4,10-bis((±)-5-benzoyl-2,3-dihydro-1h-pyrrolo[1,2-a]pyrrole-1-carbonyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5,5,0,03,11,05,9]dodecane as analgetic means and method of its obtaining
SUBSTANCE: invention relates to a novel chemical substance - 4,10-bis((±)-5-benzoyl-2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1-carbonyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5,5,0,03,11,05,9]dodecane The invention also relates to a method of its obtaining, which consists in the acylation of 2,6,8,12-tetraacetyl-2,4,6,8,10,12- hexaazatetracyclo [5,5,0,03,11,05,9]dodecane by chloranhydride 5-benzoyl-2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid.
EFFECT: novel compound, which has analgetic activity, is obtained.
2 cl, 1 tbl, 2 ex
The invention relates to pharmaceutical chemistry and pharmaceutics, namely to a new chemical - 4,10-bis((±)-5-benzoyl-2,3-dihydro-1H-imidazo[1,2-a]pyrrole-1-carbonyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5,5,0,03,11That 05,9]dodecane with analgesic ability:
Many acute and chronic diseases, injuries and medical interventions are associated with pain, requiring the use of analgesics. Pain is divided into acute and chronic. The choice of anesthesia is determined by several factors, the main of which are the etiology, intensity, type of pain, the individual characteristics. The intensity of the pain determines the choice of appropriate pain relief analgesic potential. Neopioidnye analgesics, non-narcotic drugs and releasing without a prescription, used to treat acute pain and chronic pain syndromes of low intensity [1, 2]. Non-opioid analgesics include the five drugs pharmacological groups: NSAIDs, selective cyclooxygenase-2 inhibitors (COX-2), pyrazolone derivatives, derivatives of paracetamentol and flupirtine.
One of the most used and the closest the technical result of the proposed tool is diclofenac NAT�Oia (Diclofenac Na), which is selected as the comparison drug [1, 2].
There are contraindications and limitations to the appointment of the majority of analgesics [1-4].
We first identified a pronounced analgesic activity 4,10-bis((±)-5-benzoyl-2,3-dihydro-1H-imidazo[1,2-a]pyrrole-1-carbonyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5,5,0,03,11That 05,9]dodecane (DKTAiW) related to hazard class 4 - "non-toxic means."
The problem solved by the present invention is to expand the Arsenal of analgesics with first synthesized substances.
The task is achieved by the use of newly synthesized substances 4,10-bis((±)-5-benzoyl-2,3-dihydro-1H-imidazo[1,2-a]pyrrole-1-carbonyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5,5,0,03,11That 05,9]dodecane (DKTAiW) as analgesic agents.
According to computer modeling and screening studies of derivatives of 2,4,6,8,10,12-hexaazatetracyclo exhibit diverse biological activity [5, 6].
DKTAiW is a frame polyamide - derived 2,4,6,8,10,12-hexaazatetracyclo. The substance was first obtained by acylation available industrial 2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5,5,0,03,11That 05,9]dodecane the acid chloride of 5-benzoyl-2,3-dihydro-1H-imidazo[1,2-a]pyrrole-1-carboxylic acid
The process is performed in the environment of acetonitrile at the boiling point of the reaction mass.
The structure DKTAiW fully confirmed by physico-chemical methods of research.
The technical result of the invention is a substance, method for its production and identification of analgesic actions of the new non-toxic analgesic agents.
Proposed in the invention, the analgesic agent DKTAiW synthesized in Institute of problems of chemical and energetic technologies SB RAS, Biysk). The prototype on substance and method for its production is absent.
In fsbi "Institute of pharmacology named after E. D. Goldberg, Russian Academy when conducting experimental studies revealed marked analgesic activity of the tool.
New property proposed as the means of the invention not explicitly derived from the prior art in this field and is not obvious to a specialist. The present invention may be used in medicine. Identical set of features not found in the study of the prior art by the patent and scientific and medical literature.
Based on the above, you should consider the claimed technical solution meets the criteria of "Novelty", "Inventive step", "Industrial applicability".The possibility of implementing the claimed invention is confirmed by specific example of the method of obtaining the claimed funds.
