Non-steroid anti-inflammatory agents based on pyridoxine derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to pyridoxine derivatives general formula I, where: when R2+R3=-C(CH3)2- or -CH(CH3)-; , when R1=H; R2=H; , when R1=H; R3=H; , .

EFFECT: pyridoxine derivatives, having high anti-inflammatory activity and low toxicity.

2 cl, 2 dwg, 6 ex

 

The invention relates to new derivatives of pyridoxine formula (I), which have high anti-inflammatory activity and low toxicity and can be used in medicine and veterinary medicine.

where:

when R2+R3=-C(CH3)2- or-CH(CH3)-; R1=

when R1=H; R3=H; R2=

R1=R2=R3=

Diseases of the musculoskeletal system is one of the most popular types of diseases whose treatment is a complex public health problem. To treat inflammatory diseases most commonly used non-steroidal anti-inflammatory drugs (NSAIDs).

Over the past 30 years, the number of NSAIDs has increased significantly and currently this group consists of a large number of drugs with different duration of action and application methods. The main element of the mechanism of action of NSAIDs is the inhibition of the synthesis of inflammatory mediators - prostaglandins. In the process of alteration (stage 1 inflammation) of the cell membrane are released phospholipids, which under the action of the enzyme phospholipase A2 metabolized to arachidonic acid. Arachidonic acid, in turn, metabolizer is by two ways: cyclooxygenases (COX) and lipooxygenase (LOG). NSAIDs inhibit only COX, so they block the development of only the second stage of inflammation.

There are 2 isoenzyme COX: COX-1 (constitutive, the existing norm) - controls the production of prostanoids, regulating physiological functions of the stomach, blood vessels and kidney, COX-2 (induced) - is involved in synthesis of prostaglandins in inflammation. COX-2 is absent in the norm and is formed under the action of tissue factors that induce an inflammatory response (cytokines and others). Anti-inflammatory action of NSAIDs is due to the inhibition of COX-2, and side effects result from inhibition of COX-1.

The most famous (used) NSAID is Ketoprofen (3-benzoyl-alpha-methylbenzylamine acid), ibuprofen ((RS)-2-(4-isobutylphenyl)propionic acid), diclofenac (2-[(2,6-dichlorophenyl)amino] benzene acetic acid), indomethacin (1-(4-chlorbenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid) and naproxen ((S)-6-methoxy-α-methyl-2-naphthalenyloxy acid).

The most common and dangerous side effects of NSAIDs include gastrointestinal tract (GIT), which may appear dyspepsia (nausea, vomiting), stomach erosions, peptic ulcers and gastrointestinal bleeding. Peptic ulcer disease largely associated with its own acidity NSAIDs, which in conjunction the Institute with the acidity of the stomach contents leads to disruption of the permeability of the mucosal cells and becomes the direct cause of education ulcerative processes.

Bleeding is also associated with the ability of these drugs to inhibit the synthesis of prostaglandins and thromboxanes, normally contributing to the preservation of the integrity of the mucous layer.

Protection of the carboxyl group is one of the main ways to reduce the toxicity of NSAIDs. Most often used for this ester protection. Esters NSAIDs are typical prodrugs that are in the digestive tract are subjected to enzymatic hydrolysis with the gradual release of NSAIDs, thereby providing a prolonged effect of the drug. In addition, they better penetrate the cytoplasmic membrane of the cells, due to which have less irritating effect on the mucous membrane of the digestive tract.

In the international application [WO 2008101064 A1. Method of treating arthritis, pain or inflammation with naproxen 2-(methanesulfonyl)ethyl ester and an h2 receptor antagonist/logical therapeutics inc - Publ. - 21.08.2008] proposed to use 2-(methanesulfonyl)ethyl ester of naproxen in the treatment of arthritis and inflammatory processes.

In the American patent [US 4851426. Ethoxycarbonyloxy ethyl esters of non-steroidal anti-inflammatory carboxylic acids and pharmaceutical compositions thereof / Teva pharma. Ind. - Publ. - 12.09.1989] described ethoxycarbonylmethylene esters of various NSAIDs with high anti-inflammatory and analgesic activity, along with a low gastrotoxicity.

