

Antimicrobial activity hydrochloride in comparison with iodination was studied in cultures Bcillus cereus and Staphylococcus aureus. To determine the antimicrobial action of drugs on B. cereus took 100 mg of each drug was dissolved in 10 ml of phosphate buffer (pH 7.0) and added to 1 ml in tubes containing 1 ml of molten medium No. 1 (the State Pharmacopoeia of the USSR, ed XI, issue 1, Vol.2, str) and 1 ml daily broth culture of B. cereus, diluted 1000 times the saline-solution. The contents of the tubes were immediately poured into a Petri dish containing 15 ml of a frozen environment No. 1, the cups were placed in a thermostat at a temperature of from 30 to 35°C.

To determine the antimicrobial action of drugs on the St. aureus took 100 mg of each drug was diluted in medium No. 8 (the State Pharmacopoeia of the USSR, isdh, issue 1, Vol.2, str) was added at 1 ml test tubes containing 4 ml of molten medium No. 10 (the State Pharmacopoeia of the USSR, isdh, issue 1, Vol.2, str) and 1 ml daily broth culture of Staphylococcus aureus, diluted with saline 1000 times. The contents of the tube was immediately poured into Petri dishes containing 15 ml of a frozen environment No. 10, the cups were placed in a thermostat with a temperature of 30 to 35°C. the Experiment lasted 5 days.

In the absence of growth of the test strains in appropriate nutrient media note antimicrobial activity of drugs. The results of the experiment are presented in table 7.

Table 7.

Antim is crosnoe action hydrochloride in comparison with isode-Navona.
The test-cultureHydrochlorideIodination
24 hours.48h.5 d.24 hours.48h.5 d.
S. cereus------
St. aureus-----±

+ - the presence of microbial growth

- - no growth of microorganisms

± - low growth of microorganisms

As the results of experiments hydrochloride has a bactericidal effect on microorganisms B. cereus and pronounced bacteriostatic action on St. aureus.

The proposed method of obtaining compounds of formula (I) is illustrated by the following example.

Example

Mix 1.26 g (0.01 mole) of the hydrazide of isonicotinic acid and 2,245 g (0.01 mol) of 6-methyluracil-5-sulfochloride in acetonitrile at the boiling temperature of the solvent for 5 hours.

Filtered, precipitated precipitated hydrochloride and purified in several stages as follows: 0.5 g of the hydrochloride is boiled in 15 ml of ethanol for 10 minutes, then filtered, washed precipitate of 6 ml of ethanol, air-dried. So autonaut one or two more times until when there will be only trace amounts of impurities.

Get 3,115 g of 6-methyl-5-(2-isonicotinohydrazide)uracil-hydrochloride (approximately yield 90%), which is a crystalline powder white to cream color. TPL= 253-254°

Examples of formulations of pharmaceutical compositions

Capsules

Hydrochloride in gelatin capsules to 0.1 g and 0.2 g get packing by hand in capsules No. 1 and No. 0 using capsules with locking device. Composition: hydrochloride 0.1 g and 0.2 g without fillers or preservatives.

A portion of the hydrochloride of 10.0 g placed on the plate of capsulize, spread over the surface of the plate, and further in accordance with the description of the process of working with capsulize.

Gelatin capsules consist of: quinoline EPS - 0.05%, the titanium dioxide is 1.0%, gelatin - up to 100%. Included in the capsules of the substance are allowed for medical use in Russia.

Tablets

Active ingredient is the compound of formula (I) in an amount of 100 mg, 200 mg is the mass fraction of 40%. Targeted supplements (lactose, Aerosil, calcium stearate) - mass fraction of 60%.

Mix the main and auxiliary substances in the ratios shown in table 8 (based on the weight of the tablet):

Table 8
The weight of tablets (Mt ), gMass composition, %
0,2500,500
Hydrochloride - a 0.1hydrochloride - 0,240
Lactose - 0,144Lactose - in 0.28857,6
Aerosil - 0,004Aerosil - 0,0081,6
Stearate CA - 0,002Stearate CA - 0,0040,8

The diameter of the balls 5 mm Weight 100g balls on prepared forms - 500g

Pressing tablets carry on the press RTM-12. The tablets are coated on the basis of acetylcellulose (AFC) apparatus Strea-1". The coating composition (mass part): acetone - of 56.4; ethanol 96% - 37,6; castor oil - 1,0; AFC - 5,0; tropeolin type to light-brown color of the solution. Coverage: amount of coverage (ml) = 50% by weight of tablets (g).