Getting 4,10-bis((±)-5-benzoyl-2,3-dihydro-1H-imidazo[1,2-a]pyrrole-1-carbonyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5,5,0,03,11That 05,9]dodecane (DKTAiW)
Of 27.4 g (0.1 mol) of acid chloride of 5-benzoyl-2,3-dihydro-1H-imidazo[1,2-a]pyrrole-1-carboxylic acid were dissolved at 40°C in 300 ml dry acetonitrile and transferred into a flask with stirrer and reflux condenser. Then added 7,73 g (0,023 mol) 2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5,5,0,03,11That 05,9]dodecane. The suspension is boiled under stirring for 8 hours and cooled to room temperature. The precipitated product was filtered, washed 2×50 ml of acetonitrile. The precipitate was dried in the air. Got 17.3 g (DKTAiW)-raw.
The filtrate was evaporated to a volume of 100 ml, diluted with 100 ml of diethyl ether and left overnight. The precipitate was filtered, washed with a small amount of ether and was sentenced to an additional 0.4 g (DKTAiW)-raw.
The resulting acylation product (17,7 g) was dissolved by heating in 150 ml of Ν,Ν-dimethylformamide, cooled with stirring slowly added 200 ml of ethanol. The precipitated product was filtered, washed 3×50 ml of ethanol. Was dried in the air. Received 16.0 g of colorless kristallicheskoj� product with a basic substance content of 98.5% (by HPLC method) and a melting point 330-332°C. Output (DKTAiW) was 85.8% of theoretical. According to chromatographic analysis of the MS detector (chemical ionization) molecular weight product is 810.310±0.005 (calculated molecular mass 810,85).
C44H42N8O8. Found (Percent): C, 64.83; H, 5.25; N, 13.52. Calculated (%): C, 65.17; H 5.22; N, 13.82; O 15.79.
The IR spectrum: 3029; 2976; 1670; 1625; 1613; 1574; 1526; 1432; 1404; 1358; 1273; 1167; 1048; 974; 950; 905; 892; 797; 758; 724; 700; 625; 579 cm-1.
The NMR spectrum1H (DMSO, δ, MD), 7.78-7.68 (m), 7.64-7.56 (m), 7.56-7.46 (m), 7.45-7.32 (m); 7.23-6.82 (m), 6.82-6.76 (m), 6.76-6.67 (m), 6.67-6.6 (m); 6.34-6.33 (d); 6.2-6.1 (m), 6.1-6.0 (m), 5.94-5.85 (m), 5.5-5.49 (e); 4.9-4.75 (m), 4.25-4.5 (m); 4.5-4.22 (m), 4.2-4.11 (m), 3.03-2.88 (m), 2.89 (C); 2.82-2.71 (m), 2.73 (C); 2.2-1.87 (m).
The NMR spectrum13C (DMSO, δ, M. D.) 183.7, 184,5 (C=O); 172.7, 171.9, 171.2 (C=O); 168.0, 167.8 (C=O); 144.9, 144.2, 143.0 (C=O); 138,9, 138.6 (Car); 132.0, 131.9 (CHar; Are 128.9, 128.8, 128.7 (CHar); 126.9, 126.6 (Cpir); 125.0, 124.6 (CHpir); 104.0, 102.7 (CHpir); 72.1, 67.0, 65.3, 64.2 (CH); 48.2,47.6 (CH2); 33.7, 31.8 (CH2); 22.4, 21.3 (CH3).
For a better understanding of the invention provide an example of the results of the study analgesic activity of the proposed drug in comparison with the effect of diclofenac sodium.
Study of analgesic activity of 4,10-bis((±)-5-benzoyl-2,3-dihydro-1H-imidazo[1,2-a]pyrrole-1-carbonyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5,5,0,03,11That 05,9]dodecane (DKTAiW) compared to the reference drug diclofenac sodium�
Experiments were performed on 52 outbred mice CD-1 both sexes (7-8 weeks, weight 20 g) the first category is conventional, obtained from the nursery of the Department of experimental biomedical modeling, Institute of pharmacology, SB RAMS (certificate from 07.10.2012, veterinary certificate 270 S. No. 0007293 from 28.11.2013). The keeping of animals and the design of the experiments were approved by the Ethics Committee of the Institute of pharmacology named after E. D. Goldberg" SB RAMS and adheres to the rules adopted by the European Convention for the protection of vertebrate animals (Strasbourg, 1986); Order of the MOH of the Russian Federation No. 708 H of August 28, 2010; Guidance for conducting pre-clinical trials of drugs(2012) [2, 7].