The proposed morpholinosydnonimine the haunted esters NSAIDs, significantly less gastrotoxic compared to the baseline NSAIDs [US 2005004118. Prodrugs of non-steroidal anti-inflammatory and carboxylic acid containing compounds / Jilani Jamal A., Publ. - 19.12.2000].

A number of esters of N-substituted of glycolamide of naproxen. These compounds possess equivalent to naproxen anti-inflammatory activity, while in vivo being much more secure [Ranatunge R.R., Augustyniak M.E., V. if you and others. Synthesis and anti-inflammatory activity of a series of N-substituted naproxen glycolamides: nitric oxide-donor naproxen prodrugs // Bioorg. Med. Chem. - 2006. - V.14. - P.2589-2599].

As analogues to the claimed technical solution can also be considered and esters of naproxen and pyridoxine on hydroxymethylene group in 5-position described in U.S. patent [US 4260613. Pyridoxine derivatives / Crinos Industria Farmacobiologica. - Publ. - 07.04.1981]. These compounds revealed the ability to inhibit inflammatory processes caused by model carragenine edema in rats.

The task of the invention are new, low-toxic compounds with high anti-inflammatory activity, expanding Arsenal of known means specified destination.

The technical result of the claimed invention is to provide new compounds of General formula (I)containing in its composition as a piece of natural compounds (pyridoxine, which is a part of vitamin B6), and FR is gment non-steroidal anti-inflammatory drug naproxen.

The problem is solved, and the specified technical result is achieved by obtaining the claimed new derivatives of pyridoxine formula (I)

according to the scheme below in one, two or three stages:

R1R2R3
I-1R2+R3=-C(CH3)2-
I-2R2+R3=-CH(CH3)-
I-3HH
I-4

Characteristics of the new compounds are given in the examples of specific performance. The structure of the obtained compounds were confirmed by mass spectrometry,1H and13C NMR SPECT is octopii. NMR spectra were recorded on a device Bruker AVANCE-400. The chemical shift was determined relative to the signals of the residual protons of the deuterated solvents (1H and13C). Monitoring the progress of reactions and the purity of the compounds was performed by TLC on plates Sorbfil Plates.

Mass MALDI spectra were recorded on a wall-mounted device III Bruker equipped with a solid-state laser and a time-of-flight mass analyzer. Accelerating voltage of 25 kV. Samples were applied to the target Anchor Chip. The recording of the spectra was carried out in positive ion mode. The resulting spectrum was the sum of 300 spectra obtained at different points of the sample. As the matrices used 2,5-dihydroxybenzoic acid (DHB) (Acros, 99%) and n-nitroaniline (PNA). For preparation of matrices used chloroform. Application of samples to the target was performed by the method of "dried droplet".

Examples of specific performance of the claimed technical solution

Example 1

3,3,8-Trimethyl-1,5-dihydro-[1,3]doxepin[5,6-c]pyridin-9-ol (IIIa)

Through a suspension of 20 g (97.3 mmol) of piridoksingidrohlorid (II) in 300 ml of acetone, cooled to 3-5°C and stirring miss 22g (603 mmol) of hydrogen chloride. The resulting reaction mixture is stirred for 20 hours the Precipitate is filtered off, washed with ether and neutralized with an aqueous solution of potash. The product is filtered and recrystallization from ethanol. Yield 19.1 g (94%), colorless crystals. TPL 184.5-186°C (184-185°C [W. Korytnyk A seven-membered cyclic ketal of pyridoxol // J. Org. Chem. - 1962. - V.27, n 10. - P.3724-3726]).

Example 2

3,8-Dimethyl-1,5-dihydro-[1,3]doxepin[5,6-c]pyridin-9-ol (IIIb)

Synthesize and develop similarly to the compound (IIIa) of 20 g (0.096 mol) of piridoksingidrohlorid, 300 ml of acetaldehyde and 22 g (603 mmol) of hydrogen chloride. Yield 65%, colorless crystals. TPL 186-186 .5°C (lit. 186-186 .5°C [Fedorenko V.Yu., Lodochnikova O.A., Petukhov A.S., Kataeva O.N., Litvinov I.A., Shtyrlin Yu.G., Klimovitskii, E.N. Crystal structure of the seven-member ed acetals with furan and pyridine planar fragments // J. Mol. Struct. - 2003. - V. 644, N 1-3 - P.89-96].