Solution for injection

Hydrochloride for injection is a wastage of powder medicinal product comprising the active substance and its pharmaceutically acceptable salt in a dosage of 0.1-0.5 g

Specific compounds are listed in table 9.

Table 9
ComponentsNumber, ml
123
the compound of formula (I), g0,10,20,5
SolventAcceptable solvent5-
Acceptable solvent-5
Acceptable solvent5

Experiment on animals (rabbits) showed that about 50% of this compound in constant videobeautiful in the products of their activity. Biological testing hydrochloride (I) showed that its effect on humorally the immune system when taken orally slightly higher than that of the compound (C), while injecting the same effect is achieved by the introduction of 8 times smaller doses of the hydrochloride.

Hydrochloride compared with the above-mentioned compound (C) showed antimicrobial activity, in the case of B. cereus - bactericidal, and in the case of St. aureus - bacteriostatic, as evidenced by the data of table 10.

1. 6-Alkyl-5-(2-isonicotinohydrazide)aracelytokarz General formula (I)

where R is an alkyl with 1-4 carbon atoms.

2. Hydrochloride according to claim 1, reavley antimycobacterial and immunotropic activity.

3. Pharmaceutical composition having antimycobacterial and immunotropic activity, including active substance and additives target, characterized in that the active substance it contains 6-alkyl-5-(2-isonicotinohydrazide)aracelytokarz General formula (I) according to claim 1 in an effective amount.



 

Same patents:

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention elates to novel derivatives of uracil of the formula [I] possessing herbicide activity, a herbicide composition based on thereof and to a method for control of weeds. In derivatives of uracil of the formula [I] the group Q-R3 represents a substituted group taken among:

wherein a heterocyclic ring can be substituted with at least a substitute of a single species taken among the group involving halogen atom, (C1-C6)-alkyl-(C1-C6)-alkoxy; Y represents oxygen, sulfur atom, imino-group or (C1-C3)-alkylimino-group; R1 represents (C1-C3)-halogenalkyl; R2 represents (C1-C3)-alkyl; R3 represents OR7, SR8 or N(R9)R10; X1 represents halogen atom, cyano-group, thiocarbamoyl or nitro-group; X2 represents hydrogen or halogen atom wherein each among R7, R8 and R10 represents independently carboxy-(C1-C6)-alkyl and other substitutes given in the invention claim; R9 represents hydrogen atom or (C1-C6)-alkyl. Also, invention relates to intermediate compounds used in preparing uracil derivatives.

EFFECT: improved preparing method, valuable properties of compounds.

40 cl, 16 sch, 12 tbl, 65 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to compounds that inhibit binding ligands with α4β1-integrin (VLA-4) selectively. Compounds have the formula (I):

wherein W means unsubstituted phenyl or phenyl substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom, (C1-C4)-alkoxy-group and halogen alkyl; W1 means unsubstituted phenylene or phenylene substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom and (C1-C4)-alkoxy-group, pyridylene, pyridylene substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom and (C1-C4)-alkoxy-group, 2-oxopyrrolylene or thiazolylene; A means oxygen atom (O); R means -(CH2)n- wherein n = 1 or 2; X means -C(O)-; M is taken among the following groups: a)