Test "acetic cramps" (Abdominal constriction test) is aimed at the study of the acute visceral and deep somatic pain. Specific pain response - "cramps" (characteristic movements of animals, including reduction of abdominal muscles, alternating with relaxation, stretching of the hind limbs and can Flex back) - caused by intraperitoneal injection of 0.75% acetic acid (GOST 61-75) to mice at a dose of 0.1 ml/10 g of body weight [2, 8]. Analgesic effect was assessed by the ability of potential drugs (within 15 min after injection) to reduce (in %) number of writhing in comparison with the control group animals (criterion �effektivnosti - reducing the pain response by at least 50%) and delayed the time of onset of the pain response. Euthanasia of the animals after the experiments performed in the cranio-cervical dislocation.
Determination of acute toxicity 4,10-bis((±)-5-benzoyl-2,3-dihydro-1H-imidazo[1,2-a]pyrrole-1-carbonyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5,5,0,03,11That 05,9]dodecane (DKTAiW)
In determining acute toxicity DKTAiW injected 6 outbred mice-females and 6 outbred mice-males CD1 intragastrically once a maximum dose of 5000 mg/kg in 0.5 ml of solvent (0.5 ml of Dimexidum and 5.5 ml of distilled water). Within 2 weeks, no deaths were observed, mice had no deviations in health status and behavior, therefore, the test substance is DKTAiW referred to hazard class 4 - "non-toxic assets" in accordance with GOST 12.1007-76 "Hazardous substances. Classification and General safety requirements" and "guidelines for conducting pre-clinical trials of drugs, 2012". In connection with the inability to determine the LD50 for screening assessment of the influence of the test substances on the development of pain response DKTAiW was administered to mice by gavage at a dose of 50 and 100 mg/kg. Used daily dose of diclofenac sodium for mice (10 mg/kg) corresponded to the average daily dose for humans (according to the instructions for use Diklo�of Anak sodium). Each animal within the group were assigned a unique number from 1 to 10, we will use the labels focaccina. The mice were divided into groups randomly, using as a criterion of body weight, so that the individual weight should not deviate from the average value within the same sex more than ±10%. Data (weight and number) of animals selected were ranked in descending order of weight, using the computer program Excel with the SORT command.
In the experiments used the following groups of outbred female mice of CD1:
1. Animals received the solvent in the total volume of 0.5 ml/mouse daily intragastrically by gavage for four days, the last day of the introduction was carried out for 1 h before injection of 0.75% R-RA acetic acid (n=10);
2. Animals received diclofenac sodium at the dose of 10 mg/kg in a volume of solvent of 0.5 ml/mouse daily intragastrically by gavage for four days, the last day of the introduction was carried out for 1 h before injection of 0.75% R-RA acetic acid (n=10);
3. Animals were injected DKTAiW dose of 50 mg/kg in a volume of solvent of 0.5 ml/mouse daily intragastrically by gavage for four days, the last day of the introduction was carried out for 1 h before injection of 0.75% R-RA acetic acid (n=10);
4. Animals were injected DKTAiW at a dose of 100 mg/kg in a volume of 0.5 ml solvent/mouse daily nutrigold�but through the probe within four days on the last day of the introduction was carried out for 1 h before injection of 0.75% R-RA acetic acid (n=10).
Statistical processing of obtained results was performed using standard methods of variation statistics. Intergroup differences were assessed using nonparametric Mann-Whitney test (U-test). Differences were determined at 0.05% confidence level .
The amount of acetic "writhing" 27,40±3,13 and latent time of occurrence was 276±15 seconds show the development of a full-fledged pain response in untreated animals (table. 1). Preventive administration to mice of diclofenac had led to reduced levels of pain response by 33.6%, as the number of "writhing" in this group was statistically significantly decreased in 1,5 times in comparison with the corresponding figure in the control group. The development of pain response was not different from that of the values in untreated animals. The results of the reference control correspond to the data of literature.
The use DKTAiW dose of 50 mg/kg reduced the severity of the pain response by 39.1% (P<0.01), showed a statistically significant decrease in latency time to the onset of the pain response relative to similar result, untreated group (table. 1).
In the case of the introduction DKTAiW at a dose of 100 mg/kg the value of the inhibition of pain response increased�subscribe to 57.7%. It should be noted a statistically significant decrease in the number of acetic "writhing" in 2.4 and 1.6 times respectively compared to the same indicators in animals treated with the solvent and diclofenac (table. 1). The test substance DKTAiW (100 mg/kg) had a preferential activity compared to the reference drug diclofenac sodium (57,7% versus 33.6 percent).