Example 3

3,3,8-Trimethyl-4H-[1,3]doxepin[5,6-c]pyridin-9-ol (2S)-(6-methoxynaphthalene-2-yl)propionate (I-1)

To 0.3 g (1.44 mmol) of the compound (IIIa) at 20°C was added 0.4 g (1,95 mmol) dicyclohexylcarbodiimide (DCC), 0.2 g (1,64 mmol) of 4-(dimethylamino)pyridine (DMAP) and 0.33 g (1.44 mmol) of naproxen. After 20 minutes the precipitate was filtered, the filtrate was concentrated in vacuo and was purified by column chromatography (eluent ethyl acetate : petroleum ether 1:1). The yield of 0.48 g (79%), colorless crystals. TPL 136-137°C. [α]24D=+54,21° (c=2.50, CH2Cl2). An NMR spectrum1H (400 MHz, CDCl3) δ ppm: 1.36 (3H, CH3), 1.39 (3H, CH3), 1.73 (3H,2JHH=-7.1 Hz, CH3), 2.10 ush (3H, CH3), 3.87 (3H, OCH3), 4.14 (1H,2JHH=-7.1 Hz, CH), 4.44 ush (2H, CH2), 4.77 (2H, CH2), 7.14-7.78 (m 2H, ar), 8.05 (1H, CH). NMR3 C {N} (100 MHz, CDCl3) δ, ppm: 18.20, 18.99, is the 23.60, 23.70, 45.48, 55.44, 58.99, 61.65, 102.73, 105.77, 119.45, 126.14, 126.50, 127.63, 129.05, 129.41, 133.39, at 134.14, 134.31, 139.93, 142.42, 144.04, 150.24, 158.02, 171.92. Mass spectrum: Found [M+H]+408. C24H25NO5. Calculated M 407.

Example 4

3,8-Dimethyl-1,5-dihydro-[1,3]doxepin[5,6-c]pyridin-9-ol (2S)-(6-methoxynaphthalene-2-yl)propionate (I-2)

Synthesize and develop similarly to compound (I-1) of 0.3 g (1.54 mmol) of the compound (IIIb), 0,43 g (of 2.08 mmol) dicyclohexylcarbodiimide (DCC)and 0.22 g (of 1.80 mmol) of 4-(dimethylamino)pyridine (DMAP) and 0.35 g (1.54 mmol) of naproxen. Output 0,46 g (75%), colorless crystals. TPL 119,5-to 121.5°C. an NMR Spectrum1H (400 MHz, CD2Cl2:CS2=1:1) (mixture of two diastereoisomers 1:1) δ, ppm: 1.28 ush (3H, CH3), 1.72 d (1.5H,2JHH=3 Hz, CH3), 1.73 d (1.5H,2JHH=3 Hz, CH3), 2.07 ush (3H, CH3), 3.90 (3H, OCH3), 4.131 (0.5H,2JHH=-7 Hz, CH), 4.130 (0.5H,2JHH=-7 Hz, CH) 4.32, 4.53 ush (2H, CH2), 4.64, 4.84 (AB,2JHH=-11.6 Hz, CH2), 4.96 ush (1H, CH), 7.12-7.75 m (6H, ar), 8.04 (1H, CH). NMR13C {H} (100 MHz, CDCl3) (mixture of two diastereoisomers 1:1) δ, ppm: 18.22, 19.11, 19.16, 19.72, at 45.44, 55.40, 65.57, 65.78, 105.74, 119.43, 126.04, 126.08, 126.49, 127.63, 129.02, 129.40, 133.57, 134.11, 134.16, 134.23, 140.26, 142.28, 142.40, 144.35, 150.84 158.00, 172.10. Mass spectrum: Found [M+H]+408. C24H25NO5. Calculated M 407.

