(57) Abstract:Offers new imidazole derivatives, which are intermediate compounds in the synthesis of valuable biologically active medicinal substances. 1 C.p. f-crystals. The invention relates to the field of synthesis of organic compounds and relates to new derivatives of imidazole, which are intermediate products in the synthesis of imidazole derivatives having valuable biological properties. These biologically active imidazole derivatives are subject to the proposal N 48944882/04 on which the decision of Rospatent from February 27, 1995 on patent of Russia and from which selected for this proposal.The object of this application are the new imidazole derivatives of General formula
< / BR>where R1butyl;
R4a hydrogen atom or alkyl (C1-C6);
R3a hydrogen atom or a group-OR4;
r is 0, 1 or 2.Obtaining new compounds according to the invention described in the example below.These compounds involved in the synthesis of imidazole derivatives of General formula
< / BR>where R5alkyl (C3-C7);
Geterotsiklicheskikh the rest of the group: imidazo-(1.2 a)-pyridyl, imidazo-(1.2 a) pirimidil, benzoxazolyl, benzo-(b)-thiophenyl, and this residue may be substituted by one or two identical or different residues selected from the group of chlorine, tetrazolyl, carboxyl, carboxy-(C1-C4)-alkyl, (C1-C4-alkoxycarbonyl and phenyl, possibly substituted by fluorine;
r is 0, 1 or 2.These target imidazole derivatives turned out to be unexpectedly effective antagonists of angiotensin II receptors, both in vitro and in vivo.Their synthesis is that (in General) a compound of General formula
< / BR>where R5and R7have the above values;
R6chlorine or a group S-R8where R8has the above value, and when the substituent R7carboxyl group, it may be protected,
subjected to interaction with the compound of the formula
where A1the above-mentioned heterocyclic residue, substituted by one or two identical or different residues selected from the range containing chlorine, cyano, carboxyl, carboxy-(C
U tsepliaeva group,
obtaining compounds of General formula
< / BR>where R5, R7and A1have the above meanings;
R6- chlorine or a group S-R8where R8has the above value, and, when R7carboxyl group, it may be protected,
in the case of obtaining compounds of formula II in which R6means a group S(O)rR8where R8has the above meaning, r is 1 or 2, the compound of formula IIa, where R6means the group of S-R8where R8has the above meaning, is subjected to the interaction with the oxidant, or in the case of obtaining compounds of General formula I, in which A Deputy contains tetrazolyl residue, the compound of formula IIa, where A Deputy1contains a cyano, subjected to interaction with collisuem agent with the subsequent removal if necessary carboxyamide group and the allocation of target compounds in free form or in the form of a physiologically tolerable salt.Under physiologically tolerated salts of the compounds of formula II understand their organic and inorganic salts.Amuli I replace the metal atom, the hydrogen atom, coupled with a carbon atom, for example in the presence of a base. Preferred bases are metal hydrides of the formula MN, such as, for example, lithium hydride, sodium or potassium, such as DMF or DMSO as solvents or metal oxides of the formula R, and R means methyl, ethyl, tert-butyl, and the reaction is carried out in the corresponding alcohol, DMF or DMSO. Educated thus salts of azoles are dissolved in an aprotic solvent like DMF or DMSO and mixed with the required amount of alkylation agent.An alternative possibility of deprotonization isoprostane represented, for example, reaction with potassium carbonate in DMF or DMSO.Reactions are conducted at temperatures from below room temperature up to the boiling temperature of the reaction mixture, mainly between +20oC and the boiling temperature of the reaction mixture for about 1-10 hoursCorresponding to the invention the compounds of formula I antagonistically affect the angiotensin-II-receptor can therefore be used for treatment of dependent hypertension angiotensin II. The application may then in heart failure, cardiotoxic, myocardial infarction, hypertrophy of the heart, art is Torno ischemic attacks and apoplexy. The following are examples to obtain compounds of the formula I, which is the subject of this application, and the final compounds of formula II.Example 1 (production of compounds of formula (I).To 35 g (0,246 mol) of 2-ethyl oxime ether 1-cyanoglucosides acid in 350 ml of water and 280 ml of saturated sodium bicarbonate solution added at room temperature portions (15 min) 119 g dithionite sodium. After then heated 1 h 35oC; then saturated with NaCI and extracted 5 times with dichloromethane. After drying with calcium chloride the organic phase is condensed. Get to 11.8 g of ethyl ester of 2-amino-2-cyano-acetic acid in the form of oil