wherein means divalent 5- or 6-membered heterocyclic radical wherein nitrogen atom is located in the joining point to X wherein Q represents -CH2-, -O- or -S-; R1, R2 and R3 are taken independently among the group involving: hydrogen atom (-H), hydroxyl group (-OH), quinolinyloxy-group, -NH2, mono- or dialkylamino-group, (C1-C6)-alkylsulfonylamino-, arylsulfonylamino-, naphthyloxy-, phenyloxy-group substituted optionally with di-(C1-C6)-alkylamine, (C1-C6)-alkyl, benzyloxymethyl, halogen atom, phenyl, (C1-C4)-alkoxy-group; or two adjacent R1, R2 and R3 taken in common can form alkylene- or alkylenenedioxy-group substituted optionally with 1-3 alkyl groups; R4 means hydrogen atom (H), lower alkyl; Y is taken among a bond, (C2-C8)-alkenylene group, (C2-C8)-alkynylene group, -C(O)-, -C(O)NH- and -(CH2)kY2 wherein k is taken among 1, 2 and 3; Y2 means a direct bond or divalent radical taken among -O-, -S-, -S(O)-, -S(O)2- and -NY3- wherein Y3 is taken among hydrogen atom (H), lower alkyl; Z means (C3-C8)-cycloalkylene, optionally substituted phenylene, pyridylene, piperidylene, piperazinylene; A1 means a direct bond, -(CH2)t-alkynyl wherein t is taken among 1, 2 and 3; R5 means -OH, lower alkoxy-group, , ; b) means wherein R11 is taken among , -NR12- wherein R12 is taken among hydrogen atom (-H), optionally substituted lower alkyl, lower alkenyl, lower alkynyl, phenyl; Z3 is taken among a direct bond, (C1-C12)-alkyl wherein one or some carbon atoms can be replaced with -O- or -NR13- wherein R13 means hydrogen atom (-H), lower alkyl, wherein x = 0 or 1; y = 1, 2 or 3; R14 means hydrogen atom (-H), ; and when R11 means NR12 then Z3 is taken among: wherein 14Ra means hydrogen (H), halogen atom; , and ; Q2 means wherein R17 and R18 mean hydrogen atom (H), lower alkyl; or phenylene that can be substituted; L1 means -COOH or -COOR19 wherein R19 means lower alkyl. Compounds of the formula (I) inhibit activity of VLA-4-mediated adhesion of cells that allows their using in pharmaceutical compositions.

EFFECT: valuable medicinal properties of compounds and compositions.

21 cl, 11 tbl, 283 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds. Invention describes compounds or their salts of the general formula (I): A-B-N(O)s (I) wherein s = 2; A means R-T1- wherein R represents radical of a medicinal substance under condition that a medicinal substance by the formula R-T1-Z or R-T1-OZ wherein Z represents hydrogen atom (H) or (C1-C5)-alkyl is taken among paracetamol, salbutamol, ambroxol, alendronic acid,, cetirizine, ampicillin, aciclovir, doxorubicin, simvastatin, diphylline, tacrine, clopidogrel, dimethylomeprazol, diclofenac, ferulic acid, enalapril, propranolol, benfurodil hemisuccinate, tolrestate or sulindac; T1 means (CO), oxygen atom (O) or NH; B means TB-X2-O- wherein TB means bivalent radical R1B-X-R2B wherein R1B and R2B are similar or different and represent linear or branched (C1-C6)-alkylenes and X represents a bond, oxygen (O), sulfur (S) atom or NR1C wherein NR1C represents hydrogen atom (H) or linear or branched (C1-C6)-alkyl; corresponding precursor B is represented by the formula -TB-X2-OH wherein TB means (CO) and free valence in TB represents -OZ wherein Z is determined above, or TB means oxygen atom (O), and free valence in TB represents hydrogen atom (H) under condition that in the formula (I) when X2 in precursor B represents linear or branched (C2-C20)-alkylene then a medicinal substance by the formula R-T1-Z or R-T1-OZ used in the formula (I) doesn't belong to the following substances: enalapril (ACE inhibitors) and diclofenac (NSAID). Also, invention describes pharmaceutical compositions for using in cases of oxidative stress and 4-nitroxybutanoic acid 4'-acetylaminophenyl ester. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of medicinal substances and compositions.

7 cl, 8 tbl, 32 ex

FIELD: organic chemistry, medicine, gastroenterology, pharmacy.