Example 5

(3-Hydroxy-5-hydroxymethyl-2-methylpyridin-4-yl)methyl (2S)-(6-methoxymethyl the h-2-yl)propionate (I-3)

A solution of 0.25 g (0.59 mmol) of the compound (I-1) in 15 ml of water, 5 ml of ethanol and 0.2 ml of conc. HCl was stirred for 12 h at 20°C, and then neutralize the solution to pH=7 solution of NaHCO3. The solvent is kept in vacuum, the residue was extracted with ethanol and purified using column chromatography (eluent ethyl acetate-ethanol 8:1). Output 0,067 g (30%), colorless crystals. TPL 140-142°C. [α]24D=-12,93° (c=0.58, CH2Cl2). An NMR spectrum1H (400 MHz, CDCl3) δ ppm: 1.73 (3H,3JHH=7.1 Hz, CH3), 2.56 (3H, CH3), 4.00 (1H,3JHH=7.1, CH), 4.08 (3H, CH3), 4.83 (2H, CH2), 5.09, 5.14 (AB,2JHH=-12.4 Hz, CH2), 6.29 ush (2H, 2OH), 7.29-7.84 m (6H, ar), 7.95 (1H, CH). NMR13C {H} (100 MHz, CDCl3) δ, ppm: 18.23, 18.33, 45.47, 55.46, 60.34, 62.03, at 105.75, 119.33, 126.03, 126.14, 127.38, 128.93, 129.27, 130.15, 130.91, 133.80, 135.33, 139.31, 148.36, 151.88, 157.86, 174.14. Mass spectrum: Found [M]+382. C22H23NO5. Calculated M 381.5.

Example 6

(5-{[(2S)-2-(6-Methoxynaphthalene-2-yl)propanol]oxy}-4-({[(2S)-2-(6-methoxynaphthalene-2-yl)propanol]oxy}methyl)-6-methylpyridin-3-ol)methyl (2S)-2-(6-methoxynaphthalene-2-yl)propionate (I-4)

Synthesize and develop similarly to compound (I-1) of 0.3 g (of 1.46 mmol) pyridoxine hydrochloride (II), 1.31 g (6,36 mmol) dicyclohexylcarbodiimide (DCC), of 0.53 g (of 4.38 mmol) of 4-(dimethylamino)pyridine (DMAP) and 1.01 g (of 4.38 mmol) of naproxen. The output of 0.82 g (70%), colorless crystals. TPL 125°C. [α]24the D=+5,93° (c=8.10, CH2Cl2). An NMR spectrum1H (400 MHz, CDCl3) δ ppm: 1.46 (3H,3JHH=6.2 Hz, CH3), 1.53 (3H,3JHH=7.1 Hz, CH3). 1.63 (3H,3JHH=7.1 Hz, CH3), 2.04 ush (3H, CH3), 3.6 ush (1H, CH), 3.79 (1H,3JHH=7.1 Hz, CH), 3.91 (3H, CH3), 3.92 (3H, CH3), 3.94 (3H, CH3), 3.96 (1H,3JHH=7.1 Hz, CH), 4.67 ush (1H, CH3), 4.92 ush (1H, CH2), 5.08, 5.17 (AB,2JHH=-12.8 Hz, CH2), 7.10-7.71 m (6H, ar), 8.29 (1H, CH). NMR13C {H} (100 MHz, CDCl3) δ, ppm: 17.99, 18.41, 18.52, 19.33, 45.04, at 45.36, at 45.44, 55.37, 57.16, 61.69, 105.69, 105.76, 119.11, 119.15, 119.35, 125.94, 126.08, 126.16, 126.56, 127.27, 127.34, 129.37, 133.79, 133.82, 134.05, 134.21, 135.25, 135.65, 144.66, 147.59, 152.91, 157.77, 157.81, 157.97, 171.97, 173.98. Mass spectrum: Found [M]+806. C50H47NO9. Calculated M 805.9.

The study of the acute toxicity of the compounds obtained

Toxicity studies were carried out on outbred mice of line CD-I SPF (kennel laboratory animals "Pushchino"). Mice were kept according to the Rules of the animals in plastic vented boxes, on a bed of paper, under conditions of constant temperature of 22-25°C and humidity, in the normal light mode and free access to food and water. The animals were given feed grain, specialized feed. For days before and after the injection the animals were seized food, and 5 hours is water.

After the drug was watching the behavior of mice and symptoms, we registered the time of death, the surviving animals were Manasarovar using the slumber carbon dioxide. When this register available compared to control diseases, which could be associated with injurious substances.