Identified analgesic activity of new substances 4,10-bis((±)-5-benzoyl-2,3-dihydro-1H-imidazo[1,2-a]pyrrole-1-carbonyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5,5,0,03,11That 05,9]dodecane (DKTAiW), comparable with the efficacy of diclofenac sodium at a dose of 50 mg/kg and higher dose of 100 mg/kg on models of chemical pain of peritoneal irritation in mice.
It is shown that preventive course intragastric gavage application of 4,10-bis((±)-5-benzoyl-2,3-dihydro-1H-imidazo[1,2-a]pyrrole-1-carbonyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5,5,0,03,11That 05,9]dodecane (DKTAiW) at a dose of 100 mg/kg reduced the severity of the pain response by more than 50%, which makes it a promising material for creation on its basis substance and further study as analgesic agents .
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1. 4,10-bis((±)-5-benzoyl-2,3-dihydro-1H-imidazo[1,2-a]pyrrole-1-carbonyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5,5,0,03,11That 05,9]dodecane with analgesic activity.
2. A method of producing 4,10-bis((±)-5-benzoyl-2,3-dihydro-1H-imidazo[1,2-a]pyrrole-1-carbonyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5,5,0,03,11That 05,9]dodecane according to claim 1, which consists in the acylation 2,6,8,12-tetraacetyl-2,4,6,8,10,12-exauste�reciclo[5,5,0,0 3,11That 05,9]dodecane the acid chloride of 5-benzoyl-2,3-dihydro-1H-imidazo[1,2-a]pyrrole-1-carboxylic acid.
SUBSTANCE: invention relates to nickel complex of 5,10,15,20-tetrakis [3',5'-di(2"-methylbutyloxy)phenyl]-porphin of formula
EFFECT: invention makes it possible to obtain nickel complex, demonstrating property of stationary phase for gas chromatography.
SUBSTANCE: invention relates to method of obtaining 2,6-dialkyl-hexahydro-1H,5H-2,3a,4a,6,7a,8a-hexaazacyclopenta [def]fluorene -4,8-dions of general formula (1): where Alkyl=t-Bu; i-Pr, cyclo-C6H11, consisting in interaction of N,N-bis(methoxymethyl)alkylamines of general formula Alkyl-N(CH2OMe)2 (where Alkyl =said above) with glycoluryl in presence of catalyst samarium chloride crystallohydrate SmCl3·6H2O with molar ratio Alkyl-N(CH2OMe)2:glycoluryl:SmCl3·6H2O=20:10:(0,3-0,7) at temperature 60°C and atmospheric pressure in mixture of solvents CHCl3 - EtOH (1:2, volume) for 4-8 h.
EFFECT: obtaining compound with high selectivity.
1 tbl, 1 ex
SUBSTANCE: invention relates to amino amides in the bacteriochlorophyll a series, having the general formula: where n=2, 4, 8, 10, having photo-induced anti-tumour activity, and to a method for production thereof by reacting methyl ether of bacteriopheophorbide a with a diaminoalkane of formula NH2(CH2)nNH2, where n=2, 4, 8, 10, in pyridine.
EFFECT: obtaining highly efficient photosensitisers, amino amides in the bacteriochlorophyll a series based on bacteriochlorin e, having high photo-induced anti-tumour activity.
2 cl, 4 dwg, 11 ex
SUBSTANCE: invention relates to chemistry and chemical technology, namely to synthesis of modified silicagels, containing molecules of substituted phthalocyanines covalently bound with them, and their application for water photoremediation. Method of water photoremediation with application of radiation of visible range in presence of oxygen and heterogenic sensibiliser of general formula: , where R=H is either SPh; X is anion; n=4-8; M=Zn, AlL, GaL, SiLz; L=Cl, OH; M=1-4.
EFFECT: invention makes it possible to carry out efficient purification of water from bacteriological contamination.
2 cl, 3 tbl, 11 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to medicine, namely to a photosensitiser for photodynamic therapy. What is declared is methyl ester 13,17-bis(N-methyl-N,N-diethylammonioethylamide) chlorine e6 ditosylate as a photosensitiser having formula: .
EFFECT: compound is stable, possesses high photobactericidal activity in vitro and high photodynamic effectiveness.