SUBSTANCE: invention relates to compounds represented by the formula (Ia) and compositions used in treatment of gastroenteric diseases based on thereof and their complexes being optionally in combination with compounds of the formula (Ib) . Also, invention describes pharmaceutical preparations and methods for their preparing these compounds. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds.

28 cl, 115 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: claim describes substituted anthranylamides of the general formula (I): wherein A means group =NR7; W means oxygen atom; D, E, F, G, X, Z, R1, R2, R7 and R9 have values given in the description and their isomers and salts also. Also, claim describes intermediate compounds used in preparing indicated anthranylamides. Also, invention relates to medicinal agents, their compositions and their using. Proposed compounds can be used in treatment of diseases associated with persistent angiogenesis that can be cause of different diseases, such as psoriasis, arthritis, for example, rheumatic arthritis, hemangioma, angiofibroma, ophthalmic diseases, for example, diabetic retinopathy, neovascular glaucoma, kidney diseases, for example, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombosis microangiopathy, rejection of transplants and glomerulopathy, fibrosis diseases, for example, hepatic cirrhosis, diseases associated with proliferation of mesangial cells and arteriosclerosis that can result to progression of these diseases. Invention provides the development of the corresponding medicinal agent designated for treatment of abovementioned diseases. The development of the preparation allows expanding assortment of agents used in treatment of such diseases.

EFFECT: valuable medicinal properties of compounds.

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to new amide derivatives of general formula I

1, as well as to pharmaceutical acceptable salts or cleaving in vivo esters thereof. Claimed compounds are capable to inhibit cytokine production due to inhibition of p38 kinase action and are useful in treatment of various diseases such as inflammation or allergic disorders. Also are disclosed methods for production the same, pharmaceutical composition and method for inhibition of TNFα cytokine production. In formula I X is -NHCO- or -CONH-; m = 0-3; R1 is halogen, C1-C6-alkoxy, N-(C1-C6)-alkyl-di{(C1-C6)-alkyl]-amino-(C2-C6)-alkylamino, or heterocyclyl, heterocyclyl-(C1-C6)-alkyl, heterocyclyloxy, heterocyclyl-(C1-C6)-alkoxy, heterocyclylamino, N-(C1-C6)-alkylheterocyclylamino, heterocyclyl-(C1-C6)-alkylamino, N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino, heterocyclylcarbonylamino, heterocyclylsulfonylamino, N-heterocyclylsulfamoyl, heterocyclyl-(C2-C6)-alkanoylamino, heterocyclyl-(C1-C6)-alkoxy-(C1-C6)-alkyl, heterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, or N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, wherein any of heterocylyl in R1 optionally may contain 1 or 2 substituents selected from oxo- or thioxogroup; n = 0-2; R2 is hydrogen or C1-C6-alkyl; R2 is hydrogen, C1-C6-alkyl or C1-C6-alkoxy; q = 0-4; Q is aryl, aryloxy, etc.

EFFECT: new inhibitors of cytokine production.

13 cl, 8 tbl, 20 ex

FIELD: organic chemistry, chemical technology, biochemistry.

SUBSTANCE: invention relates to new substituted 6-sulfo-2-oxo-1,2-dihydroquinoline 4-carboxylic acids and their derivatives of the general formula (1):

eliciting physiological activity, in particular, capacity to inhibit activity of protein kinase, and also to intermediate compounds for their preparing and to the focused library, for search compound-leaders and medicinal candidates obtaining on the basis of screening combinatory libraries. In compounds of the general formula (1) R1 represents hydrogen atom or electrophilic substitute; R2 represents hydrogen atom or inert substitute; R3 represents optionally substituted hydroxyl group, optionally substituted amino-group and optionally substituted azaheterocycle; R4 represents optionally substituted amino-group and optionally substituted azaheterocycle. Also, invention relates to compounds of the general formula (1.1):

wherein R1, R2 and R3 have above given values; R5 represents hydroxyl or chlorine atom, and to their applying for preparing compounds of the general formula (1.2):

and (1.3):

wherein R1, R2 and R4 have above given values.

EFFECT: valuable medicinal and biochemical properties of compounds.