To identify acute toxicity of the compounds obtained in the form of a suspension in mineral oil was administered orally via a cannula once in the following doses: 1343 mg/kg, 2686 mg/kg, 4060 mg/kg According to the results of studies of acute toxicity of all mice in the experimental groups survived, so to calculate the dose LD50and LD10it was not possible. It is obvious that LD50the claimed compounds are more 4060 mg/kg, which corresponds to the category of "relatively harmless" (class VI toxicity) [Izmerov NF, Sanotski I., Sidorov, K.K. Settings toxicometric industrial poisons in a single (Reference). - M.: Medicine, 1977. - 197 p] or moderately dangerous [according to GOST 12.1.007-76] and more than 3 times larger than the value LD50for naproxen [http://www.drugs.com/pro/naproxen.html].

According to the autopsy and postmortem studies of abnormalities in the structure of the bodies of animals not found. The coat was shiny, neat appearance. Allocation of natural holes were missing. Front and rear legs remained unchanged. Deformat and limbs were observed. The teeth were saved. Visible mucous membranes were pale, shiny, smooth.

Upon examination of the thoracic and abdominal cavities irregularities in the position of the internal organs were noted.

The pleura, pericardium and peritoneum were thin, shiny, smooth.

Thymus had a triangular shape, whitish color and moderately firm consistency.

Aortic diameter was uniform throughout. The intima of the aorta was smooth, shiny, whitish color. The size and shape of the heart changes were introduced.

The muscle of the heart was moderately dense, uniformly brownish color. Heart valves are thin, smooth, shiny. In the cavities of the heart contained a small amount of liquid blood.

Light was spadolini at the opening of the chest. The size and shape of their changes were introduced. The surface of the lungs had a uniform pale pink color. The lumen of the trachea and large bronchi was wide. Mucosa - shiny, pale pink, smooth.

Mucosa of the esophagus was shiny, smooth, pale color. The size and shape of the stomach changes were introduced. The lumen was filled with food items.

The lumen of the duodenum 12 changes were introduced, the mucosa of the intestine was shiny, smooth, pale pink. The mucous membrane of the small intestine was also pale pink, shiny, smooth is. The mucous membrane of the colon had a slightly grayish hue, was smooth and shiny.

The size and shape of the liver changes were introduced. The surface of the liver was smooth, uniform dark red color. The liver tissue at the incision was dark red. The liver capsule was thin, transparent. The consistency of the liver was normal density.

Form of pancreatic changes were introduced. Iron had lobed structure, pale pink color and moderately firm consistency.

The size and shape of the splenic changes were introduced. The surface of the spleen had a uniform dark cherry color, was smooth.

The consistency of the spleen was moderately dense. In the context of organ stood out greyish small-cell follicles.

The size and shape of the kidneys are also not represented changes. The capsule of the kidney can be easily removed. The surface was smooth, uniformly brownish-grayish color. In the context of the body were distinct cortical and brain substance. The consistency of the kidneys was moderately tight.

The adrenal glands have a rounded form, whitish-yellow in color and moderately firm consistency. In the context of clearly stood out dark brown cerebral substance.

The bladder was filled with a transparent, pale urine. The mucous membrane of the bladder was smooth, shiny, bled the first color.

The lining of the brain were thin, transparent. The brain substance was a little potowatami to the touch, the surface of the brain was smooth. On the front the size of ventricular enlargement were observed.

Anti-inflammatory activity of the compounds obtained

Mouse CD-1 were divided into groups of 5 animals each in accordance with the number of tested compounds.

The induction of formalin edema was performed as follows: 50 μl of 1%formalin solution was injected to the mice subplanetary the aponeurosis of the right rear foot [Gabriel RU Guidance on experimental (preclinical) study of new pharmacological substances. - M.: Medicine, 2005. - 832 C.]. After 2 hours and 5 hours after injection of formalin measured by the following indicators: dimensions feet (height, width, length) using oncometer.

The next day started anti-inflammatory therapy. The drugs were injected intragastrically via a cannula 1 time per day for 7 days. The dose of injected drugs were respectively 26,5-27,5 mg/kg

Figure 1. Typical dependence of the degree of the inflammatory process in the formalin model of edema in mice from the time when the introduction of compounds I-1 and I-2.

Figure 1 presents data on anti-inflammatory activity of the most active compounds is rd. The results of these studies showed that these compounds within experimental error definitions have the same with naproxen anti-inflammatory activity (Fig.1).