4 dwg, 2 tbl, 9 ex
SUBSTANCE: claimed is method of obtaining photosensibiliser, which consists in the following: 3-pyridylcarboxaldehide is condensed with pyrrole in mixture propionic acid-propionic anhydride with their ratio 3-4:1-2 in boiling for 80-100 min. product of condensation is reduced with p-toluenesulfonylhydrazide in pyridine medium in presence of potassium carbonate with its 30-35-fold excess and 5-10% quinoline at temperature 85-95°C for 4-5 hours. After that, obtained product is N-methylated in dimethylformamide in boiling for 50-65 min, precipitated with benzene, filtered and dried. Also claimed is photosensibiliser, obtained in accordance with claimed method, which contains 5,10,15,20-tetrakis(N-methyl-3'-pyridyl)chlorine in quantity 15-25% and 5,10,15,20-tetrakis(N-methyl-3'-pyrydyl)bacteriochlorine in quantity 75-85%.
EFFECT: increase of target product output, reduction of tumour growth rate and dissemination, prevention of tumout tissue necrotisation, complete and uniform saturation of tumour tissue with medication.
3 cl, 1 dwg, 1 tbl, 2 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to methods for producing bacteriochlorines presented by formulas (I), (III), wherein the radical values X1-X8, R1-R8, Y, R' are specified in cl. 1, 2 of the patient claim, for a photodynamic therapy (PDT) of hyperproliferative tissues, such as tumours, hyperproliferative blood vessels and other PDT-responding diseases or anomalies.
EFFECT: higher effectiveness of the method.
2 cl, 22 dwg, 21 ex
SUBSTANCE: invention relates to novel substituted metal phthalocyanines, particularly to cobalt or copper tetra-(4-tert-butyl-5-nitro)phthalocyanine (I) which exhibits a polymer material dye property.
EFFECT: metal complexes of tetra-(4-tert-butyl-5-nitro)phthalocyanine (I) widen the colour gamma of metal complexes of tetra-4-tert-butylphthalocyanines with a similar structure to light-blue and blue when dyeing polymer materials.
6 dwg, 3 ex
SUBSTANCE: invention relates to organic chemistry, particularly to chemistry of natural compounds and production of methyl pheophorbide (a), which is meant for synthesis of porphyrins and chlorins for photodynamic therapy purposes. The disclosed method of producing methyl pheophorbide (a) is realised as follows: extracting chlorophyll (a) from Spirulina Platensis microalgae and demetallisation thereof by treating with concentrated acetic acid while exposing the reaction mass to ultrasound at frequency 25-30 kHz for 2.0-2.5 hours at temperature of 45-50°C. The formed pheophytin (a) is then extracted by precipitation with water, after which it is methylated in a medium of tetrahydrofuran in the presence of sulphuric acid at 50-55°C for 1.0-1.5 hours; the end product is extracted by precipitation with water and purified by twofold precipitation from methylene chloride into ethanol.
EFFECT: invention significantly reduces physiological and environmental hazard of the process due to the 55-60-fold reduction of the amount of toxic methanol used, 4-5-fold reduction of the duration of the process and twofold increase in output of the product.
1 tbl, 1 ex
SUBSTANCE: described is a novel method of producing non-metal tetraazachlorins of general formula or or R2=R3=R4=R5=H, Br, CI; R3=R4=R5=H, R2=NO2, PhSO2, PhS; R2=R4=R5=H, R3=NO2, PhSO2, t-Bu; R2=R5=H, R3=R4=PhS; by mixed condensation of tetramethylsuccinonitrile (TMSN) with corresponding 1,2-dinitriles of unsaturated aliphatic or aromatic acids in the presence of indium chloride, with molar ratio TMSN:dinitrile:indium chloride of 1-5:1:1 and catalytic amounts of ammonium molybdate in quinoline at 230-238°C, followed by demetallisation of the intermediate indium complexes with hydrochloric acid.
EFFECT: method considerably increases output of end products.