6 cl, 4 tbl, 5 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new inhibitors of farnesyltransferase of the formula (I):

wherein R1 means hydrogen atom (H), group of the formula R5C(O)- wherein R5 means phenyl, pyridyl or N-methylpiperidine; R2 means hydrogen atom (H), isopropyl, cyclopentyl or N-methyltetrahydropyridyl; R3 means hydrogen atom (H), halogen atom; R4 means hydrogen atom (H), halogen atom; L means -CH2-Z- wherein Z means NH; Y means sulfur atom (S), S(O) or S(O)2; or its salt. Compounds of the formula (I) inhibit activity of enzyme, farnesyl(protein)transferase, that allows their using in pharmaceutical composition in cancer treatment.

EFFECT: valuable medicinal properties of inhibitors.

18 cl, 3 tbl, 3 sch, 6 ex

FIELD: veterinary science.

SUBSTANCE: the present innovation deals with cooling selected fertilized uninfected eggs at 2-4 C up to 7 d followed by homogenization, diluting with physiological solution of egg mass, bactericidal treatment, conservation with phenol solution up to its concentration being 0.3% at subsequent filtration of target product. Moreover, egg mass should be diluted with physiological solution at the ratio of 1:5, then comes thermal treatment upon water bath at 70-80 C for 1 h and before conservation one should cool the target product in bactericidal chamber under the lamp with ultraviolet irradiation for 30-40 min. The method provides increased total and specific body resistance, it enables to obtain cheaper and more acceptable biostimulant and simplified way for preparing.

EFFECT: higher efficiency.

4 ex, 3 tbl

FIELD: medicine, biopharmacology, immunology.

SUBSTANCE: invention relates to manufacturing curative-prophylactic preparations based on leukocyte interferon and natural cytokines. The preparation based on complex of natural cytokines is prepared by induction of human leukocytes with Newcastle disease virus of strain "H". Indicated complex of natural cytokines is prepared by at least two treatments of leukocytes before induction stage with virus with the same natural complex of cytokines prepared in previous stage of induction. Complex is purified from foreign proteins of inductor and comprises 104 IU of antiviral activity of human interferon-alpha in one ampoule, not less, and cellular cytokines, phosphate buffer for maintaining pH 6.9-7.5, sodium chloride and mannitol. The end product is lyophilized for preparing the injection preparation. Invention provides increasing activity of the preparation and to retain the natural complex of cytokines.

EFFECT: improved preparing method, valuable medicinal properties of preparation.

3 cl, 2 ex

FIELD: medicine, gastroenterology, pharmacy.

SUBSTANCE: invention relates to agents used in treatment of ulcerous-erosion injures in gastroduodenal region. Method involves diluting 100 mcg of dry lyophilized powder of immunomodulating agent "Superlimf" in 3-5 ml of 0.9% isotonic solution and irrigation of ulcer or erosion with this solution 1 time per a day by the endoscopy method. The treatment course is 3-4 procedures with break for 4-5 days. Method provides alteration of cytokine pattern of tissues, induction of influx of mononuclear phagocytes to the injure focus that results to localization of inflammation and the complete epithelization of ulcers and erosions.

EFFECT: improved and effective method for treatment.

1 ex

FIELD: medicine, pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a method for preparing an anti-inflammatory, wound-healing, capillary-strengthening, immunomodulating agent. Method for preparing an anti-inflammatory, wound-healing, capillary-strengthening, immunomodulating agent is carried out for four stages. At the first stage violet tricolor and/or field milled herb is extracted with fluidized carbon dioxide under the definite condition followed by separation of grist from lipophilic fraction of extract; at the second stage defatted grist is subjected for three-fold extraction by remaceration method under the definite condition followed by treatment and purification of combined extract, treatment, condensation and preparing liquid alcoholic extract; at the third stage liquid alcoholic extract is used for preparing polysaccharide and flavonoid complexes by precipitation of polysaccharide with three-fold volume of 96% ethyl alcohol and the following drying at the definite temperature; at the forth stage grist after isolation of polysaccharide and flavonoid complexes is used for preparing pectins by treatment with three-fold volume of ammonium oxalate solution at the definite temperature, evaporation and drying. Liquid alcoholic is evaporated to 1/5 of the parent volume, dried by spraying drying or lyophilic drying at definite temperatures. Each end product prepared at each stage can be used as both independent medicinal formulation and can be used for preparing other medicinal formulations (tablets, capsules, suppositories, films). Also, invention relates to a method for preparing an anti-inflammatory, wound-healing, capillary-strengthening, immunomodulating agent that involves extraction of violet tricolor and/or field milled herb with 70% ethyl alcohol by infusion for a definite time followed by purification of the end product, settling at the definite temperature and filtration. Method provides preparing agent with broad pharmacological pattern of action and provides the maximal using the medicinal vegetable raw.