Thus, the use of esters of NSAIDs based on the derivatives of pyridoxine is of interest in the development of new low-toxic NSAIDs.

1. Derivatives of pyridoxine General formula (I)

where:
when R2+R3=-C(CH3)2- or-CH(CH3)-; R1=
when R1=H; R3=H; R2=
R1=R2=R3=

2. Derivatives of pyridoxine according to claim 1, which has anti-inflammatory activity.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to pyridoxine derivatives of general formula

,

where R1-is a hydrogen atom or methyl, R2 is a hydrogen atom, methyl, linear, branched or cyclic alkyl or R1 and R2 together form a cyclic alkyl capable of powder second-harmonic generation (SHG).

EFFECT: invention can be used in laser technology and communication equipment.

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19 cl, 62 tbl, 332 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to particular compounds, which demonstrate inhibiting activity with respect to ERK, whose structure formula is given in description, to their pharmaceutically acceptable salts, based on them pharmaceutical composition and their application for treatment of cancer, mediated by ERK activity.

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5 cl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof: (I) where R1, R2 and R3, which are identical or different, denote H, lower alkyl; R4, R5, R6, R7 and R8, which are identical or different, denote H, lower alkyl, halogen, nitro, -X-OR0, -X-NR10R11, -X-NR0C(O)R10, -X-O-halogen lower alkyl, -X-O-X-phenyl; or R6 and R7 are combined to form -O-lower alkylene-O-; R, which is identical or different, denotes H, lower alkyl; R10, R11, which are identical or different, denote H, lower alkyl; X, which is identical or different, denotes a bond, lower alkylene.

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15 cl, 11 tbl, 13 ex

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SUBSTANCE: invention refers to substituted pyrazolopyrimidines derivatives of formula , wherein Y1, Y2, Y3, Y4 represent N or C-, wherein at least, two groups of Y1-Y4 represent carbon atom, R1 represents chlorine or bromine, R2-R7 represent, e.g. hydrogen, methyl or ethyl; and R10 and R11 independently represent, e.g. hydrogen or C1-C6alkyl, their optical isomers and pharmaceutically acceptable salts. Also, the invention refers to using said compounds for treating and preventing a number of acute and chronic mGluR5 related neurological disorders, such as, e.g. pains of various character, dyskinesia, Parkinson's disease, anxiety disorder, Alzheimer's disease and others, a pharmaceutical composition containing specified compounds and methods for preparing them.

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21 cl, 2 tbl, 274 ex

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12 cl, 408 ex, 38 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of benzodiazine of the formula (1), which possess properties of inhibiting proliferative action and can be used during treatment of hyper-proliferative diseases like cancer. In formula (I) G1 and G2 each independently representing a halogen; X1 -R1 selected C1-C6-alkoxy, X2 represents a simple bond; Q1 represents a non-aromatic saturated 3-7-member monocyclic heterocyclic ring with 1 circular heteroatom of nitrogen and not necessarily 1 or 2 heteroatoms, selected from nitrogen, oxygen and sulphur, where Q1 does not necessarily have 1, 2 or 3 substitute groups, which can be similar or different , selected from cyano, carbamoyl, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkyl-sulfinyl C1-C6-alkyl-sulfonyl, N-C1-C6-alkyl-carbamoyl N,N-di-[C1-C6-alkyl]carbamoyl, C1-C6-alkanoyl, sulfamoyl, N-C1-C6-alkyl-sulfamoyl, N,N-di-[C1-C6-alkyl-]sulfamoyl, carbamoyl C1-C6-alkyl, N-C1-C6-alkyl-carbamoylC1-C6-alkyl, N,N-di-[C1-C6-alkyl]carbamoylC1-C6-alkyl, sulfamoylC1-C6-alkyl, N-C1-C6-alkyl-sulfamoylC1-C6-alkyl, N,N-di-[C1-C6-alkyl]sulfamoylC1-C6-alkyl, C1-C6-alkanoylC1-C6-alkyl, or from the group with the formula: Q2 -X3-, where X3 represents CO and Q2 represents a non-aromatic saturated 3-7-member monocyclic heterocyclic ring with 1 circular nitrogen heteroatom and not necessarily 1 or 2 heteroatoms, selected from nitrogen and sulphur, and where. Q2 does not necessarily have 1, 2 or 3 substitute groups, which can be similar or different, selected from halogens, C1-C4-alkyl, and where any C1-C6-alkyl and C2-C6-alkaloid groups within the limits of Q1 does not necessarily have one or more substitute groups, which can be similar or different, selected from hydroxy and C1-C6-alkyl and/or not necessarily a substitute selected from cyano, C1-C6-alkoxy, C2-C6-alkanoxy and NRaRb, where Ra represents hydrogen or C1-C4-alkyl and Rb represents hydrogen or C1-C4-alkyl, or Ra and Rb together with a nitrogen atom, to which they are attached, they form a 4-, 5- or 6- member non-aromatic saturated monocyclic heterocyclic ring with 1 circular heteroatom of nitrogen and not necessarily 1 or 2 heteroatoms, selected from nitrogen, oxygen and sulphur, which not necessarily have 1 or 2 substitutes, which can be similar or different, on the available carbon atom, and selected from halogens and C1-C3-alkilenedioxy.