1 cl, 12 ex, 1 tbl
SUBSTANCE: invention relates to organic chemistry and specifically to novel heterocyclic compounds of general formula (I) or enantiomers, diastereomers or pharmaceutically acceptable salts thereof, where Y is: phenyl or a heteroaryl selected from thiazolyl, pyridyl, pyrimidinyl, 1,3,5-triazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl and 1,3,4-thiadiazolyl; wherein the phenyl or heteroaryl is optionally substituted with one substitute selected from fluorine, chlorine, bromine, iodine, C1-4alkyl, trifluoromethyl, C1-4alkoxy, C1-4alkylthio, nitro and cyano; r=1-2; R2 is absent or is an oxo-group; Z is: (a) phenyl substituted with NRaRb; where Ra is: H or C1-4alkyl; where Rb is: C1-4alkyl, cycloalkyl, phenyl, furanylmethyl, or phenyl(C1-2alkyl); and wherein the phenyl or the furanyl are optionally substituted with iodine; alternatively, Ra and Rb are taken together with the nitrogen atom to which they are bonded to form a 5-8 member heterocyclyl, which is optionally condensed to a benzene ring; (b) biphenyl-3-yl or biphenyl-4-yl; where the interior phenyl ring, attached to the carbonyl in formula (I) is optionally substituted with a fluorine atom; and where the terminal phenyl ring is optionally substituted with a substitute selected from trifluoromethyl, C1-4alkoxy, chlorine, dichloro, fluorine, and iodine; (c) phenyl substituted with a substitute selected from C5-8cycloalkyl, -NHC(=O)cyclohexyl, phenyloxy, phenylcarbonyl, phenyl(C1-3)alkyl, phenyl(C1-3)alkoxy, pyrrolyl, pyrazolyl, imidazolyl, isoindol-2-yl-l,3-dione, 2,3-dihydro-isoindol-2-yl; l-(tert- butoxycarbonyl)piperidin-4-yloxy, and 1-(tert-butoxycarbonyl)piperidin-4-yl; (d) phenyl substituted with 1-2 substitutes independently selected from: C1-6alkyl, C1-4alkoxy, iodine, chlorine and nitro; (e) phenyl(C1-2)alkyl; where the phenyl is optionally substituted with 1 or 2 substitutes independently selected from iodine, fluorine, C1-6alkyl, phenyl and NRcRd; where Rc: H or C1-4alkyl; where Rd is: C1-4alkyl or C1-6cycloalkyl(C1-4)alkyl; and where the C1-2alkyl of phenyl(C1-2)alkyl is optionally substituted with phenyl; (f) phenyl(C2-4)alkenyl; where the phenyl is optionally substituted with a substitute selected from C1-4alkyl, C1-4alkoxy, trifluoromethyl, trifluoromethylthio and phenyl; (g) naphthyl; where the naphthyl is optionally substituted with one C1-4alkoxy substitute; (h) fluorenyl or xanthenyl; where the fluorenyl or xanthenyl is optionally substituted with an oxo group; (i) C5-8cycloalkyl; where the C5-8cycloalkyl is optionally substituted with one C1-6alkyl substitute; (j) benzene ring-condensed C5-8cycloalkyl or benzene ring-condensed C5-8cycloalkyl(C1-4)alkyl; where said C5-8cycloalkyl fragment is optionally substituted with 1-4 methyl groups; (k) bicyclo[2.2.2]octyl-1-yl; where the bicyclo[2.2.2]octyl-l-yl is optionally substituted with C1-6alkyl; (1) a heteroaryl or benzene ring-condensed heteroaryl selected from benzooxazolyl, quinolinyl, benzimidazolyl, pyridinyl, indolyl, thienyl, furanyl, pyrazolyl, oxazolyl, benzothienyl and benzofuranyl; where the heteroaryl or benzene ring-condensed heteroaryl is optionally substituted with 1 or 2 substitutes independently selected from C1-4alkyl, trifluoromethyl, C5-8cycloalkyl, phenyl, phenyl(C1-2)alkoxy, phenyl(C2-4)alkynyl and dichlorophenoxy; and where the phenyl substitute in the heteroaryl is further optionally substituted with C1-4alkyl, C1-4alkoxy or trifluoromethyl; (m) l,5-diphenyl-lH-pyrazol-3-yl; where the pyrazol-3-yl is optionally substituted with a methyl group; and where each of the phenyl groups of the 1,5-diphenyl substitutes is also optionally substituted with substitutes selected from chlorine, dichloro or aminosulphonyl; (n) 1,2,3,4-tetrahydroquinolin-6-yl; where the 1,2,3,4-tetrahydroquinolin-6-yl is optionally substituted with phenyl or trifluoromethyl-substituted phenyl; and (o) benzene ring-condensed heterocyclyl(C2-4)alkenyl; where the benzene ring-condensed heterocyclyl is attached to the C2-4alkenyl via the benzene ring; and where benzene ring-condensed heterocyclyl is further optionally substituted with C5-6cycloalkyl; taking into account constraining conditions indicated in claim 1. The invention also relates to a pharmaceutical composition based on the compound of formula (I), a method of producing said pharmaceutical composition, a method of treating said pathological conditions and use of the compound of formula (I).