To 3.6 g of the above compound (28,09 mmol) in 50 ml dry CH2CI2and 2.3 ml (28,09 mmol) of pyridine dotted at a temperature of from -5o0oC 3,39 ml (28,09 mmol) valerylchloride in 5 ml of CH2CI2. Then stirred for 1 h at room temperature. The organic phase is then washed 3 times with water, 1 time with saturated NaCI solution, dried with calcium chloride and thickens. Crystallization from diisopropyl ether gives 1.7 g of ethyl ester of 2-cyano-2-N. butyl-Carbonia-aminouksusnoy acid.RfRf(CH2CI2/ethyl acetate 4/1)=0,3
TPL=120oC.To 4,17 g (20.0 mmol) of pentachloride phosphorus in 20 ml of CH2CI2was added dropwise at -78oC of 2.44 g (20 mmol) of 4-dimethylaminopyridine in 12 ml of CH2CI2. After 5 min was added dropwise to 2.42 g (10.0 mmol) of the above compound in 25 ml of CH2CI2. Then raise the temperature to room temperature and diluted with 30 ml of CH2CI2. After 2 h while cooling with ice, add 300 ml of IR. solution of sodium bicarbonate and stirred for 1 h Then the phases are separated, the aqueous phase is extracted 3 times EE, and the combined organic phases are dried with calcium chloride. Chromatography on SiO2with CH2CI2/ethyl acetate (9/1) are obtained in the form of oil, 1.4 g of ethyl ester of 2-N. butyl-4-methylthiazole-5-carboxylic acid.Rf(CH2< 180 mg (0.38 mmol) of the compound of General formula
< / BR>in 2 ml of ethanol is mixed with 0.5 ml of water In. NaOH and stirred for 20 to 60 hours at a temperature of 25oC. Then the solution is concentrated, and the residue purified by chromatography on SiO2with CH2CL2/MeOH (8/2) as a carrier fluid, and acid is formed in the form of amorphous powder.Example 3 ( obtaining the compounds of formula (II).0.2 g (1.07 mmol) of 2-butyl-4-chloro-5-formylindole, 0,38 g (1.07 mmol) of 6-methyl bromide-3-etoxycarbonyl-2-phenylimidazo-[1,2-a] pardina, 0.15 g K2CO3(1.07 mmol) and 0.5 g of powdered molecular sieves was stirred 5 h at a temperature of 60oC in 5 ml of DMF. Next, add 100 ml ethyl acetate and washed 3 times with water. After drying with Na2SO4concentrated, and the residue chromatographic on SiO2with ethyl acetate/n heptane (1/1) as eluent.MS (DXV) 465 (M+H+)
Rf[SiO2; ethyl acetate/n heptane (1:1)]0,18 l 1. Imidazole derivatives of General formula I
< / BR>where R1butyl;
R3group (OR4), where R4hydrogen or C1- C4-alkyl.2. Imidazole derivatives under item 1 of General formula I, where R1butyl, R2methyl, R3group (OR4), where R
< / BR>where R is C1-C4-alkyl, does not necessarily substituted by one or more groups, or R is:
< / BR>a benzyl, robotjam, 2-deoxyribosyl or (CH2)n-OR1where n is 1 or 2, and R1is CH2CH2OH or< / BR>or their salts
(l) where R is a C1-C4-alkyl, optionally substituted by one or more hydroxyl groups, or R is
a benzyl, ribosom, 2-deoxyribosyl or (CH2)n-OR SIG1where n is 1 or 2, and R1is CH2CH2HE or CHor their salts
< / BR>where R1- alkyl, or alkenyl; R2and R3is hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, aryl, or aryl, fused with cycloalkyl; R4is hydrogen, alkyl, alkanoyl, alkenyl, arylcarbamoyl, alkoxycarbonyl, tetrahydropyranyl, tetrahydropyranyl, tetrahydrofuryl, tetrahydrofuryl, a group of the formula-SiRaRbRc, Ra,Rband Rcare alkyl or aryl, alkoxymethyl, alkoxyalkane the stands, halogenoacetyl, aralkyl, aryl or alkanolammonium; R5- carboxyl group, or a group of the formula-CONR8R9in which R8and R9are hydrogen atoms or alkyl, or R8and R9together form alkylene; R6is hydrogen, alkyl, alkoxy or halogen; R7- carboxyl group, or tetrazol-5-ilen group; or their pharmaceutically acceptable salts and esters
FIELD: medicine, oncology.
SUBSTANCE: the present innovation deals with treating patients with uterine cervix cancer with relapses in parametral fiber and in case of no possibility for radical operative interference and effect of previous radiation therapy. During the 1st d of therapy one should intravenously inject 30 mg platidiam incubated for 1 h at 37 C with 150 ml autoblood, during the next 3 d comes external irradiation per 2.6 G-r. During the 5th d of therapy one should introduce the following composition into presacral space: 60 ml 0.5%-novocaine solution, 1 ml hydrocortisone suspension, 2 ml 50%-analgin solution, 1 ml 0.01%-vitamin B12 solution, 1.6 g gentamycine, 800 mg cyclophosphan, 10 mg metothrexate. These curative impacts should be repeated at mentioned sequence four times. The method enables to decrease radiation loading and toxic manifestations of anti-tumor therapy at achieving increased percent of tumor regression.