EFFECT: obtaining new derivatives benzodiazine, which possess properties of inhibiting proliferative action and can be used during the treatment of hyper-proliferative diseases such as cancer

27 cl, 73 ex

FIELD: chemistry.

SUBSTANCE: in general formula (I) , R1 represents similar or different 2 groups, each of which is selected from group consisting of C1-3alkyl, or when R1 are two adjacent groups, two groups R1, taken together, can form saturated or unsaturated 5- or 6-member cyclic group, which can have 1 or 2 oxygens as heteroatom; X represents oxygen or sulphur; values of other radicals are given in invention formula.

EFFECT: increase of composition efficiency.

16 cl, 11 tbl, 31 ex

FIELD: medicine.

SUBSTANCE: invention refers to phosphonium salt of pyridoxine derivatives of general formula (I) which may be used in medicine and veterinary science wherein if R1=CH3; R2=CH3; X=H; n=1; R1=CH3; R2=H; X-H; n=1; R1=CH3; R2=CH3; X-CH2P*Ph3; n=2; R,=CH3; R2=H; X=CH2P+Ph3; n=2; R,=CH3; R2=C(CH3)2; X=CH2P+Ph3; n=2.

EFFECT: there are presented new compounds with antibacterial activity on Staphylococcus aureus, including multiresistant strains, as well as low toxicity.

1 cl, 1 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to phenyl alkyl piperazines of formula (I) , in which: R1 represents independently on each other hydrogen atom, halogen atom, (C1-C5)alkyl group, (C1-C5)halogenalkyl group, (C1-C2)perfluoroalkyl group, (C1-C5)alkoxyl group or (C1-C2)perfluoroalkoxyl group; R2 stands for (C1-C5)alkyl group or (C1-C5)alkoxyl group, R3 represents (C1-C5)alkyl group; A represents =CH- and =N-; in form of base or additive salt with acid. Invention also relates to pharmaceutical composition for modulation of activity of TNF-alpha, which contains claimed compounds, and to method of their obtaining.

EFFECT: obtained are novel compounds which can be applied in medicine as medications for treating or preventing pain and/or diseases, associated with inflammatory of immune disorders.

24 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where A is a 6-member heteroaryl, having 1 nitrogen atom as a heteroatom, substituted with 2-3 substitutes such as indicated in the claim, R5 is a halogen atom, cyano or C1-C6alkyl, optionally substituted with a halogen atom; R6 is C1-C6 alkyl, optionally substituted with OH; C1-C3 alkenyl; a 5-member heteroaryl, having 2-4 heteroatoms, each independently selected from N, O or S, substituted with 0-2 substitutes such as indicated in the claim, R10 is a 5-member heteroaryl, having 2-3 heteroatoms, each selected from N, O or S, substituted with 0-2 substitutes, which are C1-C3 alkyl; R7, R8, R17 denote a hydrogen or halogen atom. The invention also relates to a pharmaceutical composition, having BK B2 receptor inhibiting activity, which contains compounds of formula (I), a method of inhibiting, a method of localising or detecting the BK B2 receptor in tissue, use of the compounds of compositions to produce a medicinal agent and methods for treatment.