EFFECT: obtaining novel heterocyclic compounds having MGL inhibiting activity.
21 cl, 5 tbl, 11 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to pharmaceutical industry and represents a pharmaceutical composition for control of pain accompanying individual's joint diseases containing hyaluronic acid, which is cross-linked by cycling a double bond in a group of cinnamic acid in partially amidated hyaluronic acid presented by formula (1) to form a cyclobutane cycle, wherein in the above formula, Ar represents a phenyl group, n is equal to an integer 2 or 3; HA represents a carboxy residue of hyaluronic acid, and m represents a relation of amidation of hyaluronic acid to all the carboxyl groups and is equal to 3-50% in relation to all the carboxyl groups, and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition represents a product for injection, wherein the pharmaceutical composition represents the product for injection, wherein the amount of the cross-linked hyaluronic acid makes 1 wt % at the total amount of the product for injection, wherein a single dose of the product for injection makes 2-3 ml, wherein the pharmaceutical composition represents a single-use preparation, which is administered every 13 weeks and more.
EFFECT: invention provides the extremely long analgesic action after the single administration, earlier onset of the analgesic action.
15 cl, 1 dwg, 5 tbl, 1 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to pharmaceutical industry, namely to a method for preparing a medicinal product possessing choleretic activity. The medicinal product possessing choleretic activity and prepared by extracting an elevated part of Lomatogonium carinthiacum in 96% ethanol twice at room temperature, them in 40% ethanol with an extractant added in an amount equal to a discharged one, twice; the filtered aqueous-alcoholic extracts are combined; the extraction cake is extracted in purified water; the aqueous extract is filtered; the aqueous residues of the aqueous-alcoholic extracts are combined with the aqueous extract, concentrated, dried in a vacuum drying cabinet to produce the dry extract in the certain environment.
EFFECT: medicinal product prepared as described above possesses the evident choleretic activity.
11 tbl, 3 ex
SUBSTANCE: using a polyphenolic complex produced by extracting milled ash berry in 40% ethanol, condensing the alcohol-water extract, adding 95% ethanol, centrifuging the residue, filtering and condensing the supernatant in the certain environment, as an agent possessing anti-inflammatory action.
EFFECT: polyphenolic complex possesses pronounced anti-inflammatory action.
1 dwg, 9 tbl, 7 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to pharmaceutical composition, containing compound of formula or for prevention or treatment of diseases, associated with oxidative stress, selected from group, consisting of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke episodes), MERRF syndrome (myoclonic epilepsy with ragged red fibres) or Kearns-Sayre syndrome, arrhythmia, cardioplegia or myocardium infarction. in formula (1) na stands for 1 or 2, Aa represents 5-membered heteroaryl or heterocycle, each of which has 2 heteroatoms, selected from N, O and S, Rla represents R5a-Xa-Ba-X′a-, Ba represents direct bond, Xa and X′a independently on each other represent direct bond or -OC(O)-, R5a represents hydrogen or 6-9-membered monocyclic or condensed cyclic heterocycle or heteroaryl, each of which has from 1 to 3 heteroatoms, selected from N, O and S, and is optionally substituted with oxo or C1-C6-alkyl, R2a represents -(CR8aR9a)pa-Ya-R7a , pa stands for number from 0 or 1, Ya represents direct bond or -O-, R7a represents hydrogen or phenyl, R3a, R8a, R9a, R10a represent hydrogen, R4a represents -(CH2)pa-Da-R10a-, Da represents C5-cycloalkyl or 6-membered heterocycle, which has 1 heteroatom, selected from N, S and O. Radical values for formula (2) are give in invention formula.
EFFECT: obtaining compositions for prevention or treatment of diseases, associated with oxidative stress.
19 dwg, 5 tbl, 3 ex
SUBSTANCE: invention relates to a method of producing 9-aryl-6,8,20-trioxa-13-azapentacyclo-[11.8.0.01,10.02,7.014,19]heneicosa-9,14,16,18-tetraene-11,12,21-triones (IIa-d), which includes reacting 3-aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones (Ia-d) with 3,4-dihydro-2H-pyran in a medium of an inert aprotic solvent, followed by separation of the end products. In general formula (I) Ar=Ph (a, d), C6H4Br-4 (b), C6H4OMe-4 (c), R=H (a-c), Cl (d).