EFFECT: higher efficiency of therapy.
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):
wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.
EFFECT: valuable medicinal properties of compounds.
16 cl, 9 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to new 1-(p-thienylbenzyl)-imidazoles of the formula (I): , wherein indicated residues represent the following values: R(1) means halogen atom, (C1-C4)-alkoxyl, (C1-C8)-alkoxyl wherein one carbon atom can be replaced with heteroatom oxygen atom (O); R(2) means CHO; R(3) means aryl; R(4) means hydrogen halogen atom; X means oxygen atom; Y means oxygen atom or -NH-; R(5) means (C1-C6)-alkyl; R(6) means (C1-C5)-alkyl in their any stereoisomeric forms and their mixtures taken in any ratios, and their physiologically acceptable salts. Compounds are strong agonists of angiotensin-(1-7) receptors and therefore they can be used as a drug for treatment and prophylaxis of arterial hypertension, heart hypertrophy, cardiac insufficiency, coronary diseases such as stenocardia, heart infarction, vascular restenosis after angioplasty, cardiomyopathy, endothelial dysfunction or endothelial injures, for example, as result of atherosclerosis processes, or in diabetes mellitus, and arterial and venous thrombosis also. Invention describes a pharmaceutical composition based on above said compounds and a method for their applying also.
EFFECT: valuable medicinal properties of compounds and composition.
10 cl, 19 ex
FIELD: organic chemistry and pharmaceutical compositions.
SUBSTANCE: invention relates to new 3-(5)-heteroaryl-substituted pyrazoles of formula I , tautomers or pharmaceutically acceptable salt of compounds and tautomers. In formula R1 is hydride, piperidinyl substituted with methyl, lower alkyl optionally substituted with halogen, hydroxyl, lower alkylanimo or morpholino; R2 is hydride, lower alkyl, amino, aminocarbonylamino, lower alkylaminocarbonylamino, lower alkylsulfonylamino, aminosulfonylamino, lower alkylaminosulfonylamino; Ar1 is phenyl optionally substituted with one or more independently selected halogen; HetAr2 is pyridinyl with the proviso that R2 is not amino or n-propyl when HetAr2 is pyridinyl; and HetAr2 is not 2-pyriridinyl when R2 is hydrogen or lower alkyl. Compounds of formula I have kinase p38 inhibitor activity and are useful in pharmaceutical compositions for treatment of various diseases.
EFFECT: new effective kinase p38 inhibitors.
23 cl, 6 dwg, 1 tbl, 1 ex
FIELD: veterinary science.
SUBSTANCE: a dog should be introduced with 4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole-1-il]benzene sulfonamide or its pharmaceutically acceptable salt at daily dosage ranged about 0.1-10 mg/kg body weight.
EFFECT: higher efficiency of therapy.
4 cl,262 ex, 12 tbl
FIELD: medicine, gynecology, anesthesiology.
SUBSTANCE: invention concerns to a method for carrying out the anesthesiology assistance for woman in childbirth with accompanying bronchial asthma. Method involves administration of atropine, dimedrol, analgin and clophelin. Method involves additional intravenous administration of transamine for 5-7 min. Transamine is administrated in doses 12-14 and 15-17 mg/kg in woman in childbirth with body mass 75 kg and above and 74 kg and less, respectively. Method provides enhancing quality and safety of anesthesia in this class of woman in childbirth.
EFFECT: improved assistance method.
7 tbl, 4 ex
FIELD: medicine, dermatology, chemical-pharmaceutical industry, pharmacy.
SUBSTANCE: invention relates to an antifungal gel pharmaceutical composition based on ketoconazole and clotrimazole that are derivatives of imidazole. The composition comprises ketoconazole or clotrimazole as an active component, polyethylene glycol-400 (PEG-400) as a solvent, carboxyvinyl polymer as a gel-forming agent, polyethylene glycol as a gel stabilizing agent, organic amine or inorganic bas as a regulator of pH and water taken in the definite ratio of components. The composition is prepared by dissolving active component in PEG-400, dispersing carboxyvinyl polymer in water, successive addition to dispersion propylene glycol as a stabilizing agent and regulator of pH and combination of prepared solution and gel followed by stirring the mixture up to preparing the gel composition with pH 5-7. Invention provides preparing antifungal composition with reduced adverse effect.
EFFECT: improved preparing method, valuable medicinal properties of composition.
2 cl, 1 tbl, 11 ex
FIELD: veterinary science.
SUBSTANCE: the present innovation deals with applying selector as a selenium-containing organic preparation to be introduced for cows and calves monthly intramuscularly at the dosage of 10 mcg/kg body weight. The method provides decreased fodder expenses for the synthesis of the production obtained.
EFFECT: higher productivity in cattle.
2 ex, 7 tbl