EFFECT: compounds of formula (I) as BK B2 receptor inhibitors.

22 cl, 1 tbl, 54 ex

FIELD: medicine.

SUBSTANCE: present invention refers to biotechnology and medicine. What is presented is a method for preventing or treating an inflammatory disease, comprising the stages of producing an NR10 antibody having NR10-neutralising activity, and selecting an antibody inhibiting IL-31-dependent cell line growth, and administering the antibody to a patient with an inflammatory disease that is atopic dermatitis, chronic dermatitis, rheumatism or osteoarthritis.

EFFECT: present invention can find further application in the therapy of the inflammatory diseases.

10 cl, 13 dwg, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an implantable drug depot applicable for the release, prevention or treatment of a postoperative pain in a patient in need thereof; the implantable drug depot contains a therapeutically effective amount of clonidine or its pharmaceutically acceptable salt and polymer; the drug depot is implantable into percutaneously for the release, prevention or treatment of postoperative paints; the drug depot can release: 1) approximately 5% approximately to 45% of clonidine or its pharmaceutically acceptable salt to total clonidine or its pharmaceutically acceptable salt as a part of the depot for a first period making up to 48 hours; 2) approximately 55% approximately to 95% of clonidine or its pharmaceutically acceptable salt to total clonidine or its pharmaceutically acceptable salt as a part of the depot for the following period making at least 3 days.

EFFECT: implantable form enables the easy accurate implantation of the drug depot with minimum physical and psychological traumas of the patient.

15 cl, 2 tbl, 20 dwg, 6 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to indole benzylamino compound of formula I

and pharmaceutically acceptable salts thereof. The invention also relates to use of the compound to treat a patient in such a physiological state or susceptible to such a physiological state which needs improvement by inhibiting tryptase and involves administering a therapeutically effective amount of the compound to the patient. The present invention also relates to a pharmaceutical composition containing a pharmaceutically effective amount of the compound of formula I for treating the physiological state by inhibiting tryptase.

EFFECT: novel compound which can be used as a tryptase inhibitor is obtained and described.

17 cl, 13 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: method refers to preventive medicine and concerns decreasing total BAEE-esterase activity. For this purpose, soya protein isolate 30 gram has been daily introduced into the subjects for 2 months.

EFFECT: decreasing the BAEE-esterase activity of protein-degrading enzymes can be used to prevent inflammatory processes.

1 ex, 1 tbl

FIELD: biotechnologies.

SUBSTANCE: invention refers to new positively charged NSAIA prodrugs of a common formula (1, 2a, 2b, 2c or 2d) of "1, 2a, 2b, 2c or 2d structure"

Structure 1, Structure 2a,

Structure 2b, Structure 2c, Structure 2d. Values of R, R1, R2, R3, R4, R5, Ary, X radicals are presented in Claims 1,2.

EFFECT: increasing agent penetration speed.

22 cl, 14 tbl

FIELD: biotechnologies.

SUBSTANCE: peptide of DGSVVVNKVSELPAGHGLNVNTLSYGDLAAD structure is used for suppression of allergic inflammation of respiratory passages, for prophylaxis and treatment of arthritis, as well as for pain relief. A peptide is effective as an adjuvant and for stimulation of IL-12 products in a cell.

EFFECT: peptide allows increasing IL-12 products by 10 times relative to normal levels of IL-12 cellular production.

19 cl, 25 dwg, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is described is a pharmaceutical composition of polydeoxyribonucleotides extracted from natural sources. The composition contains a fraction of polydeoxyribonucleotides extracted from fish sperm cells, wherein the above polydeoxyribonucleotides possess polymer chains of various molecular weights 70 kDa to 240 kDa.

EFFECT: composition is applicable as a therapeutic agent for treating osteoarticular diseases, especially osteoarthritis by an intra-articular injection to provide a required joint fluid viscosity.

8 cl, 13 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present group of inventions refers to medicine, namely to therapy and dermatology, and concerns using boron-based small molecules as anti-inflammatory drugs. That is ensured by administering boron-based small molecules having a specific chemical composition in the effective amount.

EFFECT: invention provides treating various inflammatory diseases by reducing anti-inflammatory cytokines.

35 cl, 21 dwg, 20 ex

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