EFFECT: obtaining 9-aryl-6,8,20-trioxa-13-azapentacyclo-[11,8,0,01,10,02,7,014,19]heneicosa-9,14,16,18-tetraene-11,12,21-triones.
2 cl, 1 tbl, 5 ex
SUBSTANCE: invention refers to a new compound, namely to 2-[(2-methylphenyl)imino]-9-oxo-7-phenyl-8-(3-phenyl-2-quinoxalinyl)-1,6-dioxaspiro[4,4]none-3,7-diene-3,4-dicarboxylic acid dimethyl ester of formula possessing antinociceptive activity, and a method for producing it consisting in synthesis of 4-(3-phenylquinoxalin-2-yl)-5-phenylfurane-2,3-dione, acetylene dicarboxylic acid dimethyl ester and o-methylphenylisonitrile.
EFFECT: preparing the new compound.
2 cl, 1 tbl, 4 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to compound, represented by the following formula
or its pharmaceutically acceptable salt. In claimed formula each symbol has values, determined in formula of invention. Versions of formula [I] compound and particular compounds are also objects of invention. In addition, invention relates to pharmaceutical composition, ITK inhibitor and means for treatment or prevention of inflammatory diseases, allergic diseases, autoimmune diseases, transplant rejection and other diseases and methods of treating said diseases.
EFFECT: claimed compounds inhibit induced T-cellular kinase (ITK).
32 cl, 86 tbl, 387 ex
SUBSTANCE: application of a compound of the general formula 1 or its spatial isomers as analgesic means is claimed.
EFFECT: compounds have high efficiency, low toxicity, can be applied in medicine.
4 tbl 8 ex
SUBSTANCE: invention relates to novel compounds of formula
possessing properties of binding with delta opioid receptors. In formula I R1 is selected from the group, consisting of phenyl, pyridinyl and thiazolyl, with R1 being optionally substituted with one or two substituents, independently selected from the group, consisting of C1-4alkoxy, fluorine atom, chlorine atom, bromine atom and cyanogroup; in addition, R1 is optionally substituted with di(C1-4alkyl)aminocarbonyl; Y represents O, S, H3, vinyl, ethinyl or S(O); R2 represents a substituent, selected from the group, consisting of hydrogen, C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluorine atom, chlorine atom, bromine atom and hydroxy; Ra represents hydrogen or methyl; R3 is selected from the group, consisting of pyrrolidin-2-ylmethyl; pyrrolidin-3-ylmethyl; piperidin-2-ylmethyl, piperidin-3-ylmethyl, piperidin-4-ylmethyl, piperidin-2-ylethyl, piperidin-3-ylethyl, piperidin-4-ylethyl, pyridine-4-yl-(C1-2)alkyl, azetidin-3-ylmethyl; morpholin-2-ylmethyl, morpholin-3-ylmethyl, imidazolylmethyl, thiazolylmethyl, (amino)-C3-6cycloalkyl, 3-hydroxy-2-aminopropyl, 8-azabicyclo[3.2.1]octanyl, 1-azabicyclo[2.2.2]octanyl, guanidinylethyl, 4-(imidazol-1-yl)phenylmethyl, 2-(methylamino)ethyl, 2-diethylaminoethyl, 4-diethylaminobut-2-yl, piperidin-3-yl, piperidin-4-yl and pyrrolidin-3-yl; with piperidin-3-yl being optionally substituted on a carbon atom with phenyl; with pyrrolidin-2-yl in pyrrolidin-2-yl-methyl, pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl being optionally substituted on a nitrogen atom with methyl, phenylmethyl, phenethyl or methylcarbonyl.
EFFECT: compounds can be used in the treatment of pain, induced by diseases or conditions, such as osteoarthritis, rheumatoid arthritis, migraine, burn, fibromyalgia, cystitis, rhinitis, neuropathic pain, idiopathic neuralgia, toothache, etc.
24 cl, 3 tbl, 19 ex
SUBSTANCE: praziquantel is administered in a single dose of 20 mc/kg for the first day of treatment in the daytime, and withdrawn; on the following day, the conducted therapy is added with introducing Gelmicide, a biologically active food supplement, in a dose of 2 capsules with meals for 21 days; the course is repeated 10 days later in a dose of 2 capsules 2 times a day with meals for 14 days.
EFFECT: reducing the rate of complications and increasing the high dishelminthisation efficacy.