EFFECT: improved preparing method, valuable medicinal properties of agent.

5 cl, 5 tbl, 17 ex

FIELD: medicine.

SUBSTANCE: means has lipid fraction obtained from Berryteuthis Magister Comandor squid liver containing 10% of polyunsaturated fatty acids and 50% of alkyl-diacylglycerides showing marked lipid-correcting and immunomodulating properties.

EFFECT: enhanced effectiveness in treating lipid metabolism disorders and immunity system disorders.

4 tbl

FIELD: medicine.

SUBSTANCE: method involves administering inmmunotherapy with recombinant interferon-α2b in daily dose of 3x106 MU. It is incubated in thermostat during 1 h at 37°C with 100 ml of autoblood and then it is intravenously introduced to a patient during 1-1.5h daily under blood formula control to reach leukocyte content of>4*109 /l, granulocytes >2*109 /l.

EFFECT: eliminated leukopenia and dose-limiting toxicity risk; accelerated treatment course; reduced risk of infectious complications.

FIELD: agriculture, veterinary science.

SUBSTANCE: during the 1st d after forming raising groups one should once inject intramuscularly a solution of "Complex A" preparation at the dosage of 0.30-0.32 mg/kg body weight for 45-60-d-aged piglets and simultaneously with fodder one should introduce "Lactobifadol" preparation at the quantity of 0.50-0.52 g/kg body weight during the first 1-5 d. The present innovation enables to activate immune system, increase total protein and hemoglobin in blood that in its turn, prevents bronchopneumonia and remove stress in piglets after forming special raising groups.

EFFECT: higher efficiency of prophylaxis.

1 ex, 1 tbl

FIELD: medicine, ophthalmology.

SUBSTANCE: as an immunomodulating remedy one should introduce tamerite per 0.5 ml subconjunctivally and per 1.5 ml i/m daily for 5 d. The method provides normalization of immunity values due to additional local complex manifestation of immunomodulating, antiphlogistic, antioxidant and regenerating effects of tamerite.

EFFECT: higher efficiency of complex therapy.

2 ex

FIELD: food industry.

SUBSTANCE: invention relates to food additives that can be used to prevent immunodeficiency conditions. Immunomodulator is prepared via homogenization of lymphatic nodes in sodium chloride solution, autolysis, centrifugation, heating of supernatant to 80°C, cooling, removal of precipitate, and drying of supernatant by cooling it and placing it into atmospheric sublimation installation followed by subsequent post-drying using IR drying technique.

EFFECT: simplified immunomodulator preparation process and preserved biological and food values of finished product without creation of special temperature regime.

5 tbl, 2 ex

FIELD: applied immunology.

SUBSTANCE: composition contains, wt parts: borax decahydrate1-25, sodium thiosulfate pentahydrate 10-5-10-4, potassium carbonate 30-150, refined sugar 30-200, and water 100-200 per 100 wt parts of sodium metasilicate pentahydrate. In addition to its capability of improving resistance to diseases, body weight increase, productivity of agricultural plants, quality of crop, and ripening term (harvest time), composition according to invention possesses nonspecific immunostimulating activity, including production of antibodies and enhancement of immunity through activation of immunocytes thereby maximally strengthening vaccination effect regarding diseases caused by malignant neoplasm viruses.

EFFECT: increased assortment of immunostimulating agents.

10 cl, 11 dwg, 12 ex

The invention relates to the field of medicine and for new dosage forms of demoliton
Up!